DORYX (doxycycline hyclate) Delayed-Release Tablets, for oral administration, contain specially coated pellets of doxycycline hyclate, a broad-spectrum antibiotic synthetically derived from oxytetracycline, in a delayed-release formulation for oral administration.

The structural formula for doxycycline hyclate is:

with a molecular formula of C₂₂H₂₄N₂O₈, HCl, ½ C₂H₆O, ½ H 2O and a molecular weight of 512.9. The chemical designation for doxycycline hyclate is [4S(4aR,5S,5aR,6R,12aS)] -4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6­methyl-1,11-deoxonapthtacene-2-carboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. Doxycycline hyclate is a yellow crystalline powder soluble in water and in solutions of alkali hydroxides and carbonates. 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 in the tablet formulation are: lactose monohydrate; microcrystalline cellulose; sodium lauryl sulfate; sodium chloride; talc; anhydrous lactose; corn starch; crospovidone; magnesium stearate; cellulosic polymer coating.

Last updated on RxList: 7/22/2008

To reduce the development of drug-resistant bacteria and maintain the effectiveness of DORYX and other antibacterial drugs, DORYX 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 a tetracycline-class antimicrobial indicated in the following conditions or diseases:

Rickettsial infections

Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae.

Sexually transmitted infections

Uncomplicated urethral, endocervical or rectal infections in adults caused by Chlamydia trachomatis.
Nongonococcal urethritis caused by Ureaplasma urealyticum.
Lymphogranuloma venereum caused by Chlamydia trachomatis.
Granuloma inguinale caused by Calymmatobacterium granulomatis.

Respiratory tract infections

Respiratory tract infections caused by Mycoplasma pneumoniae.
Psittacosis (ornithosis) caused by Chlamydia psittaci.

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 microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug:

Respiratory tract infections caused by Haemophilus influenzae.
Respiratory tract infections caused by Klebsiella species.
Upper respiratory infections caused by Streptococcus pneumoniae.

Specific bacterial infections

Relapsing fever due to Borrelia recurrentis.
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.

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 bacteriological testing indicates appropriate susceptibility to the drug:

Escherichia coli
Enterobacter aerogenes
Shigella species
Acinetobacter species
Urinary tract infections caused by Klebsiella species.

Ophthalmic infections

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

Inclusion conjunctivitis caused by Chlamydia trachomatis.

Anthrax including inhalational anthrax (post-exposure)

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

Alternative treatment for selected infections when penicillin is contraindicated

When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of the following infections:

Syphilis caused by Treponema pallidum.
Yaws caused by Treponema pertenue.
Vincent's infection caused byFusobacterium fusiforme.
Actinomycosis caused by Actinomyces israelii.
Infections caused by Clostridium species.

Adjunctive therapy for acute intestinal amebiasis and severe acne

In acute intestinal amebiasis, doxycycline may be a useful adjunct to amebicides. In severe acne, doxycycline may be useful adjunctive therapy.

Prophylaxis of malaria

Doxycycline is indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers ( < 4 months) to areas with chloroquine and/or pyrimethamine­sulfadoxine resistant strains. [See DOSAGE AND ADMINISTRATION and PATIENT COUNSELING INFORMATION.]

Usual 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) 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 children above eight years of age: The recommended dosage schedule for children weighing 45 kg (100 lb) or less is 4.4 mg/kg (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 4.4 mg/kg (2 mg/lb) of body weight may be used. For children over 45 kg (100 lb), the usual adult dose should be used.

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 or milk [see CLINICAL PHARMACOLOGY].

When used in streptococcal infections, therapy should be continued for 10 days.

Uncomplicated urethral, endocervical, or rectal infection in adults caused by Chlamydia trachomatis: 100 mg by mouth twice a day for 7 days.

Nongonococcal urethritis (NGU) caused by C. trachomatis and U. urealyticum: 100 mg by mouth twice a day for 7 days.

Syphilis - early: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice a day for 2 weeks.

Syphilis of more than one year's duration: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice a day for 4 weeks.

Acute epididymo-orchitis caused by C. trachomatis: 100 mg, by mouth, twice a day for at least 10 days.

For prophylaxis of malaria

For adults, the recommended dose is 100 mg daily. For children over 8 years of age, the recommended dose is 2 mg/kg given once daily up to the adult dose. Prophylaxis should begin 1-2 days before travel to the malarious area. Prophylaxis should be continued daily during travel in the malarious area and for 4 weeks after the traveler leaves the malarious area.

Inhalational anthrax (post-exposure)

ADULTS: 100 mg, of doxycycline, by mouth, twice a day for 60 days.

CHILDREN: weighing less than 45 kg (100 lb) 2.2 mg/kg (1 mg/lb) of body weight, by mouth, twice a day for 60 days. Children weighing 45 kg (100 lb) or more should receive the adult dose.

Sprinkling the tablet over applesauce

DORYX Tablets may also be administered by carefully breaking up the tablet and sprinkling the tablet contents (delayed-release pellets) on a spoonful of applesauce. The delayed-release pellets must not be crushed or damaged when breaking up the tablet. Any loss of pellets in the transfer would prevent using the dose. The applesauce/DORYX mixture should be swallowed immediately without chewing and may be followed by a glass of water if desired. The applesauce should not be hot, and it should be soft enough to be swallowed without chewing. In the event that a prepared dose of applesauce/DORYX Tablet cannot be taken immediately, the mixture should be discarded and not stored for later use.

Dosage Forms And Strengths

DORYX® (doxycycline hyclate) Delayed-Release Tablets, 75 mg are white oval tablets containing yellow pellets and debossed with “D75” on one face and plain on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 75 mg of doxycycline.

DORYX® (doxycycline hyclate) Delayed-Release Tablets, 100 mg are white oval tablets containing yellow pellets and debossed with “D100” on one face and plain on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 100 mg of doxycycline.

DORYX® (doxycycline hyclate) Delayed-Release Tablets, 150 mg are white, oval scored tablets containing yellow pellets and debossed with “D1|50” on one face and plain on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 150 mg of doxycycline.

Storage And Handling

DORYX® (doxycycline hyclate) Delayed-Release Tablets, 75 mg: Bottles of 60 tablets N 0430-0111-20

DORYX® (doxycycline hyclate) Delayed-Release Tablets, 100 mg: Bottles of 100 tablets N 0430-0112-24

DORYX® (doxycycline hyclate) Delayed-Release Tablets, 150 mg: Bottles of 60 tablets N 0430-0113-20

Store at 25° d to 15° C Controlled Room Temperature]; dispense in a tight, light-resistant container (USP).

REFERENCES

5. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - 7^th ed. Approved Standard, CLSI document M7-A7, Vol. 26. CLSI, Wayne, PA. January 2006.

6. CLSI. Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests - 9^th ed. Approved Standard, CLSI document M2-A9, Vol. 26. CLSI, Wayne, PA. January 2006.

7. CLSI. Performance Standards for Antimicrobial Susceptibility Testing - 18th Informational Supplement. Approved Standard, CLSI document M100-S18, Vol. 28. CLSI, Wayne, PA. January 2008.

Manufactured by: Mayne Pharma International Pty Ltd, 1538 Main North Road, Salisbury South, South Australia 5106. Marketed by: Warner Chilcott (US), LLC Rockaway, NJ 07866. 1-800-521-8813 Revised June 2008. FDA revision date: 6/20/2008

Last updated on RxList: 7/22/2008

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 rarely. 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 AND PRECAUTIONS].

Renal

Rise in BUN has been reported and is apparently dose-related [see WARNINGS AND PRECAUTIONS].

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.

Benign Intracranial Hypertension

Bulging fontanels in infants and benign intracranial hypertension in adults [See WARNINGS AND PRECAUTIONS].

Thyroid Gland Changes

When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function are known to occur.

Anticoagulant Drugs

Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.

Penicillin

Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin.

Antacids and Iron Preparations

Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron-containing preparations.

Oral Contraceptives

Concurrent use of tetracycline may render oral contraceptives less effective.

Barbiturates and anti-epileptics

Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.

Penthrane

The concurrent use of tetracycline and Penthrane®(methoxyflurane) has been reported to result in fatal renal toxicity.

Drug/Laboratory Test Interactions

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

Last updated on RxList: 7/22/2008

Included as part of the PRECAUTIONS section.

Tooth Development

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.

Pseudomembranous Colitis

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including DORYX Tablets, 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.

Photosensitivity

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.

Superinfection

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

Benign Intracranial Hypertension

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.

Growth and Development

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 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 embryotoxicity also 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.

Antianabolic Action

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.

Incision and Drainage

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

Malaria

Doxycycline offers substantial but not complete suppression of the asexual blood stages of Plasmodium strains.

Doxycycline does not suppress P. falciparum's sexual blood stage gametocytes. Subjects completing this prophylactic regimen may still transmit the infection to mosquitoes outside endemic areas.

Development of Drug Resistant Bacteria

Prescribing DORYX 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.

Syphilis Testing

In venereal disease when coexistent syphilis is suspected, dark-field examinations should be done before treatment is started and the blood serology repeated monthly for at least 4 months.

Laboratory Monitoring for Long-Term Therapy

In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic studies should be performed.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the 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.

Use In Specific Populations

Pregnancy

Teratogenic Effects. Pregnancy Category D

There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is 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 the 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.¹

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.²

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.³

Nonteratogenic effects

[See WARNINGS AND PRECAUTIONS].

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.⁴ Because of the potential for serious 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 AND PRECAUTIONS.]

Pediatric use

Because of the effects of drugs of the tetracycline class on tooth development and growth, DORYX should not be used in pediatric patients to the age of 8 years, except for inhalational anthrax (post-exposure), unless other drugs are not likely to be effective or are contraindicated. [See WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION.]

Geriatric use

Clinical studies of DORYX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

DORYX 75 mg tablets contain 4.5 mg (0.196 mEq) of sodium.

DORYX 100 mg tablets contain 6 mg (0.261 mEq) of sodium.

DORYX 150 mg tablets contain 9 mg (0.392 mEq) of sodium.

Renal Impairment

Administration of doxycycline at the usual recommended dose does not result in excessive accumulation in patients with renal impairment. Dosage adjustment is not necessary in patients with renal impairment [see CLINICAL PHARMACOLOGY].

REFERENCES

1. Friedman JM, 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.

Last updated on RxList: 7/22/2008

In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.

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

Last updated on RxList: 7/22/2008

Mechanism of Action

Doxycycline is an antimicrobial drug.

Pharmacokinetics

Doxycycline is virtually completely absorbed after oral administration. Following administration of a single 200 mg dose to adult volunteers, average peak serum doxycycline levels were 2.6 mcg/mL at 2 hours, decreasing to 1.45 mcg/mL at 24 hours. The mean Cmax and AUC_0-∞ of doxycycline are 24% and 13% lower, respectively, following single dose administration of DORYX tablets, 100 mg with a high fat meal (including milk) compared to fasted conditions. The mean Cmax of doxycycline is 19% lower and the AUC 0-∞ is unchanged following single dose administration of DORYX Tablets, 150 mg with a high fat meal (including milk) compared to fasted conditions. The clinical significance of these decreases is unknown.

When DORYX Tablets are sprinkled over applesauce and taken with or without water, the extent of doxycycline absorption is unchanged, but the rate of absorption is increased slightly.

Tetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with a creatinine clearance of about 75 mL/min. This percentage may fall as low as 1-5%/72 hours in individuals with a creatinine clearance below 10 mL/min.

Studies have shown no significant difference in the serum half-life of doxycycline (range 18-22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the 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 between tetracyclines is common.

Because isolates of the following gram-negative, gram-positive, anaerobic and other microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility testing when possible is recommended prior to initiating therapy.

Gram-Negative Microorganisms

Acinetobacter species
Brucella species
Calymmatobacterium granulomatis
Enterobacter aerogenes
Escherichia coli
Francisella tularensis
Haemophilus ducreyi
Haemophilus influenzae
Klebsiella species
Neisseria gonorrhoeae
Shigella species
Vibrio Cholerae
Yersinia pestis

Gram-Positive Microorganisms

Alpha-hemolytic streptococci (viridans group)
Bacillus anthracis
Enterococcus faecalis
Enterococcus faecium
Streptococcus pyogenes
Streptococcus pneumoniae

Anerobic Microorganisms

Bacteroides species
Clostridium species
Fusobacterium fusiforme
Propionibacterium acnes

Other Microorganisms

Actinomyces species
Bartonella bacilliformis
Borrelia recurrentis
Chlamydia psittaci
Chlamydia trachomatis
Mycoplasma pneumoniae
Rickettsiae
Treponema pallidum
Treponema pertenue
Ureaplasma urealyticum

Parasites

Balantidium coli
Entamoeba species
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 Test Methods

When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician 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 procedure based on dilution methods (broth, agar, or microdilution),^5,7 or equivalent using standardized inoculum and concentrations of doxycycline. The MIC values should be interpreted according to the criteria provided in Table 1.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The standard procedure^6,7 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg doxycycline to test the susceptibility of microorganisms to doxycycline. Interpretation involves the correlation of the diameter obtained in the disk test with the MIC for doxycycline. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 mcg doxycycline disk should be interpreted according to the criteria in Table 1:

Table 1: Susceptibility Test Interpretive Criteria for Doxycycline

Pathogen	Susceptibility Interpretive Criteria Minimal Inhibitory Concentration (mcg/mL)			Disk Diffusion Zone Diameter (mm) - 30 mcg disk
		I	R	S	I	R
Acinetobacter spp.	≤ 4	8	≥ 16	≤ 9	10-12	≥ 13
Enterobacteriaceae	≤ 4	8	≥ 16	≤ 10	11-13	≥ 14
Enterococcus faecalis and faecium	≤ 4	8	≥ 16	≤ 12	13-15	≥ 16
Vibrio cholerae	≤ 4	8	≥ 16	-	-	-
Yersinia pestis	≤ 4	8	≥ 16	-	-	-
Bacillus anthracisa	≤ 1	-	-	-	-	-
Brucella speciesa	≤ 1	-	-	-	-	-
Franciscella tularensisa	≤ 4	-	-	-	-	-
aThe current absence of resistance isolates precludes defining any results other than “Susceptible”. Isolates yielding results other than susceptible should be subjected to additional testing.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable. A report of “Intermediate” 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 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” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable; 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.^5,6,7 Standard doxycycline powder should provide the MIC values provided in Table 2. For the diffusion technique using the 30 mcg tigecycline disk the criteria provided in Table 2 should be achieved.

Table 2: Acceptable Quality Control Ranges for Doxycycline to be Used for Validation of Susceptibility Test Results

Pathogen	Acceptable Quality Control Ranges Minimal Inhibitory Concentration (mcg/mL)	Disk Diffusion Zone Diameter (mm) - 30 mcg disk
Enterococcus faecalis ATCC 29212	2 - 8	NONE
Escherichia coli ATCC 25922	0.5 - 2	18 - 24
Staphylococcus aureus ATCC 25923 for Enterococcus spp.	Not Applicable	23 - 29
Staphylococcus aureus ATCC 29213 for Enterococcus spp., B. anthracis and F. tularensis	0.12 - 0.5	Not Applicable
Streptococcus pneumoniae ATCC 49619 for Brucella spp.	0.015 - 0.12	Not Applicable

Animal Toxicology and/or Pharmacology

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.

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

Last updated on RxList: 7/22/2008

Patients taking doxycycline for malaria prophylaxis should be advised:

• that no present-day antimalarial agent, including doxycycline, guarantees protection against malaria.
• to avoid being bitten by mosquitoes by using personal protective measures that help avoid contact with mosquitoes, especially from dusk to dawn (e.g., staying in well-screened areas, using mosquito nets, covering the body with clothing, and using an effective insect repellant).
• that doxycycline prophylaxis:
  • should begin 1-2 days before travel to the malarious area,
  • should be continued daily while in the malarious area and after leaving the malarious area,
  • should be continued for 4 further weeks to avoid development of malaria after returning from an endemic area,
  • should not exceed 4 months.

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 AND PRECAUTIONS].
• 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 that 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 taken with antacids containing aluminum, calcium or magnesium, bismuth subsalicylate, and iron containing preparations [See DRUG INTERACTIONS].
• 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 antibiotic. If this occurs, patients should contact their physician as soon as possible.

Patients should be counseled that antibacterial drugs including DORYX should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When DORYX 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 DORYX or other antibacterial drugs in the future.

Last updated on RxList: 7/22/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

DOXYCYCLINE DELAYED-RELEASE TABLET - ORAL

(dox-ee-SYE-kleen)

COMMON BRAND NAME(S): Doryx

USES: This medication is used to treat a wide variety of bacterial infections, including those that cause acne. This medication is known as a tetracycline antibiotic. It works by stopping the growth of bacteria.

This medication is also used to prevent malaria.

This antibiotic treats only bacterial infections. It will not work for viral infections (e.g., common cold, flu). Unnecessary use or overuse of any antibiotic can lead to its decreased effectiveness.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used to treat a certain skin condition (rosacea).

HOW TO USE: Take this medication by mouth as directed. Do not crush or chew the tablets. Doing so can destroy the long action of the drug and may increase the risk of side effects. Doxycycline is best taken on an empty stomach with a full glass of water (8 ounces or 240 milliliters), 1 hour before or 2 hours after meals. Some manufacturers state it can be taken with food or milk if you develop an upset stomach, however doxycycline might be less effective if taken with food or milk (or other products high in calcium). Do not lie down for 30 minutes after taking this medication.

Take this medication 2-3 hours before or after taking any medications containing magnesium, aluminum, calcium, iron, or zinc. Some examples include quinapril, certain forms of didanosine (chewable/dispersible buffered tablets or pediatric oral solution), vitamins/minerals, antacids, sucralfate, and bismuth subsalicylate. These medications react with doxycycline, preventing its full absorption into your bloodstream.

The dosage is based on your medical condition and response to therapy.

Take this medication as prescribed for full course of treatment. It is important you not miss any doses and that you take the drug on a regularly scheduled basis. Remember to take at the same time(s) each day.

Antibiotics work best when the amount of medicine in your body is kept at a constant level. Therefore, take this drug at evenly spaced intervals throughout the day and night.

Continue to take this medication until the full prescribed amount is finished, even if symptoms disappear after a few days. Stopping the medication too early may allow bacteria to continue to grow, which may result in a relapse of the infection.

Inform your doctor if your condition persists or worsens over the next two weeks.

When using to prevent malaria, this medication is usually taken once daily. The first dose of this medication should be taken 1-2 days before travel to an area where you may be exposed to malaria, or take as directed by your doctor. Continue to take this medication daily while in the malarial area. Upon returning home you should keep taking this medication for 4 more weeks. If you are unable to finish this course of doxycycline, contact your doctor.

If this medication is being used to prevent malaria, it is important to understand that it is still possible to get the disease even if you have used this medication. Tell your doctor immediately if you develop a fever. It is best to start treating malaria early.

SIDE EFFECTS: Stomach upset, mild diarrhea, nausea, headache, or vomiting may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: stomach pain, yellowing eyes/skin, vision changes, mental/mood changes.

Doxycycline may make you more sensitive to sunlight (photosensitive) while you are taking it and for 1-2 days after you finish it. Avoid prolonged/direct sun exposure, tanning booths, and sunlamps during this time. Use sunscreen and wear protective clothing if you must be out in the sun. Symptoms of photosensitivity include sunburn that is much quicker/more severe than usual and tingling of the hands/feet/nose.

This medication may rarely cause a severe intestinal condition (pseudomembranous colitis) due to a type of resistant bacteria. This condition may occur during treatment or weeks to months after treatment has stopped. Do not use anti-diarrhea products or narcotic pain medications if you have any of the following symptoms because these products may make them worse. Tell your doctor immediately if you develop: persistent diarrhea, abdominal or stomach pain/cramping, blood/mucus in your stool.

Use of this medication for prolonged or repeated periods may result in oral thrush or a new vaginal yeast infection (oral or vaginal fungal infection). Contact your doctor if you notice white patches in your mouth, a change in vaginal discharge, or other new symptoms.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking doxycycline, tell your doctor or pharmacist if you are allergic to it; or to any other tetracycline; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver problems, kidney problems, trouble swallowing, esophagus problems (e.g., hiatal hernia, GERD).

Before having surgery, tell your doctor or dentist that you are taking this medication.

This drug should not be used by children under 8 because treatment may lead to permanently discolored teeth or other problems. Caution is also advised in older children for similar reasons.

This drug is not recommended for use during pregnancy. Consult your doctor before using this medication.

This drug passes into breast milk and has had undesirable effects on nursing infants. Therefore, using this medication while breast-feeding is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: strontium, acitretin, tretinoin taken by mouth.

If you are currently using either of these medications listed above, tell your doctor or pharmacist before starting doxycycline.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: anti-seizure medications (e.g., carbamazepine, phenytoin), barbiturates (e.g., phenobarbital), digoxin, isotretinoin, other antibiotics, warfarin, live bacterial vaccines.

This medicine may decrease the effectiveness of birth control pills. This can result in pregnancy. You may need to use additional form(s) of reliable birth control while using this medication. Consult your doctor or pharmacist for details.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

It is important to avoid being bitten by mosquitoes when trying to prevent malaria. Avoid contact with mosquitoes, especially from dusk to dawn, by staying in well-screened areas, wearing protective clothing, and using insect repellent and bed nets.

This medication has been prescribed for your current condition only. Do not use it later for another infection unless told to do so by your doctor. A different medication may be necessary in those cases.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature below 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.