[Ranbaxy Pharmaceuticals Inc.]
|Category||DEA Schedule||Marketing Status|
|HUMAN PRESCRIPTION DRUG LABEL||Abbreviated New Drug Application|
To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline capsules and other antibacterial drugs, doxycycline capsules should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
Doxycycline is a broad-spectrum antibiotic synthetically derived from oxytetracycline. Doxycycline 100 mg, 75 mg, and 50 mg capsule contain doxycycline monohydrate, USP equivalent to 100 mg, 75 mg, or 50 mg of doxycycline for oral administration. The chemical designation of the 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-naphthacene-carboxamide monohydrate.
Each capsule for oral administration contains doxycycline monohydrate, USP equivalent to 50 mg, 75 mg or 100 mg of doxycycline. In addition, each capsule contains the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The capsule shell contains D&C Red No. 28, FD&C Blue No. 1, gelatin, and titanium dioxide. The edible printing ink contains black iron oxide, potassium hydroxide, propylene glycol, and shellac.
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.
|Average Observed Values|
|Maximum Concentration||3.61 mcg/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 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.
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 microorganisms. Cross-resistance of these microorganisms to tetracyclines is common.
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 microorganism has been demonstrated to be susceptible.
|Bartonella bacilliformis||Haemophilus ducreyi|
|Calymmatobacterium granulomatis||Neisseria gonorrhoeae|
|Campylobacter fetus||Vibrio cholerae|
|Francisella tularensis||Yersinia pestis|
|Actinomyces israelii||Fusobacterium fusiforme|
|Chlamydia psittaci||Treponema pallidum|
|Chlamydia trachomatis||Treponema pertenue|
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MIC’s). These MIC’s provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC’s should be determined using a standardized procedure. Standardized procedures are based on a dilution method 1,3 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of tetracycline powder. The MIC values should be interpreted according to the following criteria for indicated aerobic microorganisms other than Haemophilus species, Neisseria gonorrhoeae, and Streptococcus pneumoniae:
|≤ 4||Susceptible (S)|
|≥ 16||Resistant (R)|
|When testing Haemophilus spp.a|
|≤ 2||Susceptible (S)|
|≥ 8||Resistant (R)|
|When testing Neisseria gonorrhoeaeb|
|≤ 0.25||Susceptible (S)|
|0.5 to 1||Intermediate (I)|
|≥ 2||Resistant (R)|
|When testing Streptococcus pneumoniaec|
|≤ 2||Susceptible (S)|
|≥ 8||Resistant (R)|
|a. Interpretative criteria applicable only to tests performed by broth microdilution method using Haemophilus Test Medium (HTM).1,3|
|b. Interpretative criteria applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement.1,3|
|c. Interpretative criteria applicable only to tests performed by broth microdilution method using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.1,3|
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood 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 which 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 in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard tetracycline powder should provide the following MIC values:
|Enterococcus faecalis||ATCC 29212||8 to 32|
|Escherichia coli||ATCC 25922||0.5 to 2|
|Haemophilus influenzae a||ATCC 49247||4 to 32|
|Neisseria gonorrhoeae b||ATCC 49226||0.25 to 1|
|Pseudomonas aeruginosa||ATCC 27853||8 to 32|
|Staphylococcus aureus||ATCC 29213||0.12 to 1|
|Streptococcus pneumoniae c||ATCC 49619||0.12 to 0.5|
|a. Range applicable only to tests performed by broth microdilution method using Haemophilus Test Medium (HTM).1,3|
|b. Range applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement.1,3|
|c. Range applicable only to tests performed by broth microdilution method using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.1,3|
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure 2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg tetracycline or 30 mcg doxycycline to test the susceptibility of microorganisms to doxycycline.
Reports from the laboratory providing results of the standard single-disk susceptibility testwith a 30 mcg tetracycline-class disk or the 30 mcg doxycycline disk should be interpreted according to the following criteria for indicated aerobic microorganisms other than Haemophilus species, Neisseria gonorrhoeae, and Streptococcus pneumoniae:
|Zone Diameter (mm)||Interpretation|
|≥ 19||≥ 16||Susceptible (S)|
|15 to 18||13 to 15||Intermediate (I)|
|≤ 14||≤ 12||Resistant (R)|
|Zone Diameter (mm)||Interpretation|
|≥ 29||Susceptible (S)|
|26 to 28||Intermediate (I)|
|≤ 25||Resistant (R)|
|Zone Diameter (mm)||Interpretation|
|≥ 38||Susceptible (S)|
|31 to 37||Intermediate (I)|
|≤ 30||Resistant (R)|
|Zone Diameter (mm)||Interpretation|
|≥ 23||Susceptible (S)|
|19 to 22||Intermediate (I)|
|≤ 18||Resistant (R)|
c. Interpretative criteria applicable only to tests performed by disk diffusion method using a 30 mcg tetracycline-class disk and using Mueller-Hinton agar with 5% defibrinated sheep blood and incubated in 5% CO 2.2,3
Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for tetracycline or doxycycline, respectively.
As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30 mcg tetracycline-class disk or the 30 mcg doxycycline disk should provide the following zone diameters in these laboratory test quality control strains:
|Microorganism||Zone Diameter (mm)|
|Escherichia coli||ATCC 25922||18 to 25||18 to 24|
|Haemophilus influenzae a||ATCC 49247||14 to 22||—|
|Neisseria gonorrhoeae b||ATCC 49226||30 to 42||—|
|Staphylococcus aureus||ATCC 25923||24 to 30||23 to 29|
|Streptococcus pneumoniae c||ATCC 49619||27 to 31||—|
|a. Range applicable only to tests performed by disk diffusion method using a 30 mcg tetracycline-class disk and using Haemophilus Test Medium (HTM).2,3|
|b. Range applicable only to tests performed by disk diffusion method using a 30 mcg tetracycline-class disk and using GC agar base with 1% defined growth supplement.2,3|
|c. Range applicable only to tests performed by disk diffusion method using a 30 mcg tetracycline-class disk and using Mueller-Hinton agar with 5% defibrinated sheep blood and incubated in 5% CO2.2,3|
For anaerobic bacteria, the susceptibility to tetracycline as MIC’s can be determined by standardized test methods. 4 The MIC values obtained should be interpreted according to the following criteria:
|≤ 4||Susceptible (S)|
As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized tetracycline powder should provide the following MIC values:
|Bacteroides fragilis a||ATCC 25285||0.12 to 0.5|
|Bacteroides thetaiotaomicrona||ATCC 29741||8 to 32|
|a. Range applicable only to tests performed by the reference agar dilution method.|
To reduce the development of drug-resistant bacteria and maintain effectiveness of doxycycline capsules and other antibacterial drugs, doxycycline capsules 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.
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, 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 capsules, 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 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.
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.
Prescribing doxycycline capsules in the absence of 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.
–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.)
–that the absorption of tetracyclines is reduced when taken with foods, especially those which contain calcium. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk. (see Drug Interactions.)
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible
Patients should be counseled that antibacterial drugs including doxycycline capsules should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When doxycycline capsules 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 doxycycline capsules or other antibacterial drugs in the future.
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.
There are no adequate and well-controlled studies on the use of doxycycline in pregnant 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 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 riska.
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 casesb.
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 agec.
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 unknownd. Because of the potential for 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.)
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. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Rare instances of esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline class. Most of these patients took medications immediately before going to bed. (See DOSAGE AND ADMINISTRATION.)
Skin: Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme have been reported. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above. (see WARNINGS.)
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.
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 pounds 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.
Inhalational anthrax (post-exposure): ADULTS: 100 mg of doxycycline, by mouth, twice a day for 60 days. CHILDREN: weighing less than 100 pounds (45 kg); 1 mg/lb (2.2 mg/kg) of body weight, by mouth, twice a day for 60 days. Children weighing 100 pounds or more should receive the adult dose.
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%.
Doxycycline capsules, USP 50 mg have light greenish yellow powder filled in size ‘4’ blue opaque cap/blue opaque body, hard gelatin capsules, imprinted with “RX614” on cap and body in black ink. Each capsule contains doxycycline monohydrate, USP equivalent to 50 mg of doxycycline.
Doxycycline capsules, USP 75 mg have light greenish yellow powder filled in size ‘3’ reflex blue opaque cap/blue opaque body, hard gelatin capsules, imprinted with “RX615” on cap and body in black ink. Each capsule contains doxycycline monohydrate, USP equivalent to 75 mg of doxycycline.
Doxycycline capsules, USP 100 mg have light greenish yellow powder filled in size ‘2’ reflex blue opaque cap/reflex blue opaque body, hard gelatin capsules, imprinted with “RX616” on cap and body in black ink. Each capsule contains doxycycline monohydrate, USP equivalent to 100 mg of doxycycline.
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 PO4, 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.
- National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically – Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000.
- National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests – Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January, 2000.
- National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility Testing – Eleventh Informational Supplement. NCCLS Document M100-S11, Vol. 21, No. 1, NCCLS, Wayne, PA, January, 2001.
- National Committee for Clinical Laboratory Standards. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria – Fourth Edition. Approved Standard NCCLS Document M11-A4, Vol. 17, No. 22, NCCLS, Wayne, PA, December 1997.
- Friedman JM and Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press: 2000 149-195.
- Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997;89:524-528.
- Horne HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 1980; 25:315-317.
- Hale T. Medications and Mothers Milk. 9th edition. Amarillo, TX: Pharmasoft Publishing 2000; 225-226.
|Labeler - Ranbaxy Pharmaceuticals Inc. (937890044)|
|Registrant - Ranbaxy Pharmaceuticals Inc. (937890044)|
|Ohm Laboratories Inc.||051565745||manufacture|