doryx (doxycycline hyclate) tablet, delayed release
[Warner Chilcott (US), Inc.]
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 bacteria.
DORYX Tablets 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 H2O 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-6-methyl-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; microcystalline cellulose; sodium lauryl sulfate; sodium chloride; talc; anhydrous lactose; corn starch, crospovidone; magnesium stearate; cellulosic polymer coating.
Tetracyclines are readily absorbed and are bound to plasma proteins in varying degree. They are concentrated by the liver in the bile and excreted in the urine and feces at high concentrations and in a biologically active form.
Doxycycline is virtually completely absorbed after oral administration. Following a 200 mg dose, normal adult volunteers averaged peak serum levels of 2.6 mcg/mL of doxycycline at 2 hours decreasing to 1.45 mcg/mL at 24 hours. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with normal function (creatinine clearance about 75 mL/min). This percentage excretion may fall as low as 1-5%/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.
The mean Cmax and AUC0-∞ of doxycycline are reduced by 24% and 13%, respectively, following single dose administration of DORYX tablets with a high fat meal. The clinical significance of this decrease is unknown.
When Doryx Tablets are sprinkled over applesauce and taken with or without water, extent of doxycycline absorption is equivalent, but absorption rate is increased slightly.
Hemodialysis does not alter serum half-life.
Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues.
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 tetracycline is common.
Yersinia pestis (formerly Pasteurella pestis)
Francisella tularensis (formerly Pasteurella tularensis)
Vibrio cholerae (formerly Vibrio comma)
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:
Acinetobacter species (formerly Mima species and Herellea species)
Because many strains of the following groups of gram-positive microorganisms have been shown to be resistant to tetracycline, culture and susceptibility testing are recommended. Up to 44 percent of strains of Streptococcus pyogenes and 74 percent of Streptococcus faecalis have been found to be resistant to tetracycline drugs. Therefore, tetracycline should not be used for streptococcal disease unless the organism has been demonstrated to be susceptible.
Enterococcus group (Streptococcus faecalis and Streptococcus faecium)
Alpha-hemolytic streptococci (viridans group)
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.
Quantitative methods that require measurement of zone diameters give the most precise estimate of the susceptibility of bacteria to antimicrobial agents. One such standard procedure1 that has been recommended for use with disks to test susceptibility of organisms to doxycycline uses the 30 mcg tetracycline-class disk or the 30 mcg doxycycline disk. Interpretation involves the correlation of the diameter obtained in the disk test with the minimum inhibitory concentration (MIC) for tetracycline or doxycycline, respectively.
Reports from the laboratory giving results of the standard single-disk susceptibility test with a 30 mcg tetracycline-class disk or the 30 mcg doxycycline disk should be interpreted according to the following criteria:
|Zone Diameter (mm)||Interpretation|
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 high dosage is used or if the infection is confined to tissues and fluids in which high antimicrobial levels are attained. A report of “Resistant” indicates that achievable concentrations are unlikely to be inhibitory, and other therapy should be selected.
Standardized procedures require the use of laboratory control organisms. The 30 mcg tetracycline-class disk or the 30 mcg doxycycline disk should give the following zone diameters:
|Organism||Zone Diameter (mm)|
|E. coli ATCC 25922||18-25||18-24|
|S. aureus ATCC 25923||19-28||23-29|
Use a standardized dilution method2 (broth, agar, microdilution) or equivalent with tetracycline powder. The MIC values obtained should be interpreted according to the following criteria:
As with standard diffusion methods, dilution methods require the use of laboratory control organisms. Standard tetracycline powder should provide the following MIC values:
|E. coli ATCC 25922||1.0-4.0|
|S. aureus ATCC 29213||0.25-1.0|
|E. faecalis ATCC 29212||8-32|
|P. aeruginosa ATCC 27853||8-32|
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 indicated for the treatment of the following infections:
Doxycycline also is indicated for the treatment of infections caused by the following gram-negative microorganisms:
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:
Doxycycline is indicated for treatment of infections caused by the following gram-positive microorganisms when bacteriological testing indicates appropriate susceptibility to the drug:
Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.
When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of the following infections:
In acute intestinal amebiasis, doxycycline may be a useful adjunct to amebicides.
In severe acne, doxycycline may be useful adjunctive therapy.
Doxycycline is indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (<4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains. See DOSAGE AND ADMINISTRATION section and Information for Patients subsections of the PRECAUTIONS section.
The 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 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 has been reported with nearly all antibacterial agents, including doxycycline, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis.”
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.
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.
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.
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.
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.
Patients taking doxycycline for malaria prophylaxis should be advised:
All patients taking doxycycline should be advised:
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.
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.
In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic studies should be performed.
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.
Absorption of tetracyclines is impaired by bismuth subsalicylate.
Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.
The concurrent use of tetracycline and Penthrane® (methoxyflurane) has been reported to result in fatal renal toxicity.
Concurrent use of tetracycline may render oral contraceptives less effective.
False elevations of urinary catecholamines may occur due to interference with the fluorescence test.
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.
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 risk3.
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 cases4.
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 age5.
The effect of tetracyclines on labor and delivery is unknown.
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 unknown6. 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.)
See WARNINGS and DOSAGE AND ADMINISTRATION.
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.
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).
Renal toxicity: Rise in BUN has been reported and is apparently dose-related (see WARNINGS).
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.
Other: Bulging fontanels in infants and benign intracranial hypertension in adults (See PRECAUTIONS- General).
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.
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 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 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 children over 100 lb, the usual adult dose should be used.
The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage.
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 or milk (see CLINICAL PHARMACOLOGY).
Studies to date have indicated that administration of doxycycline at the usual recommended doses does not lead to excessive accumulation of the antibiotic in patients with renal impairment.
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. The dose may be administered with food, including milk or carbonated beverage, as required.
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 N. gonorrhoeae: 100 mg, by mouth, twice a day for at least 10 days.
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 100 lb (45 kg); 1 mg/lb (2.2 mg/kg) of body weight, by mouth, twice a day for 60 days. Children weighing 100 lb or more should receive the adult dose.
Sprinkling the Tablet on 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.
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, supplied in:
Bottles of 100 tablets. N 0430-0112-24
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, supplied in:
Bottles of 60 tablets. N 0430-0111-20
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]; dispense in a tight, light-resistant container (USP).
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.
U.S. Patent No: 6,958,161
FH Faulding & Co. Ltd.
1538 Main North Road
Salisbury South, South Australia 5106
Warner Chilcott (US), Inc.
Rockaway, NJ 07866
0112G032 Rev December 2006
|DORYX (doxycycline hyclate)|
|DORYX (doxycycline hyclate)|
Data are from FDA and U.S. National Library of Medicine.