DOXYCYCLINE HYCLATE- doxycycline hyclate tablet, film coated
PD-Rx Pharmaceuticals, Inc.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline hyclate and other antibacterial drugs, doxycycline hyclate should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
Doxycycline hyclate is an antibacterial drug synthetically derived from oxytetracycline, and is available as doxycycline hyclate (doxycycline hydrochloride hemiethanolate hemihydrate) capsules and tablets for oral administration. The chemical designation of this light-yellow crystalline powder is alpha-6-deoxy-5-oxytetracycline. Doxycycline has a high degree of lipoid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form. Doxycycline hyclate has the following structural formula:
Each capsule for oral administration contains doxycycline hyclate equivalent to 50 mg or 100 mg doxycycline (anhydrous). Inactive ingredients for capsules are: anhydrous lactose, croscarmellose sodium, FD&C Blue #1, gelatin, magnesium stearate, microcrystalline cellulose, and titanium dioxide. Each tablet for oral administration contains doxycycline hyclate equivalent to 100 mg doxycycline. Inactive ingredients for tablets are: anhydrous lactose, carnauba wax, croscarmellose sodium, D&C Yellow #10 aluminum lake, FD&C Red #40 aluminum lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, and titanium dioxide.
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.
Hemodialysis does not alter serum half-life.
Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues.
Population pharmacokinetic analysis of sparse concentrationtime data of doxycycline following standard of care intravenous and oral dosing in 44 pediatric patients (2-18 years of age) showed that allometrically -scaled clearance (CL) of doxycycline in pediatric patients ≥2 to ≤8 years of age (median [range]
3.58 [2.27-10.82] L/h/70 kg, N =11) did not differ significantly from pediatric patients >8 to 18 years of age (3 .27 [1.11-8.12] L/h/70 kg, N=33). For pediatric patients weighing ≤45 kg, body weight normalized doxycycline CL in those ≥2 to ≤8 years of age (median [range] 0.071 [0 .041-0.202] L/kg/h, N=10) did not differ significantly from those >8 to 18 years of age (0.081 [0.035-0.126] L/kg/h, N=8). In pediatric patients weighing >45 kg, no clinically significant differences in body weight normalized doxycycline CL were observed between those ≥2 to ≤8 years (0.050 L/kg/h, N=l) and those >8 to 18 years of age (0.044 [0.014-0.121] L/kg/h, N=25). No clinically significant difference in CL between oral and IV dosing was observed in the small cohort of pediatric patients who received the oral (N=19) or IV (N=2l) formulation alone.
Mechanism of Action
Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against a broad range of Gram-positive and Gram-negative bacteria.
Cross resistance with other tetracyclines is common.
Doxycycline has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for doxycycline hyclate.
Nocardiae and other aerobic Actinomyces species
Treponema pallidum subspecies pertenue
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.
For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.
To reduce the development of drug-resistant bacteria and maintain effectiveness of doxycycline hyclate and other antibacterial drugs, doxycycline hyclate 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:
- Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae.
- Respiratory tract infections caused by Mycoplasma pneumoniae.
- Lymphogranuloma venereum caused by Chlamydia trachomatis.
- Psittacosis (ornithosis) caused by Chlamydophila psittaci.
- Trachoma caused by Chlamydia trachomatis , although the infectious agent is not always eliminated, as judged by immunofluorescence.
- Inclusion conjunctivitis caused by Chlamydia trachomatis.
- Uncomplicated urethral, endocervical, or rectal infections in adults caused by Chlamydia trachomatis.
- Nongonococcal urethritis caused by Ureaplasma urealyticum.
- Relapsing fever due to Borrelia recurrentis.
Doxycycline is also indicated for the treatment of infections caused by the following gram-negative microorganisms:
- Chancroid caused by Haemophilus ducreyi.
- Plague due to Yersinia pestis.
- 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.
- Granuloma inguinale caused by Klebsiella granulomatis.
Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended.
Doxycycline is indicated for treatment of infections caused by the following gram-negative bacteria, when bacteriologic testing indicates appropriate susceptibility to the drug:
- Escherichia coli.
- Enterobacter aerogenes.
- Shigella species.
- Acinetobacter species.
- Respiratory tract infections caused by Haemophilus influenzae.
- Respiratory tract and urinary tract infections caused by Klebsiella species.
Doxycycline is indicated for treatment of infections caused by the following gram-positive microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug:
- Upper respiratory infections caused by Streptococcus pneumoniae.
- 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:
- Uncomplicated gonorrhea caused by Neisseria gonorrhoeae.
- Syphilis caused by Treponema pallidum.
- Yaws caused by Treponema pallidum subspecies pertenue.
- Listeriosis due to Listeria monocytogenes.
- Vincent’s infection caused by Fusobacterium fusiforme.
- Actinomycosis caused by Actinomyces israelii.
- Infections caused by Clostridium species.
In acute intestinal amebiasis, doxycycline may be a useful adjunct to amebicides.
In severe acne, doxycycline may be useful adjunctive therapy.
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 subsection of the PRECAUTIONS section.)
This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines.
The use of drugs of the tetracycline class during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drugs, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use doxycycline in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including doxycycline hyclate, 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 the use of antibacterial drugs. 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 use of antibacterial drugs not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.
Severe skin reactions, such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving doxycycline. (See ADVERSE REACTIONS.) If severe skin reactions occur, doxycycline should be discontinued immediately and appropriate therapy should be instituted.
Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including doxycycline hyclate. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin and doxycycline hyclate should be avoided because isotretinoin is also known to cause pseudotumor cerebri.
Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize.
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 6 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 has also been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking this drug, 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 antibacterial drugs, use of doxycycline hyclate may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, doxycycline hyclate should be discontinued and appropriate therapy instituted.
Incision and drainage or other surgical procedures should be performed in conjunction with antibacterial 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 doxycycline hyclate 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.
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