DOXYCYCLINE: Package Insert and Label Information

DOXYCYCLINE- doxycycline capsule
REMEDYREPACK INC.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline and other antibacterial drugs, doxycycline should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Doxycycline is a broad-spectrum antibacterial synthetically derived from oxytetracycline. Doxycycline Capsules USP, 100 mg, 75 mg, and 50 mg capsules contain doxycycline monohydrate equivalent to 100 mg, 75 mg, or 50 mg of doxycycline for oral administration. The chemical designation of the light-yellow crystalline powder is alpha-6-deoxy-5-oxytetracycline.

Structural formula:

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Doxycycline has a high degree of lipid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form.

Inert ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose and sodium starch glycolate Type A Potato. Hard gelatin capsule contains black iron oxide, gelatin, red iron oxide, titanium dioxide and yellow iron oxide. The capsules are printed with edible ink containing black iron oxide, potassium hydroxide, propylene glycol, shellac and titanium dioxide.

CLINICAL PHARMACOLOGY

Tetracyclines are readily absorbed and are bound to plasma proteins in varying degrees. They are concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in a biologically active form. Doxycycline is virtually completely absorbed after oral administration.

Following a 200 mg dose of doxycycline monohydrate, 24 normal adult volunteers averaged the following serum concentration values:

Time ( hr ): 0.5 1.0 1.5 2.0 3.0 4.0 8.0 12.0 24.0 48.0 72.0
Conc . 1.02 2.26 2.67 3.01 3.16 3.03 2.03 1.62 0.95 0.37 0.15 (mcg/mL)
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.

Hemodialysis does not alter serum half-life.

Population pharmacokinetic analysis of sparse concentration-time data of doxycycline following standard of care intravenous and oral dosing in 44 pediatric patients (2 to 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 to 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 to 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 to 0.202] L/kg/h, N=10) did not differ significantly from those >8 to 18 years of age (0.081 [0.035 to 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=1) and those >8 to 18 years of age (0.044 [0.014 to 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=21) formulation alone.

Microbiology

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.

Resistance

Cross resistance with other tetracyclines is common.

Antimicrobial Activity

Doxycycline has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections (see INDICATIONS AND USAGE).

Gram-Negative Bacteria

Acinetobacter species

Bartonella bacilliformis

Brucella species

Enterobacter aerogenes

Escherichia coli

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae

Klebsiella granulomatis

Klebsiella species

Neisseria gonorrhoeae

Shigella species

Vibrio cholerae

Vibrio fetus

Yersinia pestis

Gram-Positive Bacteria

Bacillus anthracis

Listeria monocytogenes

Streptococcus pneumoniae

Anaerobes

Clostridium species

Fusobacterium fusiforme

Propionibacterium acnes

Other Bacteria

Nocardiae and other aerobic Actinomyces species

Borrelia recurrentis

Chlamydophila psittaci

Chlamydia trachomatis

Mycoplasma pneumoniae

Rickettsiae

Treponema pallidum

Treponema pallidum subspecies 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 Testing Methods

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.

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain effectiveness of doxycycline and other antibacterial drugs,

Doxycycline 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 microorganisms, 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.

CONTRAINDICATIONS

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

WARNINGS

The use of drugs of the tetracycline class, including doxycycline, 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 of 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, 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.

Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including doxycycline. 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 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 the fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every six hours. This reaction was shown to be reversible when the drug was discontinued.

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryo toxicity has been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the fetus.

The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function.

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema.

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