Doxycycline Hyclate

DOXYCYCLINE HYCLATE- doxycycline hyclate capsule, gelatin coated
West-Ward Pharmaceutical Corp

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

DESCRIPTION

Doxycycline Hyclate Capsules, USP, are an antibacterial drug synthetically derived from oxytetracycline. The structural formula of doxycycline monohydrate is

structural formula

with a molecular formula of C22 H24 N2 O8 •H2 O and a molecular weight of 462.46. The chemical designation for doxycycline is 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrate. The molecular formula for doxycycline hydrochloride hemiethanolate hemihydrate is (C22 H24 N2 O8 •HCl)2 •C2 H6 O•H2 O and the molecular weight is 1025.89. Doxycycline is a light yellow crystalline powder. Doxycycline hyclate is soluble in water, while doxycycline monohydrate is very slightly soluble in water.

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.

Each capsule for oral administration contains doxycycline hyclate equivalent to 50 mg or 100 mg of doxycycline (anhydrous). Inactive ingredients: lactose monohydrate, microcrystalline cellulose, magnesium stearate.

The 50 mg and 100 mg capsule shells contain: gelatin, diacetylated monoglycerides, sucrose fatty acid esters, glacial acetic acid, sodium lauryl sulfate, colloidal silicon dioxide, FD&C Blue #1 and titanium dioxide. The printing ink may contain: Shellac Glaze, Iron Oxide Black, N-Butyl Alcohol, Propylene Glycol, SDA 3A Alcohol, FD&C Blue #2, FD&C Red #40, FD&C Blue #1, D&C Yellow #10.

CLINICAL PHARMACOLOGY

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% per 72 hours in individuals with normal function (creatinine clearance about 75 mL/min). This percentage excretion may fall as low as 1 to 5% per 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.

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

Microbiology

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 capsules.

Gram-Negative Bacteria

Acinetobacter species
Bartonella bacilliformis
Brucella species
Klebsiella species
Klebsiella granulomatis
Campylobacter fetus
Enterobacter aerogenes
Escherichia coli
Francisella tularensis
Haemophilus ducreyi
Haemophilus influenzae
Neisseria gonorrhoeae
Shigella species
Vibrio cholerae
Yersinia pestis

Gram-Positive Bacteria

Bacillus anthracis
Streptococcus pneumoniae

Anaerobic Bacteria

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 speciesPlasmodium 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

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals 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 test method1,2,4 (broth or agar). The MIC values should be interpreted according to criteria provided in Table 1.

Diffusion techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.1,3,4 This procedure uses paper disks impregnated with 30-μg doxycycline to test the susceptibility of microorganisms to doxycycline. The disk diffusion interpretive criteria are provided in Table 1.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method.5 The MIC values obtained should be interpreted according to the criteria provided in Table 1.

Table 1: Susceptibility Test Interpretive Criteria for Doxycycline and Tetracycline

Bacteria a

Minimal Inhibitory Concentration (mcg/mL)

Z o ne Diameter (mm)

Agar Dilution (mcg/mL)

S I R S I R S I R

Acinetobacter spp. Doxycycline Tetracycline

≤4≤4

88

≥16≥16

≥13≥15

10-1212-14

≤9≤11

Anaerobes Tetracycline

-

-

-

-

-

-

≤4

8

≥16

Bacillus anthracis b Doxycycline Tetracycline

≤1≤1

Brucella speciesb Doxycycline Tetracycline

≤1≤1

Enterobacteriaceae Doxycycline Tetracycline

≤4≤4

88

≥16≥16

≥14≥15

11-1312 -14

≤10≤11

Franciscella tularensis b Doxycycline Tetracycline

≤ 4≤ 4

Haemophilus influenzae Tetracycline

≤2

4

≥8

≥29

26-28

≤25

-

-

-

Mycoplasma pneumoniae b Tetracycline

-

-

-

-

-

-

≤2

-

-

Neisseria gonorrhoeae c Tetracycline - - - ≥38 31-37 ≤30 ≤0.25 0.5-1 ≥2

N o c a r d i a e and other aerobicActinomyces speciesb Doxycycline

≤1

2-4

≥8

-

-

-

-

-

-

Streptococcus pneumoniae Doxycycline Tetracycline

≤0.25≤1

0.5 2

≥1≥4

≥28≥28

25-2725-27

≤24≤24

-

-

-

Vibrio cholerae Doxycycline Tetracycline

≤4≤4

88

≥16≥16

Yersinia pestis Doxycycline Tetracycline

≤4≤4

88

≥16≥16

Ureaplasma urealyticum Tetracycline

-

-

-

-

-

-

≤1

-

≥2

a Organisms susceptible to tetracycline are also considered susceptible to doxycycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to doxycycline.b The current absence of resistant isolates precludes defining any results other than “Susceptible”. If isolates yielding MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.c Gonococci with 30 mcg tetracycline disk zone diameters of <19 mm usually indicate a plasmid­-mediated tetracycline resistant Neisseria gonorrhoeae isolate. Resistance in these strains should be confirmed by a dilution test (MIC ≥ 16 mcg/mL).

A report of Susceptible(S) indicates that the antimicrobial drug is likely to inhibit growth of the microorganism if the antimicrobial drug reaches the concentrations usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the bacteria 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 product 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 Resistan t (R) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.

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