Doxycycline Monohydrate

DOXYCYCLINE MONOHYDRATE- doxycycline capsule
RPK Pharmaceuticals, Inc.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Doxycycline Monohydrate Capsules and other antibacterial drugs, Doxycycline Monohydrate Capsules 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 Monohydrate Capsules 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:

C₂₂ H₂₄ N₂ O₈ • H₂ O         M.W. = 462.45

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; sodium starch glycolate; and a hard gelatin capsule which contains black iron oxide, red iron oxide, titanium dioxide, and yellow iron oxide for the 100 mg and 75 mg strengths, titanium dioxide and yellow iron oxide for the 50 mg strength. The capsules are printed with edible ink containing black iron oxide, red iron oxide, and yellow iron oxide for the 50 mg and 100 mg strengths and black iron oxide, FD&C Blue No. 2, FD&C Red No. 40, FD&C Blue No. 1, and D&C Yellow No. 10 for the 75 mg strength.

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	(μg/mL)

Average Observed Values

Maximum Concentration	3.61 μg/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 1-5%/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.

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. 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 MONOHYDRATE.

Gram-Negative Bacteria
Acinetobacter species
Bartonella bacilliformis
Brucella species
Calymmatobacterium granulomatis
Campylobacter fetus
Enterobacter aerogenes
Escherichia coli
Francisella tularensis
Haemophilus ducreyi
Haemophilus influenzae
Klebsiella species
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 Actinomyces species
Borrelia recurrentis
Chlamydophila psittaci
Chlamydia trachomatis
Mycoplasma pneumoniae
Rickettsiae
Treponema pallidum
Treponema pertenue
Ureaplasma urealyticum

Parasites
Balantidium coli
Entamoeba species

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 method (broth and/or agar).^1,2,4 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 mcg 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

* 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. † The current absence of resistance 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. ‡ Gonococci with 30 mcg tetracycline disk zone diameters of less than 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 per mL).
Bacteria *	Minimal Inhibitory Concentration(mcg per mL)			Zone Diameter (mm)			Agar Dilution (mcg per mL)
	S	I	R	S	I	R	S	I	R
Acinetobacter spp.
Doxycycline	≤ 4	8	≥ 16	≥ 13	10 -12	≤ 9	–	–	–
Tetracycline	≤ 4	8	≥ 16	≥ 15	12 — 14	≤ 11	–	–	–
Anaerobes
Tetracycline	–	–	–	–	–	–	≤ 4	8	≥ 16
Bacillus anthracis †
Doxycycline	≤ 1	–	–	–	–	–	–	–	–
Tetracycline	≤ 1	–	–	–	–	–	–	–	–
Brucella species †
Doxycycline	≤ 1	–	–	–	–	–	–	–	–
Tetracycline	≤ 1	–	–	–	–	–	–	–	–
Enterobacteriaceae
Doxycycline	≤ 4	8	≥ 16	≥ 14	11 -13	≤ 10	–	–	–
Tetracycline	≤ 4	8	≥ 16	≥ 15	12 -14	≤11	–	–	–
Franciscella tularensis †
Doxycycline	≤ 4	–	–	–	–	–	–	–	–
Tetracycline	≤ 4	–	–	–	–	–	–	–	–
Haemophilus influenzae
Tetracycline	≤ 2	4	≥ 8	≥ 29	26 — 28	≤ 25	–	–	–
Mycoplasma pneumoniae †
Tetracycline	–	–	–	–	–	–	≤ 2	–	–
Neisseria gonorrhoeae ‡
Tetracycline	–	–	–	≥ 38	31 — 37	≤ 30	≤ 0.25	0.5 to 1	≥2
Norcardiae and other aerobic Actinomyces species †
Doxycycline	≤ 1	2-4	≥ 8	–	–	–	–	–	–
Streptococcus pneumoniae
Tetracycline	≤ 2	4	≥ 8	≥ 23	19 — 22	≤ 18	–	–	–
Vibrio cholerae
Doxycycline	≤ 4	8	≥ 16	–	–	–	–	–	–
Tetracycline	≤ 4	8	≥ 16	–	–	–	–	–	–
Yersinia pestis
Doxycycline	≤ 4	8	≥ 16	–	–	–	–	–	–
Tetracycline	≤ 4	8	≥ 16	–	–	–	–	–	–
Ureaplasma urealyticum
Tetracycline	–	–	–	–	–	–	≤ 1	–	≥ 2

A report of Susceptible (S) indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. 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 Resistant (R) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test.^{1,2,3,4,5,6,7} Standard doxycycline and tetracycline powders should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg doxycycline disk the criteria noted in Table 2 should be achieved.

Table 2: Acceptable Quality Control Ranges for Susceptibility Testing for Doxycycline and Tetracycline

QC Strain	Minimal Inhibitory Concentration (mcg per mL)	Zone Diameter (mm)	Agar Dilution (mcg per mL)
Enterococcus faecalis ATCC 29212
Doxycycline	2 -8	–	–
Tetracycline	8 — 32	–	–
Escherichia coli ATCC 25922
Doxycycline	0.5 — 2	18 — 24	–
Tetracycline	0.5 — 2	18 — 25	–
Haemophilus influenzae ATCC 49247
Tetracycline	4 to 32	14 — 22	–
Neisseria gonorrhoeae ATCC 49226
Tetracycline	–	30 — 42	0.25 — 1
Staphylococcus aureus ATCC 25923
Doxycycline	–	23 — 29	–
Tetracycline	–	24 — 30	–
Staphylococcus aureus ATCC 29213
Doxycycline	0.12 — 0.5	–	–
Tetracycline	0.12 — 1	–	–
Streptococcus pneumoniae ATCC 49619
Doxycycline	0.015 — 0.12	25 — 34	–
Tetracycline	0.06 — 0.5	27 — 31	–
Bacteroides fragilis ATCC 25285
Tetracycline	–	–	0.125 — 0.5
Bacteroides thetaiotaomicron ATCC 29741
Tetracycline	–	–	8 — 32
Mycoplasma pneumoniae ATCC 29342
Tetracycline	0.06 — 0.5	–	0.06 — 0.5
Ureaplasma urealyticum ATCC 33175
Tetracycline	–	–	≥ 8