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Doryx (Doxycycline Hyclate) - Description and Clinical Pharmacology

 
 



DESCRIPTION

DORYX (doxycycline hyclate delayed-release tablets), for oral administration, contain specially coated pellets of doxycycline hyclate, a broad-spectrum antibacterial 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. Inactive ingredients in the tablet formulation are: lactose monohydrate; microcrystalline cellulose; sodium lauryl sulfate; sodium chloride; talc; anhydrous lactose; corn starch; crospovidone; magnesium stearate; cellulosic polymer coating.

CLINICAL PHARMACOLOGY

Mechanism of Action

Doxycycline is an antimicrobial drug [see Microbiology (12.4)].

Pharmacokinetics

Doxycycline is virtually completely absorbed after oral administration. Following single and multiple-dose administration of DORYX Tablets, 200 mg to adult volunteers, average peak plasma doxycycline concentration (Cmax) was 4.6 mcg/mL and 6.3 mcg/mL, respectively with median tmax of 3 hours; the corresponding mean plasma concentration values 24 hours after single and multiple doses were 1.5 mcg/mL and 2.3 mcg/mL, respectively. The mean Cmax and AUC 0-∞ of doxycycline are 24% and 13% lower, respectively, following single dose administration of DORYX Tablets, 100 mg with a high fat meal (including milk) compared to fasted conditions. The mean Cmax of doxycycline is 19% lower and the AUC 0-∞ is unchanged following single dose administration of DORYX Tablets, 150 mg with a high fat meal (including milk) compared to fasted conditions. The clinical significance of these decreases is unknown. Doxycycline bioavailability from DORYX Tablets, 200 mg was not affected by food, but the incidence of nausea was higher in fasted subjects. The 200 mg tablets may be administered without regard to meals.

When DORYX Tablets are sprinkled over applesauce and taken with or without water, the extent of doxycycline absorption is unchanged, but the rate of absorption is increased slightly.

Tetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with a creatinine clearance of about 75 mL/min. This percentage may fall as low as 1-5%/72 hours in individuals with a creatinine clearance below 10 mL/min.

Studies have shown no significant difference in the serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the 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 between tetracyclines is common.

Doxycycline has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for DORYX.

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

Anerobic Bacteria
Clostridium species
Fusobacterium fusiforme
Propionibacterium acnes

Other Bacteria
Actinomyces species
Borrelia recurrentis
Chlamydophila psittaci
Chlamydia trachomatis
Mycoplasma pneumoniae
Rickettsiae
Treponema pallidum
Treponema 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 Test 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)5,6,8. The MIC values should be interpreted according to the criteria provided in Table 2.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. Zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standard test method5,7,8. This procedure uses paper disks impregnated with 30 mcg doxycycline to test the susceptibility of bacteria to doxycycline. The disk diffusion interpretive criteria are provided in Table 2.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method9. The MIC values obtained should be interpreted according to the criteria provided in Table 2.

Table 2: Susceptibility Test Interpretive Criteria for Doxycycline and Tetracycline
Bacteria 1  

Minimal Inhibitory

Concentration

(mcg/mL)

 

 

Zone

Diameter

(mm)

 

Agar

Dilution

(mcg/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 2
    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 - -
Nocardiae and other aerobic Actinomyces species
    Doxycycline ≤1 2-4 ≥8
Neisseria gonorrhoeae 3
    Tetracycline - - - ≥38 31-37 ≤30 ≤0.25 0.5-1 ≥2
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

1 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.
2 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.
3 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 greater than or equal to 16 mcg/mL).

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 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 be inhibited 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 test5,6,7,8,9,10,11. Standard doxycycline and tetracycline powders should provide the following range of MIC values noted in Table 3. For the diffusion technique using the 30 mcg doxycycline disk the criteria noted in Table 3 should be achieved.

Table 3: Acceptable Quality Control Ranges for Susceptibility Testing for Doxycycline and Tetracycline
QC Strain

Minimal
Inhibitory
Concentration
(mcg/mL)

Zone
Diameter
(mm)

Agar
Dilution
(mcg/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 - 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 -
Staphylococcus 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

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 antibacterials (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.

Animal Toxicology and/or Pharmacology

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.

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

CLINICAL STUDIES

This was a randomized, double-blind, active-controlled, multicenter trial which enrolled 495 subjects, between 19 to 45 years of age with a confirmed diagnosis of urogenital C. trachomatis infection less than 14 days prior to enrollment, or partner(s) of a subject with a known positive test for urogenital C. trachomatis infection.

The primary purpose of this study was to evaluate the efficacy and safety of DORYX Tablets, 200 mg once daily versus doxycycline hyclate capsules, 100 mg twice daily for seven days for the treatment of uncomplicated urogenital C. trachomatis infection. The primary efficacy objective was to demonstrate non-inferiority of the DORYX Tablets, 200 mg once daily treatment regimen versus the doxycycline 100 mg twice daily treatment regimen for the indication using a negative nucleic acid amplification test (NAAT) at the test of cure visit (day 28) in the mITT population (subjects who were positive at baseline and took at least one day of study drug).

Table 4: Primary Efficacy Outcome – Microbiological Cure of C. trachomatis at Day 28
mITT Population

DORYX Tablets, 200 mg once daily

Cure Rate (%)

Doxycycline hyclate capsules, 100 mg twice daily

Cure Rate (%)

Difference

(%)

N 188 190
Microbiological Cure, n (%) 163 (86.7) 171 (90.0) -3.3%
95% Confidence Interval for Cure Rate -10.3, 3.7

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