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Minocycline (Minocycline Hydrochloride) - Description and Clinical Pharmacology

 
 



DESCRIPTION

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

DESCRIPTION
Minocycline hydrochloride is a semisynthetic derivative of tetracycline, 4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride.
Its structural formula is:



C23H27N3O7HCl M.W. 493.94
Minocycline hydrochloride capsules for oral administration contains minocycline HCl equivalent to 50 mg, 75 mg, or 100 mg of minocycline in lactose monohydrate, corn starch, and magnesium stearate.
The capsule shells contain the following inactive ingredients: black iron oxide, FD&C Blue No. 1, gelatin, titanium dioxide and yellow iron oxide. The 50 mg capsule shells also contain D&C Red No. 28, D&C Yellow No. 10, and FD&C Red No. 40.

MICROBIOLOGY

Microbiology
The tetracyclines are primarily bacteriostatic and are thought to exert their antimicrobial effect by the inhibition of protein synthesis. The tetracyclines, including minocycline, have a similar antimicrobial spectrum of activity against a wide range of gram-positive and gram-negative organisms. Cross-resistance of these organisms to tetracycline is common.
Minocycline has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:
AEROBIC GRAM-POSITIVE MICROORGANISMS
Because many strains of the following gram-positive microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility testing are especially recommended. Tetracycline antibiotics should not be used for streptococcal diseases unless the organism has been demonstrated to be susceptible. Tetracyclines are not the drug of choice in the treatment of any type of staphylococcal infection.
Bacillus anthracis 1
Listeria monocytogenes 1
Staphylococcus aureus
Streptococcus pneumoniae
AEROBIC GRAM-NEGATIVE MICROORGANISMS
Bartonella bacilliformis
Brucella species
Calymmatobacterium granulomatis
Campylobacter fetus
Francisella tularensis
Haemophilus ducreyi
Vibrio cholerae
Yersinia pestis
Because many strains of the following groups of gram-negative microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility tests are especially recommended.
Acinetobacter species
Enterobacter aerogenes
Escherichia coli
Haemophilus influenzae
Klebsiella species
Neisseria gonorrhoeae 1
Neisseria meningitidis 1
Shigella species
"OTHER" MICROORGANISMS
Actinomyces species 1
Borrelia recurrentis
Chlamydia psittaci
Chlamydia trachomatis
Clostridium species 1
Entamoeba species
Fusobacterium nucleatum subspecies fusiforme 1
Mycobacterium marinum
Mycoplasma pneumoniae
Propionibacterium acnes
Rickettsiae
Treponema pallidum subspecies pallidum 1
Treponema pallidum subspecies pertenue 1
Ureaplasma urealyticum

1 When penicillin is contraindicated, tetracyclines are alternative drugs in the treatment of infections caused by the cited microorganisms.

Susceptibility Tests
Susceptibility testing should be performed with tetracycline since it predicts susceptibility to minocycline. However, certain organisms (e.g., some staphylococci, and Acinetobacter species) may be more susceptible to minocycline and doxycycline than to tetracycline.

Dilution techniques
Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (Ref 1, Ref 3) (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of tetracycline powder. The MIC values should be interpreted according to the following criteria:
For testing aerobic gram-negative microorganisms (Enterobacteriaceae), Acinetobacter species and Staphylococcus aureus:
MIC (mcg/mL)Interpretation4.0Susceptible (S)8.0Intermediate (I)16.0Resistant (R)For testing Haemophilus influenzae 2 and Streptococcus pneumonia 3:
MIC (mcg/mL)Interpretation2.0Susceptible (S)4.0Intermediate (I)8.0Resistant (R)For testing Neisseria gonorrhoeae 4:
MIC (mcg/mL)Interpretation0.25Susceptible (S)0.5 to 1.0Intermediate (I)Resistant (R)
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard tetracycline powder should provide the following MIC values:
MicroorganismMIC Range (mcg/mL)Escherichia coli ATCC 259220.5 to 2.0Enterococcus faecalis ATCC 292128.0 to 32.0Staphylococcus aureus ATCC 292130.25 to 1.0Haemophilus influenzae ATCC 492474.0 to 32.0Streptococcus pneumoniae ATCC 496190.12 to 0.5Neisseria gonorrhoeae ATCC 492260.25 to 1.0
2 These interpretative standards are applicable only to broth microdilution susceptibility testing with Haemophilus influenzae using Haemophilus Test Medium. (Ref 1)
3 These interpretative standards are applicable only to broth microdilution susceptibility testing using cation-adjusted Muller-Hinton broth with 2 to 5% lysed horse blood.1
4 These interpretative standards are applicable only to agar dilution susceptibility testing using GC agar base and 1% defined growth supplements. (Ref 1)

Diffusion techniques
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure (Ref 2, Ref 3) requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg tetracycline (class disk) or 30 mcg minocycline to test the susceptibility of microorganisms to minocycline.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-mcg tetracycline or minocycline disk should be interpreted according to the following criteria:
For testing aerobic gram-negative microorganisms (Enterobacteriaceae), Acinetobacter species and Staphylococcus aureus:
Zone Diameter (mm)Interpretation19Susceptible (S)15 to18Intermediate (I)14Resistant (R)For testing Haemophilus influenzae 5:
Zone Diameter (mm)Interpretation29Susceptible (S)26 to 28Intermediate (I)25Resistant (R)For testing Neisseria gonorrhoeae 6:
Zone Diameter (mm)Interpretation38Susceptible (S)31 to 37Intermediate (I)30Resistant (R)For testing Streptococcus pneumoniae 7:
Zone Diameter (mm)Interpretation23Susceptible (S)19 to 22Intermediate (I)18Resistant (R)For testing Vibrio cholerae 8:
Zone Diameter (mm)Interpretation19Susceptible (S)15 to 18Intermediate (I)14Resistant (R)Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for tetracycline.
As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30-mcg tetracycline or minocycline disk should provide the following zone diameters in these laboratory test quality control strains:
MicroorganismZone Diameter Range (mm) TetracyclineMinocyclineEscherichia coli ATCC 2592218 to 2519 to 25Staphylococcus aureus ATCC 2921324 to 3025 to 30Haemophilus influenzae ATCC 4924714 to 22------Neisseria gonorrhoeae ATCC 4922630 to 42--------Streptococcus pneumoniae ATCC 4961927 to 31-------
5 These zone diameter standards are applicable only to susceptibility testing with Haemophilus influenzae using Haemophilus Test Medium and a 30-mcg tetracycline disk. (Ref 2)
6 These interpretative standards are applicable only to disk diffusion testing using GC agar and 1% growth supplements, and a 30-mcg tetracycline disk. (Ref 2)
7 These interpretative standards are applicable only to disk diffusion testing using Muller-Hinton agar adjusted with 5% sheep blood and a 30-mcg tetracycline disk. (Ref 2)
8 These interpretative standards are applicable only to disk diffusion testing performed with a 30-mcg tetracycline disk. (Ref 2)



INACTIVE INGREDIENT

INACTIVE INGREDIENTS:
LACTOSE MONOHYDRATE

STARCH, CORN
MAGNESIUM STEARATE
TITANIUM DIOXIDE
GELATIN
FERROSOFERRIC OXIDE
FD&C BLUE NO. 1
FERRIC OXIDE YELLOW

CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY
Following a single dose of two minocycline hydrochloride 100 mg capsules administered to 18 normal fasting adult volunteers, maximum serum concentrations were attained in 1 to 4 hours (average 2.1 hours) and ranged from 2.1 to 5.1 mcg/mL (average 3.5 mcg/mL). The serum half-life in the normal volunteers ranged from 11.1 to 22.1 hours (average 15.5 hours).
When minocycline hydrochloride capsules were given concomitantly with a high-fat meal, which included dairy products, the extent of absorption of minocycline hydrochloride capsules was unchanged compared to dosing under fasting conditions. The mean Tmax was delayed by one hour when administered with food, compared to dosing under fasting conditions. Minocycline hydrochloride capsules may be administered with or without food.
In previous studies with other minocycline dosage forms, the minocycline serum half-life ranged from 11 to 16 hours in 7 patients with hepatic dysfunction, and from 18 to 69 hours in 5 patients with renal dysfunction. The urinary and fecal recovery of minocycline when administered to 12 normal volunteers was one-half to one-third that of other tetracyclines.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY

ANIMAL PHARMACOLOGY AND TOXICOLOGY
Minocycline hydrochloride capsules have been observed to cause a dark discoloration of the thyroid in experimental animals (rats, minipigs, dogs, and monkeys). In the rat, chronic treatment with minocycline hydrochloride has resulted in goiter accompanied by elevated radioactive iodine uptake and evidence of thyroid tumor production. Minocycline hydrochloride has also been found to produce thyroid hyperplasia in rats and dogs.

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