Minocycline Hydrochloride: Package Insert and Label Information

MINOCYCLINE HYDROCHLORIDE- minocycline hydrochloride capsule
Ranbaxy Pharmaceuticals Inc.

MINOCYCLINE HYDROCHLORIDE CAPSULES, USP

Rx on ly

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

DESCRIPTION

Minocycline hydrochloride, USP, 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:

minostructure
(click image for full-size original)

C23 H27 N3 O7 •HCl M.W. 493.95

Each minocycline hydrochloride capsule, USP for oral administration, contains the equivalent of 50 mg, 75 mg or 100 mg of minocycline. In addition each capsule contains the following inactive ingredients: corn starch and magnesium stearate.

The 50 mg, 75 mg and 100 mg capsule shells contain: gelatin and titanium dioxide.

The 75 mg and 100 mg capsule shells also contain black iron oxide.

The imprinting ink contains: black iron oxide, potassium hydroxide, propylene glycol, and shellac.

CLINICAL PHARMACOLOGY

Following a single dose of two minocycline hydrochloride capsules, 100 mg 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.

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:

GRAM-POSITIVE BACTERIA

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

GRAM-NEGATIVE BACTERIA

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 gonorrhoea 1

Neisseria meningitidis 1

Shigella species

“OTHER” MICROORGANISMS

Actinomyces species1

Borrelia recurrentis

Chlamydia psittaci

Chlamydia trachomatis

Clostridium species1

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 (Ref1, Ref3) (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 spp., and Staphylococcus aureus:

MIC (mcg/mL) Interpretation
≤ 4 Susceptible (S)
8 Intermediate (I)
≥ 16 Resistant (R)

For testing Haemophilus influenzae 2 and Streptococcus pneumoniae 3

MIC (mcg/mL) Interpretation
≤ 2 Susceptible (S)
4 Intermediate (I)
≥ 8 Resistant (R)

2 These interpretative standards are applicable only to broth microdilution susceptibility testing with Haemophilus influenzae using Haemophilus Test Medium.

3 These interpretative standards are applicable only to broth microdilution susceptibility testing using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.

For testing Neisseria gonorrhoeae 4:

MIC (mcg/mL) Interpretation
≤ 0.25 Susceptible (S)
0.5 to 1 Intermediate (I)
≥ 2 Resistant (R)

4 These interpretative standards are applicable only to agar dilution susceptibility testing using GC agar base and 1% defined growth supplements.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism 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 which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Quality Control

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:

Microorganism MIC Range (mcg/mL)
Escherichia coli ATCC 25922 0.5 to 2
Staphylococcus aureus ATCC 29213 0.12 to 1
Haemophilus influenzae ATCC 49247 4 to 32
Streptococcus pneumoniae ATCC 49619 0.06 to 0.5
Neisseria gonorrhoeae ATCC 49226 0.25 to 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 Ref2 , Ref3 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 Enterobacteriaceae and Acinetobacter spp.:

Zone Diameter (mm) Interpretation MIC (mcg/mL)
≥ 16 Susceptible (S) ≤ 4
13 to 15 Intermediate (I) -
≤ 12 Resistant (R) ≥ 16

These zone diameter standards are applicable only to susceptibility testing using Mueller-Hinton agar and 30 mcg minocycline disk.

For testing Staphylococcus aureus:

Zone Diameter (mm) Interpretation MIC (mcg/mL)
≥ 19 Susceptible (S) ≤ 4
15 to 18 Intermediate (I) -
≤ 14 Resistant (R) ≥ 16

These zone diameter standards are applicable only to susceptibility testing using Mueller-Hinton agar and a 30 mcg minocycline disk.

For testing Haemophilus influenzae 5:

Zone Diameter (mm) Interpretation MIC (mcg/mL)
≥ 29 Susceptible (S) ≤ 2
26 to 28 Intermediate (I) -
≤ 25 Resistant (R) ≥ 8

5 These zone diameter standards are applicable only to susceptibility testing with Haemophilus influenzae using Haemophilus Test Medium and a 30 mcg tetracycline disk.

For testing Neisseria gonorrhoeae 6:

Zone Diameter (mm) Interpretation MIC (mcg/mL)
≥ 38 Susceptible (S) ≤ 0.25
31 to 37 Intermediate (I) -
≤ 30 Resistant (R) ≥ 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.

For testing Streptococcus pneumoniae 7:

Zone Diameter (mm) Interpretation MIC (mcg/mL)
≥ 23 Susceptible (S) ≤ 2
19 to 22 Intermediate (I) -
≤ 18 Resistant (R) ≥ 8

7 These interpretative standards are applicable only to disk diffusion testing using Mueller-Hinton agar adjusted with 5% sheep blood and a 30 mcg tetracycline disk.

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:

Microorganism Zone Diameter Range (mm)
Tetracycline Minocycline
Escherichia coli ATCC 25922 18 to 25 19 to 25
Staphylococcus aureus ATCC 25923 24 to 30 25 to 30
Haemophilus influenzae ATCC 49247 14 to 22 -
Neisseria gonorrhoeae ATCC 49226 30 to 42 -
Streptococcus pneumoniae ATCC 49619 27 to 31 -
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