Minocycline Hydrochloride

MINOCYCLINE HYDROCHLORIDE- minocycline hydrochloride capsule
Preferred Pharmaceuticals Inc.

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:

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 µg/mL (average 3.5 µg/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 T_max 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

Mechanism of Action

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.

Antimicrobial Activity

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

Bacillus anthracis

Listeriamonocytogenes

Staphylococcus aureus

Streptococcus pneumoniae

Gram-negative Bacteria

Bartonella bacilliformis

Brucella species

Klebsiella granulomatis

Campylobacter fetus

Francisella tularensis

Haemophilus ducreyi

Vibrio cholerae

Yersinia pestis

Acinetobacter species

Enterobacter aerogenes

Escherichia coli

Haemophilus influenzae

Klebsiella species

Neisseria gonorrhoeae¹

Neisseria meningitidis¹

Shigella species

Other Microorganisms

Actinomyces species

Borrelia recurrentis

Chlamydophila psittaci

Chlamydia trachomatis

Clostridium species

Entamoeba species

Fusobacterium nucleatum subspecies fusiforme

Mycobacterium marinum

Mycoplasma pneumoniae

Propionibacterium acnes

Rickettsiae

Treponema pallidum subspecies pallidum

Treponema pallidum subspecies pertenue

Ureaplasma urealyticum

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas 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 an antibacterial drug for treatment.

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 test method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of tetracycline (class) or minocycline powder^1,2. The MIC values should be interpreted according to the criteria provided in Table 1.

Diffusion techniques:

Quantitative methods that require measurement of zone diameters 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 method^2,3. This procedure uses paper disks impregnated with 30 µg tetracycline (class disk) or 30 µg minocycline to test the susceptibility of microorganisms to minocycline. The disk diffusion interpretive criteria are provided in Table 1.

Table 1: Susceptibility Test Interpretive Criteria for Minocycline and Tetracycline

a Organisms that are susceptible to tetracycline are also considered susceptible to minocycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to minocycline.
b The current absence of resistance isolates precludes defining any result other than susceptible. If isolates yielding MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.
Species	Minimal Inhibitory Concentration (mcg/mL)			Zone Diameter(mm)			Agar Dilution (mcg/mL)
	S	I	R	S	I	R	S	I	R
Enterobacteriaceaea Minocycline Tetracycline	≤4≤4	88	≥16≥16	≥16≥15	13 to 15 12 to 14	≤12≤11
Acinetobactera Minocycline Tetracycline	≤4 ≤4	8 8	≥16 ≥16	≥16 ≥15	13 to 15 12 to 14	≤12 ≤11
Haemophilus influenzae Tetracycline	≤2	4	≥8	≥29	26 to 28	≤25
Streptococcus pneumoniae Tetracycline	≤1	2	≥4	≥28	25 to 27	≤24
Staphylococcus aureusa Minocycline Tetracycline	≤4≤4	88	≥16≥16	≥19≥19	15 to 1815 to 18	≤14≤14
Vibrio choleraea Minocycline Tetracycline	≤4 ≤4	88	≥16≥16	≥16≥19	13 to 1515 to 18	≤12≤14
Neisseria meningitidisb Minocycline	—	—	—	≥26	—	—	≤2	—	—
Bacillus anthracisb Tetracycline	≤1	—	—
Francisella tularensisb Tetracycline	≤4	—	—
Yersinia pestis Tetracycline	≤4	8	≥16

A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the microorganism if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) 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 (R) indicates that the antimicrobial drug is not likely to inhibit growth of the microorganism, if the antimicrobial drug-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 supplies and reagents used in the assay, and the techniques of the individuals performing the test ^1,2,3. Standard tetracycline (class compound) or minocycline powder should provide the following range of MIC values noted in Table 2. For the disc diffusion technique, using the 30 mcg tetracycline or 30 mcg minocycline disk the criteria in Table 2 should be achieved.

Table 2: Acceptable Quality Control Ranges for Minocycline and Tetracycline

Species	Minimal Inhibitory Concentration (mcg/mL)	Zone Diameter (mm)	Agar Dilution (mcg/mL)
Enterococcus faecalis ATCC 29212 Minocycline Tetracycline	1 to 48 to 32	—-	—-
Escherichia coli ATCC 25922 Minocycline Tetracycline	0.25 to 10.5 to 2	19 to 2518 to 25	—-
Haemophilus influenzae ATCC 49247 Tetracycline	4 to 32	14 to 22	—
Neisseria gonorrhoeae ATCC 49226 Tetracycline	—	30 to 42	0.25 to 1
Staphylococcus aureus ATCC 25923 Minocycline Tetracycline		25 to 3024 to 30	—-
Staphylococcus aureus ATCC 29213 Minocycline Tetracycline	0.06 to 0.50.12 to 1		—-
Streptococcus pneumoniae ATCC 49619 Tetracycline	0.06 to 0.5	27 to 31	—