Vancomycin Hydrochloride for Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
Россия
  • Россия
  • Украина

Vancomycin Hydrochloride for Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Bacteremia, Bacterial Endocarditis Prevention (Bacterial Endocarditis Prophylaxis), Bacterial Infection, Bone infection (Osteomyelitis), Methicillin-Resistant Staphylococcus Aureus Infection, Nosocomial Pneumonia, Pneumonia, Sepsis, Skin or Soft Tissue Infection, Surgical Prophylaxis
Class: Glycopeptide antibiotics
Form: Intravenous (IV), Powder
Ingredients: Vancomycin Hydrochloride

Pharmaceutical Information

Drug Substance

Proper Name: vancomycin hydrochloride
Chemical Name: (Sa)-(3S,6R,7R,22R,23S,26S,36R,38aR)-44-[[2-O-(3-Amino-2,3,6-trideoxy-3-C-methyl-alpha-L-lyxo-hexopyranosyl)-beta-D-glucopyranosyl]oxy]-3-(carbamoylmethyl)-10,19-dichloro-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-7,22,28,30,32-pentahydroxy-6-[(2R)-4-methyl-2-(methylamino)valeramido]-2,5,24,38,39-pentaoxo-22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno-1H,16H-[1,6,9]oxadiazacyclo-hexadecino[4,5-m][10,2,16]-benzoxadiazacyclotetracosine-26-carboxyliacid, monohydrochloride
Structure:
Molecular Formula: C66H75C12N9O24●HC1
Molecular Weight: 1485.68
Description: Vancomycin hydrochloride is an off-white to light-tan lyophilized plug. It forms a clear, colourless solution with a pH range of 2.5 to 4.5 when reconstituted in water.

Composition

Each vial contains vancomycin hydrochloride equivalent to 500 mg, 1 g, 5 g and 10 g vancomycin base.

Stability and Storage Recommendations

Store the unreconstituted product between 15 °C and 30 °C.

Reconstitution

500 mg vial: The addition of 10 mL of Sterile Water for Injection provides a reconstituted solution containing approximate average vancomycin concentration of 50 mg/mL.

1 g vial: The addition of 20 mL of Sterile Water for Injection provides a reconstituted solution containing approximate average vancomycin concentration of 50 mg/mL.

5 g vial: The addition of 100 mL of Sterile Water for Injection provides a reconstituted solution containing approximate average vancomycin concentration of 50 mg/mL.

Note: Further dilution is required.

10 g vial: The addition of 95 mL of Sterile Water for Injection provides a reconstituted solution containing approximate average vancomycin concentration of 100 mg/mL.

Note: Further dilution is required.

For Intermittent Intravenous Infusion

500 mg vial: Dilution of reconstituted solutions is required using at least 100 mL of 0.9% Sodium Chloride Injection or 5% Dextrose in Sterile Water for Injection.

1 g vial: Dilution of reconstituted solutions is required using at least 200 mL of 0.9% Sodium Chloride Injection or 5% Dextrose in Sterile Water for Injection.

5 g vial: Further dilution of the reconstituted solution is required. The 5 g vial is a Pharmacy Bulk Package intended for pharmacy use only.

10 g vial: Further dilution of the reconstituted solution is required. The 10 g vial is a Pharmacy Bulk Package intended for pharmacy use only.

For Continuous Intravenous Infusion

The vial contents are first reconstituted by adding Sterile Water for Injection as follows:

500 mg vial: add 10 mL of Sterile Water for Injection

1 g vial: add 20 mL of Sterile Water for Injection

The reconstituted solution is then added to one of the following i.v. solutions:

5% Dextrose Injection

5% Dextrose and 0.9% Sodium Chloride Injection

0.9% Sodium Chloride Injection

As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Single-dose vials. Discard unused portion.

Pharmacy Bulk Package

The availability of the Pharmacy Bulk Package is restricted to hospitals with a recognized intravenous admixture program.

Directions for Dispensing from Maxivials (Pharmacy Bulk Package)

Vancomycin Hydrochloride for Injection, USP is available in a single use vial for pharmacy use only, referred to as a Maxivial. Like the single-dose vial, Maxivial is not for direct infusion. Maxivial comes with a hanging vial label and should be suspended as a unit in a laminar flow hood. Entry into the vial must be made with a sterile dispensing device and contents dispensed in aliquots using aseptic technique (see Dosage and Administration). Use of syringe/needle is not recommended as it may cause leakage. Any unused portion of the reconstituted stock solution should be discarded within 8 hours after initial entry.

Stability of Solutions

Storage

If stored at room temperature, reconstituted solutions and further diluted infusion mixtures should be used within 24 hours. However, if stored under refrigeration (4 °C), they should be used within 96 hours.

Incompatibility

The following are some of the specific substances found to be incompatible: aminophylline, amobarbital sodium, chloramphenicol sodium succinate, chlorothiazide sodium, dexamethasone sodium phosphate, methicillin sodium, vitamin B complex with C, heparin sodium, penicillin G potassium, phenobarbital sodium, phenytoin sodium, secobarbital sodium, sodium bicarbonate and warfarin sodium.

Availability of Dosage Forms

Vancomycin Hydrochloride for Injection, USP is available as a sterile lyophilized powder as follows:

500 mg 10 mL single-dose vials containing vancomycin hydrochloride equivalent to 500 mg vancomycin base. Flip-top vials in packages of 10 or 25.
1 g 20 mL single-dose vials containing vancomycin hydrochloride equivalent to 1 g vancomycin base. Flip-top vials in packages of 10.

Pharmacy Bulk Packages:

5 g 100 mL single use vials containing vancomycin hydrochloride equivalent to 5 g vancomycin base. Flip-top vial individually packaged.
10 g 100 mL single use vials containing vancomycin hydrochloride equivalent to 10 g vancomycin base. Flip-top vial individually packaged.

Microbiology

Vancomycin hydrochloride has not demonstrated cross-resistance with other classes of antibiotics. A slow, stepwise laboratory-induced resistance has been reported to occur. Neither changes in pH nor the presence of serum significantly alter vancomycin's activity. Most strains of the following organisms are sensitive in vitro and in clinical infections to vancomycin:

Staphylococcus aureus (including heterogenous methicillin-resistant strains)

Clostridium difficile

S. epidermidis (including heterogenous methicillin-resistant strains)

Streptococcus pneumoniae (including multiple-resistant strains)

S. pyogenes (group A beta-hemolytic)

S. agalactiae (group B beta-hemolytic)

S. bovis

Alpha-hemolytic streptococci (viridans groups)

Enterococci (e.g., S. faecalis)

Bacillus sp.

Listeria monocytogenes

Lactobacillus sp.

Neisseria sp.

Diphtheroids

Actinomyces sp.

Note: In vitro, many strains of streptococci, staphylococci, C. difficile and other gram-positive bacteria are susceptible to concentrations of 0.5 to 5 µg/mL. A small proportion of S. aureus strains requires 10 to 20 µg/mL for inhibition whereas staphylococci are generally susceptible to less than 5 µg/mL of vancomycin hydrochloride. In vivo and invitro resistance to vancomycin has been reported in clinically significant coagulase negative staphylococci identified as S. hemolyticus.

Enterococci of various species resistant to vancomycin and related glycopeptide antibiotics have been isolated from hospitalised patients in France, UK, and in the USA. Transfer of resistance to E. faecium, or E. fecalis, and to Streptococcus sanguis has also been documented.

In vitro, vancomycin is not effective against gram-negative bacilli, mycobacteria or fungi.

TABLE 1
In Vitro Activity of Vancomycin
Organism Number of Strains MIC (µg/mL) Range Median
Staphylococcus aureus 7343835 *≤ 1.0
0.25 - 1.0
0.8 - 6.25
-
S. aureus (methicillin-resistant) 241554 1.0 - 4.0
0.25 - 2.0
0.5 - 1.0
-
S. epidermidis 29488 0.1 - 6.25
*≤ 2.0
-
Streptococcus pneumoniae 18 ≤ 0.06 - 0.5
0.3 - 1.0
-
Strep. pyogenes 12 0.8 - 3.1 -
Strep. viridans 8221 0.39 - 1.56
*≤ 1.0
0.78
-
Strep. fecalis 382 0.8 - > 100 3.1
Clostridium perfringens 43 0.4 - 1.6 0.8
C. ramosum 49 3.1 - 12.5 6.2
C. difficile 1478 < 0.4 - 3.1
1.0 - 4.0
-

* Given in reference as MIC100.

Methods of Susceptibility Testing

A 30 µg disc of vancomycin should produce a zone of more than 11 mm when in contact with "susceptible" organisms when the standardized method of disc susceptibility testing is used. Intermediate susceptibility is indicated by a zone size of 10 - 11 mm and resistance is indicated by a zone size of 9 mm or less.

Susceptibility to vancomycin is indicated by an MIC of ≤ 5 µg/mL with the WHO-ICS agar dilution and broth dilution methods.

Assay Methods

Bennett's agar-well diffusion method, which can quantitatively measure vancomycin concentrations from 0.5 to 8 µg/mL, can be used to determine vancomycin serum and tissue levels.

Two disc-diffusion assay methods, both using Bacillus subtilis as the test organism, are available for vancomycin. Antibiotic medium No. 5 is used in the first method which is capable of measuring vancomycin levels from approximately 5 to 40 µg/mL. Vancomycin concentrations from about 0.8 to 25 µg/mL can be detected with the second method which uses minimal salt agar. A reliable bioassay for vancomycin (in concentrations of 0.78 to 50.0 µg/mL) in the presence of rifampin or aminoglycosides is permitted with modification of the latter assay. An automated fluorescence polarization immunoassay and a radio- immunoassay are two available commercially prepared assay methods.

Pharmacology

Human Pharmacology

Adults

Intravenous Administration

Multiple 500 mg dosages infused over 30 minutes every 6 hours gave peak concentrations ranging from 41 - 57 µg/mL. Mean peak plasma concentrations were 64 µg/mL immediately post infusion,

12.5 µg/mL at 6 hours and 7 µg/L at 12 hours post infusion following multiple 60 minute 1 g i.v. infusions of vancomycin in healthy volunteers.

A single i.v. injection of 1 g infused over a period of 30 minutes produced peak levels of 85 µg/mL after 2 hours, 11 µg/mL at 6 hours, and 5.1 µg/mL at 12 hours. A single injection of 500 mg resulted in mean serum concentrations of 51 µg/mL, with levels of 18.6 µg/mL, and

5.8 µg/mL at 6, and 12 hours respectively. Plasma half-life ranged from 3 - 8 hours with a mean of 4.5 hours.

Renal Insufficiency

Twenty-nine anephric patients were infused with 1 g of vancomycin in 250 mL of D5W over 30 minutes. The serum concentration was still 3.5 µg/mL after 18 days with intermittent dialysis at 3-day intervals. The half-life of elimination was about 7.5 days.

Table 2. Pharmacokinetic parameters of vancomycin in anephric and normal patients, as analyzed by two-compartment distribution.
Type of patient Parameter*
CpO
(μg/ml)
K21
(days-1)
Kel
(days-1)
K12
(days-1)
t1/2(β)
(days)
Cl
(ml/min)
Vd
(liters)
Vc
(liters)
Anephric 48.3 5.74 0.32 10.69 7.5 6.88 67.6 24.5
Normal [8] 33.4 5.95 10.25 18.64 0.37 110 119.1 14.97

* CpO = peak concentraction in serum;

K21 and K12 = first –order rate constants for distribution of drug from tissue into plasma and from plasma into tissue, respectively;

Kel = elimination rate constant;

t1/2(β) = elimination half-life;

Cl = rate of drug clearance;

Vd = apparent volume of distribution;

Vc = volume of distribution in central compartment. Values given are means.

This group was composed of patients with normal renal function.

(Cunha et al. 1981)

Oral Administration

Vancomycin is poorly absorbed after oral administration, only trace amounts are found in urine and blood. Following a dose of 125 mg orally four times daily, the mean concentration of vancomycin in stools was approximately 350 µg/g. After up to ten daily doses of 2 g, a mean level of 3100 µg/g (with a range of 905 - 8760 µg/g) was detected in feces of patients with pseudomembranous colitis.

Tissue Penetration and Distribution

Central Nervous System

Vancomycin does not readily diffuse across normal meninges into spinal fluid, but penetrates into spinal fluid when the meninges are inflamed.

Other Tissues and Fluids

Vancomycin concentrations in human bile, pleural, ascitic, pericardial, and synovial fluids reach approximately one-third of the equivalent serum level after single i.v. doses. A level of 7.6 µg/mL was achieved in the brain cyst of an infant following i.v. infusion of 40 mg/kg daily for 4 days.

Toxicology

Acute Toxicity

TABLE 3
LD50 (mg/kg) of Vancomycin in Various Animals
Route of Administration Rat Mouse Dog
Intravenous 319 ± 14 489 ± 41 229 ± 29
Intraperitoneal 2218 ± 240 1734 ± 227  
Subcutaneous   > 5000  
Oral   > 5000  

Dogs died several days after drug administration, generally from kidney failure, while rats died quickly from CNS-mediated effects.

Vancomycin caused a slight dose-related drop in blood pressure when administered intravenously in a 5 percent solution to dogs at a rate of 0.6 mL/minute. Blood pressure dropped dramatically, as much as 40%, when the same dogs were given the same doses at a rate of 15 mL/minute. It is unknown, at present, whether the response is due to a direct effect on histamine receptors, or to the possible release of histamine from mast cells.

Chronic Toxicity

Vancomycin was given to dogs in daily doses of 12.5, 25 and 50 mg/kg for 21 - 311 days. Renal damage was seen in 4/22 dogs receiving 50 mg/kg/day.

Irritation at the injection site was the only toxic effect resulting from the daily i.v. administration of 25 or 50 mg/kg to monkeys for 16 to 187 days.

No evidence of systemic toxicity was seen in cats receiving daily i.m. doses of 25 and 50 mg/kg for 3 months.

Nine guinea pigs that received 100 mg vancomycin subcutaneously did not develop anaphylaxis when challenged 25 days later with a 25 mg i.v. dose.

Neither 150 mg vancomycin nor 60 mg tobramycin given alone to rats produced nephrotoxicity. However, significant renal toxicity occurred when administered together.

Ototoxicity was not produced in a guinea pig model administered 1000 mg/kg vancomycin and 40 mg/kg ethacrynic acid concurrently.

Neuromuscular blocking has not been demonstrated in rabbits treated with vancomycin.