Vancomycin Hydrochloride: Package Insert and Label Information (Page 2 of 2)

8.5 Geriatric Use

In clinical trials, 54% of vancomycin-treated subjects were >65 years of age. Of these, 40% were between the ages of >65 and 75, and 60% were >75 years of age.

Clinical studies with vancomycin in diarrhea associated with Clostridioides difficile have demonstrated that geriatric subjects are at increased risk of developing nephrotoxicity following treatment with oral vancomycin, which may occur during or after completion of therapy. In patients >65 years of age, including those with normal renal function prior to treatment, renal function should be monitored during and following treatment with vancomycin to detect potential vancomycin induced nephrotoxicity [see Warnings and Precautions (5.3), Adverse Reactions (6.1), and Clinical Studies (14.1)].

Patients >65 years of age may take longer to respond to therapy compared to patients ≤65 years of age [see Clinical Studies (14.1)]. Clinicians should be aware of the importance of appropriate duration of vancomycin treatment in patients >65 years of age and not discontinue or switch to alternative treatment prematurely.

10 OVERDOSAGE

Supportive care is advised, with maintenance of glomerular filtration. Vancomycin is poorly removed by dialysis. Hemofiltration and hemoperfusion with polysulfone resin have been reported to result in increased vancomycin clearance.

To obtain current information about the treatment of overdose, contact a certified Poison Control Center (1-800-222-1222 or www.poison.org). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics.

11 DESCRIPTION

Vancomycin Hydrochloride Capsules USP for oral administration contain chromatographically purified vancomycin hydrochloride, a tricyclic glycopeptide antibiotic derived from Amycolatopsis orientalis (formerly Nocardia orientalis), which has the chemical formula C66 H75 Cl2 N9 O24 •HCl. The molecular weight of vancomycin hydrochloride is 1485.73; 500 mg of the base is equivalent to 0.34 mmol.

Each capsule contains 125 mg vancomycin (equivalent to 128 mg vancomycin hydrochloride) or 250 mg vancomycin (equivalent to 256 mg vancomycin hydrochloride). The capsules also contain FD&C Blue No. 2, gelatin, iron oxide, polyethylene glycol, titanium dioxide, and other inactive ingredients.

Vancomycin hydrochloride has the structural formula:

chemical structurechemical structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Vancomycin is an antibacterial drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

Vancomycin is poorly absorbed after oral administration. During multiple dosing of 250 mg every 8 hours for 7 doses, fecal concentrations of vancomycin in volunteers exceeded 100 mg/kg in the majority of samples. No blood concentrations were detected and urinary recovery did not exceed 0.76%. In anephric subjects with no inflammatory bowel disease who received vancomycin oral solution 2 g for 16 days, blood concentrations of vancomycin were less than or equal to 0.66 mcg/mL in 2 of 5 subjects. No measurable blood concentrations were attained in the other 3 subjects. Following doses of 2 g daily, concentrations of drug were >3100 mg/kg in the feces and <1 mcg/mL in the serum of subjects with normal renal function who had C. difficile -associated diarrhea. After multiple-dose oral administration of vancomycin, measurable serum concentrations may occur in patients with active C. difficile -associated diarrhea, and, in the presence of renal impairment, the possibility of accumulation exists. It should be noted that the total systemic and renal clearances of vancomycin are reduced in the elderly [see Use in Specific Populations (8.5)].

12.4 Microbiology

Mechanism of Action

The bactericidal action of vancomycin against Staphylococcus aureus and the vegetative cells of Clostridioides difficile results primarily from inhibition of cell-wall biosynthesis. In addition, vancomycin alters bacterial-cell-membrane permeability and RNA synthesis.

Resistance

Staphylococcus aureus
S. aureus
isolates with vancomycin minimal inhibitory concentrations (MICs) as high as 1024 mcg/mL have been reported.
The exact mechanism of this resistance is not clear but is believed to be due to cell wall thickening and potentially the transfer of genetic material.
Clostridioides difficile
Isolates of C. difficile generally have vancomycin MICs of <1 mcg/mL, however vancomycin MICs ranging from 4 mcg/mL to 16 mcg/mL have been reported. The mechanism which mediates C. difficile’s decreased susceptibility to vancomycin has not been fully elucidated.

Vancomycin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)].

Gram-positive bacteria

Staphylococcus aureus
(including methicillin-resistant isolates) associated with enterocolitis.

Anaerobic gram-positive bacteria

Clostridioides difficile
isolates associated with C. difficile associated diarrhea.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term carcinogenesis studies in animals have been conducted.

At concentrations up to 1000 mcg/mL, vancomycin had no mutagenic effect in vitro in the mouse lymphoma forward mutation assay or the primary rat hepatocyte unscheduled DNA synthesis assay. The concentrations tested in vitro were above the peak plasma vancomycin concentrations of 20 to 40 mcg/mL usually achieved in humans after slow infusion of the maximum recommended dose of 1 g. Vancomycin had no mutagenic effect in vivo in the Chinese hamster sister chromatid exchange assay (400 mg/kg IP) or the mouse micronucleus assay (800 mg/kg IP).

No definitive fertility studies have been conducted.

14 CLINICAL STUDIES

14.1 Diarrhea Associated with Clostridioides difficile

In two trials, vancomycin 125 mg orally four times daily for 10 days was evaluated in 266 adult subjects with C. difficile -associated diarrhea (CDAD). Enrolled subjects were 18 years of age or older and received no more than 48 hours of treatment with oral vancomycin or oral/intravenous metronidazole in the 5 days preceding enrollment. CDAD was defined as ≥3 loose or watery bowel movements within the 24 hours preceding enrollment, and the presence of either C. difficile toxin A or B, or pseudomembranes on endoscopy within the 72 hours preceding enrollment. Subjects with fulminant C. difficile disease, sepsis with hypotension, ileus, peritoneal signs or severe hepatic disease were excluded.

Efficacy analyses were performed on the Full Analysis Set (FAS), which included randomized subjects who received at least one dose of vancomycin and had any post-dosing investigator evaluation data (N=259; 134 in Trial 1 and 125 in Trial 2).

The demographic profile and baseline CDAD characteristics of enrolled subjects were similar in the two trials. Vancomycin-treated subjects had a median age of 67 years, were mainly white (93%), and male (52%). CDAD was classified as severe (defined as 10 or more unformed bowel movements per day or WBC ≥15000/mm3) in 25% of subjects, and 47% were previously treated for CDAD.

Efficacy was assessed by using clinical success, defined as diarrhea resolution and the absence of severe abdominal discomfort due to CDAD, on Day 10. An additional efficacy endpoint was the time to resolution of diarrhea, defined as the beginning of diarrhea resolution that was sustained through the end of the prescribed active treatment period.

The results for clinical success for vancomycin-treated subjects in both trials are shown in Table 2.

Table 2: Clinical Success Rates (Full Analysis Set)

Clinical Success Rate

95% Confidence Interval

Vancomycin % (N)

Trial 1

81.3 (134)

(74.4, 88.3)

Trial 2

80.8 (125)

(73.5, 88.1)

The median time to resolution of diarrhea was 5 days and 4 days in Trial 1 and Trial 2, respectively. For subjects older than 65 years of age, the median time to resolution was 6 days and 4 days in Trial 1 and Trial 2, respectively. In subjects with diarrhea resolution at end-of-treatment with vancomycin, recurrence of CDAD during the following four weeks occurred in 25 of 107 (23%) and 18 of 102 (18%) in Trial 1 and Trial 2, respectively.

Restriction Endonuclease Analysis (REA) was used to identify C. difficile baseline isolates in the BI group. In Trial 1, the vancomycin-treated subjects were classified at baseline as follows 31 (23%) with BI strain, 69 (52%) with non-BI strain, and 34 (25%) with unknown strain. Clinical success rates were 87% for BI strain, 81% for non-BI strain, and 76% for unknown strain. In subjects with diarrhea resolution at end-of treatment with vancomycin, recurrence of CDAD during the following four weeks occurred in 7 of 26 subjects with BI strain, 12 of 56 subjects with non-BI strain, and 6 of 25 subjects with unknown strain.

15 REFERENCES

1. Byrd RA., Gries CL, Buening M.: Developmental Toxicology Studies of Vancomycin Hydrochloride Administered Intravenously to Rats and Rabbits. Fundam Appl Toxicol 1994; 23: 590-597.

16 HOW SUPPLIED/STORAGE AND HANDLING

Vancomycin Hydrochloride Capsules USP are available in:

The 125 mg (equivalent to vancomycin) capsules have an opaque blue cap and opaque brown body imprinted with “3125” on the cap and “VANCOCIN HCL 125 MG” on the body in white ink.
NDC 62559-390-20: Carton containing 2 blister packs. Each blister pack contains 10 capsules for a total of 20 capsules per carton.
NDC 62559-390-50: Bottle of 50 capsules.

The 250 mg (equivalent to vancomycin) capsules have an opaque blue cap and opaque lavender body imprinted with “3126” on the cap and “VANCOCIN HCL 250 MG” on the body in white ink.
NDC 62559-391-20: Carton containing 2 blister packs. Each blister pack contains 10 capsules for a total of 20 capsules per carton.
NDC 62559-391-50: Bottle of 50 capsules.

Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Severe Dermatologic Reactions

Advise patients about the signs and symptoms of serious skin manifestations. Instruct patients to stop taking Vancomycin Hydrochloride Capsules immediately and promptly seek medical attention at the first signs or symptoms of skin rash, mucosal lesions or blisters [see Warnings and Precautions (5.5)].

Antibacterial Resistance

Patients should be counseled that antibacterial drugs including Vancomycin Hydrochloride Capsules should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Vancomycin Hydrochloride Capsules are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Vancomycin Hydrochloride Capsules or other antibacterial drugs in the future.

Manufactured by:
ANI Pharmaceuticals, Inc.
Baudette, MN 56623
ani

Package/Label Display Panel

NDC 62559-390-20
Vancomycin Hydrochloride Capsules USP
125 mg*
Rx only
Not a Child Resistant Container
20 Capsules

Carton-125mg
(click image for full-size original)

Package/Label Display Panel

NDC 62559-391-20
Vancomycin Hydrochloride Capsules USP
250 mg*
Rx only
Not a Child Resistant Container
20 Capsules

Carton-250mg
(click image for full-size original)

VANCOMYCIN HYDROCHLORIDE vancomycin hydrochloride capsule
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:62559-390
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
VANCOMYCIN HYDROCHLORIDE (VANCOMYCIN) VANCOMYCIN 125 mg
Inactive Ingredients
Ingredient Name Strength
FD&C BLUE NO. 2
GELATIN, UNSPECIFIED
FERRIC OXIDE RED
FERRIC OXIDE YELLOW
POLYETHYLENE GLYCOL 6000
TITANIUM DIOXIDE
Product Characteristics
Color BLUE, BROWN Score no score
Shape CAPSULE (CAPSULE) Size 18mm
Flavor Imprint Code 3125;VANCOCIN;HCL;125;MG
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:62559-390-20 2 BLISTER PACK in 1 CARTON contains a BLISTER PACK
1 10 CAPSULE in 1 BLISTER PACK This package is contained within the CARTON (62559-390-20)
2 NDC:62559-390-50 50 CAPSULE in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA authorized generic NDA050606 10/26/2015
VANCOMYCIN HYDROCHLORIDE vancomycin hydrochloride capsule
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:62559-391
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
VANCOMYCIN HYDROCHLORIDE (VANCOMYCIN) VANCOMYCIN 250 mg
Inactive Ingredients
Ingredient Name Strength
FD&C BLUE NO. 2
GELATIN, UNSPECIFIED
FERRIC OXIDE RED
FERROSOFERRIC OXIDE
POLYETHYLENE GLYCOL 6000
TITANIUM DIOXIDE
Product Characteristics
Color BLUE, PURPLE (lavender) Score no score
Shape CAPSULE (CAPSULE) Size 22mm
Flavor Imprint Code 3126;VANCOCIN;HCL;250;MG;
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:62559-391-20 2 BLISTER PACK in 1 CARTON contains a BLISTER PACK
1 10 CAPSULE in 1 BLISTER PACK This package is contained within the CARTON (62559-391-20)
2 NDC:62559-391-50 50 CAPSULE in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA authorized generic NDA050606 10/26/2015
Labeler — ANI Pharmaceuticals, Inc. (145588013)

Revised: 03/2021 ANI Pharmaceuticals, Inc.

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