Vancomycin Hydrochloride

Akorn, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Vancomycin Hydrochloride Capsules, safely and effectively. See full prescribing information for Vancomycin Hydrochloride Capsules.Vancomycin Hydrochloride Capsules, USPInitial U.S. Approval: 1986 RECENT MAJOR CHANGESDosage and Administration (12/2011) Warnings and Precautions (12/2011) INDICATIONS AND USAGETreatment of: (1) C. difficile-associated diarrhea Enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains) Important Limitations: (1) (5.1) Orally administered Vancomycin Hydrochloride Capsules is not effective for other types of infections. DOSAGE AND ADMINISTRATION C. difficile-associated diarrhea: Adult Patients (≥18 years of age): 125 mg orally 4 times daily for 10 days. (2.1) Pediatric Patients (

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 VANCOMYCIN HYDROCHLORIDE INDICATIONS AND USAGE
• 2 VANCOMYCIN HYDROCHLORIDE DOSAGE AND ADMINISTRATION
  • 2.1 Adults
  • 2.2 Pediatric Patients
• 3 DOSAGE FORMS AND STRENGTHS
• 4 VANCOMYCIN HYDROCHLORIDE CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Oral Use Only
  • 5.2 Potential for Systemic Absorption
  • 5.3 Nephrotoxicity
  • 5.4 Ototoxicity
  • 5.5 Superinfection
  • 5.6 Development of Drug-Resistant Bacteria
• 6 VANCOMYCIN HYDROCHLORIDE ADVERSE REACTIONS
  • 6.1 Clinical Trial Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
• 10 OVERDOSAGE
• 11 VANCOMYCIN HYDROCHLORIDE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
  • 12.4 Microbiology
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Diarrhea Associated with
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

Vancomycin Hydrochloride Capsules, USP

1 INDICATIONS AND USAGE

Vancomycin HCl Capsules are indicated for the treatment of C difficile-associated diarrhea. Vancomycin HCl Capsules are also used for the treatment of enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains). Parenteral administration of vancomycin is not effective for the above infections; therefore, Vancomycin HCl Capsules must be given orally for these infections.

Orally administered Vancomycin Hydrochloride Capsules, USP is not effective for other types of infections.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Vancomycin HCl Capsules and other antibacterial drugs, Vancomycin HCl Capsules should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION

2.1 Adults

Vancomycin HCl Capsules are used in treating C. difficile-associated diarrhea and staphylococcal enterocolitis.

• C. difficile-associated diarrhea: The recommended dose is 125 mg administered orally 4 times daily for 10 days.
• Staphylococcal enterocolitis: Total daily dosage is 500 mg to 2 g administered orally in 3 or 4 divided doses for 7 to 10 days.

2.2 Pediatric Patients

The usual daily dosage is 40 mg/kg in 3 or 4 divided doses for 7 to 10 days. The total daily dosage should not exceed 2 g.

3 DOSAGE FORMS AND STRENGTHS

Vancomycin HCl 125 mg* Capsules have an opaque blue cap and opaque brown body imprinted with "741" on the cap and "125 mg" on the body in white ink.

Vancomycin HCl 250 mg* Capsules have an opaque blue cap and opaque lavender body imprinted with "742" on the cap and "250 mg" on the body in white ink.

*Equivalent to vancomycin.

4 CONTRAINDICATIONS

Vancomycin HCl Capsules are contraindicated in patients with known hypersensitivity to vancomycin.

5 WARNINGS AND PRECAUTIONS

5.1 Oral Use Only

This preparation for the treatment of colitis is for oral use only and is not systemically absorbed. Vancomycin HCl Capsules must be given orally for treatment of staphylococcal enterocolitis and Clostridium difficile -associated diarrhea. Orally administered Vancomycin HCl Capsules are not effective for other types of infections.

Parenteral administration of vancomycin is not effective for treatment of staphylococcal enterocolitis and C. difficile -associated diarrhea. If parenteral vancomycin therapy is desired, use an intravenous preparation of vancomycin and consult the package insert accompanying that preparation.

5.2 Potential for Systemic Absorption

Clinically significant serum concentrations have been reported in some patients who have taken multiple oral doses of Vancomycin HCl Capsules for active C. difficile-associated diarrhea. Some patients with inflammatory disorders of the intestinal mucosa also may have significant systemic absorption of vancomycin. These patients may be at risk for the development of adverse reactions associated with higher doses of Vancomycin HCl Capsules; therefore, monitoring of serum concentrations of vancomycin may be appropriate in some instances, e.g., in patients with renal insufficiency and/or colitis or in those receiving concomitant therapy with an aminoglycoside antibiotic.

5.3 Nephrotoxicity

Nephrotoxicity (e.g., reports of renal failure, renal impairment, blood creatinine increased) has occurred following oral Vancomycin HCl Capsules therapy in randomized controlled clinical studies, and can occur either during or after completion of therapy.

The risk of nephrotoxicity is increased in patients >65 years of age (see ADVERSE REACTIONS, Clinical Trial Experience [6.1] and USE IN SPECIFIC POPULATIONS, Geriatric Use [8.5]).

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 HCl Capsules to detect potential vancomycin induced nephrotoxicity.

5.4 Ototoxicity

Ototoxicity has occurred in patients receiving vancomycin. It may be transient or permanent. It has been reported mostly in patients who have been given excessive intravenous doses, who have an underlying hearing loss, or who are receiving concomitant therapy with another ototoxic agent, such as an aminoglycoside. Serial tests of auditory function may be helpful in order to minimize the risk of ototoxicity (see ADVERSE REACTIONS, Postmarketing Experience [6.2]).

5.5 Superinfection

Use of Vancomycin HCl Capsules may result in the overgrowth of nonsusceptible bacteria. If superinfection occurs during therapy, appropriate measures should be taken.

5.6 Development of Drug-Resistant Bacteria

Prescribing Vancomycin HCl Capsules in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria.

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Vancomycin HCl Capsules in 260 adult subjects in two Phase 3 clinical trials for the treatment of diarrhea associated with C. difficile. In both trials, subjects received Vancomycin HCl Capsules 125 mg orally four times daily. The mean duration of treatment was 9.4 days. The median age of patients was 67, ranging between 19 and 96 years of age. Patients were predominantly Caucasian (93%) and 52% were male.

Adverse reactions occurring in ≥ 5% of Vancomycin HCl Capsules-treated subjects are shown in Table 1. The most common adverse reactions associated with Vancomycin HCl Capsules (≥ 10%) were nausea, abdominal pain, and hypokalemia.

Nephrotoxicity (e.g., reports of renal failure, renal impairment, blood creatinine increased) occurred in 5% of subjects treated with Vancomycin HCl Capsules. Nephrotoxicity following Vancomycin HCl Capsules typically first occurred within one week after completion of treatment (median day of onset was Day 16). Nephrotoxicity following Vancomycin HCl Capsules occurred in 6% of subjects >65 years of age and 3% of subjects ≤65 years of age (see WARNINGS AND PRECAUTIONS, Nephrotoxicity [5.3]).

The incidences of hypokalemia, urinary tract infection, peripheral edema, insomnia, constipation, anemia, depression, vomiting, and hypotension were higher among subjects >65 years of age than in subjects ≤65 years of age (see USE IN SPECIFIC POPULATIONS, Geriatric Use[8.5]).

Discontinuation of study drug due to adverse events occurred in 7% of subjects treated with Vancomycin HCl Capsules. The most common adverse events leading, to discontinuation of Vancomycin HCl Capsules were C. difficile colitis (<1%), nausea (<1%), and vomiting (<1%).

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Vancomycin HCl Capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Ototoxicity: Cases of hearing loss associated with intravenously administered vancomycin have been reported. Most of these patients had kidney dysfunction or a preexisting hearing loss or were receiving concomitant treatment with an ototoxic drug (see WARNINGS AND PRECAUTIONS, Ototoxicity [5.4]). Vertigo, dizziness, and tinnitus have been reported.

Hematopoietic: Reversible neutropenia, usually starting 1 week or more after onset of intravenous therapy with vancomycin or after a total dose of more than 25 g, has been reported for several dozen patients. Neutropenia appears to be promptly reversible when vancomycin is discontinued. Thrombocytopenia has been reported.

Miscellaneous: Patients have been reported to have had anaphylaxis, drug fever, chills, nausea, eosinophilia, rashes (including exfoliative dermatitis), Stevens-Johnson syndrome, toxic epidermal necrolysis, and rare cases of vasculitis in association with the administration of vancomycin.

A condition has been reported that is similar to the IV-induced syndrome with symptoms consistent with anaphylactoid reactions, including hypotension, wheezing, dyspnea, urticaria, pruritus, flushing of the upper body ("Red Man Syndrome"), pain and muscle spasm of the chest and back. These reactions usually resolve within 20 minutes but may persist for several hours.

7 DRUG INTERACTIONS

No drug interaction studies have been conducted.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B - The highest doses of vancomycin tested were not teratogenic in rats given up to 200 mg/kg/day IV (1180 mg/m² or 1 times the recommended maximum human dose based on body surface area) or in rabbits given up to 120 mg/kg/day IV (1320 mg/m² or 1.1 times the recommended maximum human dose based body surface area). No effects on fetal weight or development were seen in rats at the highest dose tested or in rabbits given 80 mg/kg/day (880 mg/m²or 0.74 times the recommended maximum human dose based on body surface area).

In a controlled clinical study, the potential ototoxic and nephrotoxic effects of vancomycin on infants were evaluated when the drug was administered intravenously to pregnant women for serious staphylococcal infections complicating intravenous drug abuse. Vancomycin was found in cord blood. No sensorineural hearing loss or nephrotoxicity attributable to vancomycin was noted. One infant whose mother received vancomycin in the third trimester experienced conductive hearing loss that was not attributed to the administration of vancomycin. Because the number of subjects treated in this study was limited and vancomycin was administered only in the second and third trimesters, it is not known whether vancomycin causes fetal harm. Because animal reproduction studies are not always predictive of human response, Vancomycin HCl Capsules should be given to a pregnant woman only if clearly needed.

8.3 Nursing Mothers

Vancomycin is excreted in human milk based on information obtained with the intravenous administration of vancomycin. However, systemic absorption of vancomycin is very low following oral administration of Vancomycin HCl Capsules (see CLINICAL PHARMACOLOGY, Pharmacokinetics [12.3]). It is not known whether vancomycin is excreted in human milk, as no studies of vancomycin concentration in human milk after oral administration have been done. Caution should be exercised when Vancomycin HCl Capsules is administered to a nursing woman. Because of the potential for adverse events, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

In clinical trials, 54% of Vancomycin HCl Capsules-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 HCl Capsules in diarrhea associated with Clostridium difficile have demonstrated that geriatric subjects are at increased risk of developing nephrotoxicity following treatment with oral Vancomycin HCl Capsules, 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 HCl Capsules to detect potential vancomycin induced nephrotoxicity (see WARNINGS AND PRECAUTIONS, Nephrotoxicity [5.3]; ADVERSE REACTIONS, Clinical Trial Experience [6.1] and CLINICAL STUDIES, Diarrhea Associated with Clostridium difficile [14.1]).

Patients >65 years of age may take longer to respond to therapy compared to patients ≤65 years of age (see CLINICAL STUDIES, Diarrhea Associated with Clostridium difficile [14.1]). Clinicians should be aware of the importance of appropriate duration of Vancomycin HCl Capsules 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 up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics.

11 DESCRIPTION

Vancomycin HCl 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 C₆₆H₇₅CI₂N₉O₂₄•HCl. The molecular weight of vancomycin hydrochloride is 1485.73; 500 mg of the base is equivalent to 0.34 mmol.

The 125 mg capsules contain vancomycin hydrochloride equivalent to 125 mg (0.08 mmol) vancomycin. These capsules also contain FD&C Blue No. 2, gelatin, iron oxide yellow and red, polyethylene glycol, titanium dioxide.

The 250 mg capsules contain vancomycin hydrochloride equivalent to 250 mg (0.17 mmol) vancomycin. These capsules also contain FD&C Blue No. 2, gelatin, iron oxide red and black, polyethylene glycol, titanium dioxide.

Both 125 mg and 250 mg capsules are imprinted with white ink which may contain purified shellac, purified titanium dioxide and FD&C Blue No. 1 Lake.

Vancomycin hydrochloride has the structural formula: