VANCOMYCIN HYDROCHLORIDE

VANCOMYCIN HYDROCHLORIDE — vancomycin hydrochloride capsule
Lupin Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

Vancomycin Hydrochloride Capsules are indicated for the treatment of Clostridioides difficil e -associated diarrhea. Vancomycin hydrochloride capsules are also used for the treatment of enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains) in adult and pediatric patients less than 18 years of age.

Limitations of Use .

Parenteral administration of vancomycin is not effective for the above infections; therefore, vancomycin hydrochloride capsules must be given orally for these infections.

Orally administered vancomycin hydrochloride capsules are not effective for other types of infections.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of vancomycin hydrochloride capsules and other antibacterial drugs, vancomycin hydrochloride capsules should be used only to treat or prevent 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 Hydrochloride Capsules USP, 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(less than 18 years of age)

For both C. difficile -associated diarrhea and staphylococcal enterocolitis, 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 Hydrochloride Capsules, USP are available in:

The 125 mg (equivalent to vancomycin):

Size 2, Hard gelatin capsules having an opaque blue cap imprinted with “LU” in white ink and opaque brown body imprinted with “S01” in white ink containing cream coloured hard mass.

The 250 mg (equivalent to vancomycin):

Size 0, Hard gelatin capsules having an opaque blue cap imprinted with “LU” in white ink and opaque lavender body imprinted with “S02” in white ink containing cream coloured hard mass.

4 CONTRAINDICATIONS

Vancomycin Hydrochloride is contraindicated in patients with known hypersensitivity to vancomycin.

5 WARNINGS AND PRECAUTIONS

5.1 Oral Use Only

Vancomycin hydrochloride for the treatment of colitis is for oral use only and is not systemicallyabsorbed. Vancomycin Hydrochloride must be given orally for treatment of staphylococcal enterocolitis and Clostridioides difficile- associated diarrhea. Orally administered vancomycin hydrochloride is 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 (6.1) and Use in Specific Populations (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 hydrochloride 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, (6.2)].

5.5 Severe Dermatologic Reactions

Severe dermatologic reactions such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and linear IgA bullous dermatosis (LABD) have been reported in association with the use of vancomycin.

Cutaneous signs or symptoms reported include skin rashes, mucosal lesions, and blisters.

Discontinue vancomycin hydrochloride capsules at the first appearance of signs and symptoms of TEN, SJS, DRESS, AGEP, or LABD.

5.6 Development of Drug-Resistant Bacteria

Prescribing vancomycin hydrochloride capsules in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication 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 hydrochloride 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 hydrochloride 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 hydrochloride-treated subjects are shown in Table 1. The most common adverse reactions associated with vancomycin hydrochloride (≥ 10%) were nausea, abdominal pain, and hypokalemia.

Table 1: Common (≥ 5%) Adverse Reactions *for Vancomycin Hydrochloride Reported in Clinical Trials for Treatment of Diarrhea Associated with C. difficile

* Adverse reaction rates were derived from the incidence of treatment-emergent adverse events.
System / Organ Class	Adverse Reaction	Vancomycin Hydrochloride % ( N = 260 )
Gastrointestinal disorders	Nausea	17
	Abdominal pain	15
	Vomiting	9
	Diarrhea	9
	Flatulence	8
General disorders and administration	Pyrexia	9
site conditions	Edema peripheral	6
	Fatigue	5
Infections and infestations	Urinary tract infection	8
Metabolism and nutrition disorders	Hypokalemia	13
Musculoskeletal and connective tissue disorders	Back pain	6
Nervous system disorders	Headache	7

Nephrotoxicity (e.g., reports of renal failure, renal impairment, blood creatinine increased) occurred in 5% of subjects treated with vancomycin hydrochloride. Nephrotoxicity following vancomycin hydrochloride typically first occurred within one week after completion of treatment (median day of onset was Day 16). Nephrotoxicity following vancomycin hydrochloride occurred in 6% of subjects >65 years of age and 3% of subjects ≤65 years of age [see Warnings and Precautions, (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, (8.5)].

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