vancomycin hydrochloride

Warnings and Precautions, Severe Dermatologic Reactions ( 5.5 ) 12/2020

1 INDICATIONS AND USAGE Vancomycin Hydrochloride Capsules are indicated for the treatment of Clostridioides difficile -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. Vancomycin Hydrochloride Capsules are a glycopeptide antibacterial indicated in adult and pediatric patients (less than 18 years of age) for the treatment of: ( 1 ) • Clostridioides difficile-associated diarrhea • Enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains) Limitations of Use: ( 1 ) ( 5.1 ) • 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 bacteria. ( 1 )

2 DOSAGE AND ADMINISTRATION C. difficile- associated diarrhea: $$Unorderedlist Adult Patients (18 years of age or greater): 125 mg orally 4 times daily for 10 days. (2.1) Pediatric Patients (less than 18 years of age): 40 mg/kg in 3 or 4 divided doses for 7 to 10 days. The total daily dosage should not exceed 2 g. (2.2) $$EndUnorderedlist Staphylococcal enterocolitis: $$Unorderedlist Adult Patients (18 years of age or greater): 500 mg to 2 g orally in 3 or 4 divided doses for 7 to 10 days. (2.1) Pediatric Patients (less than 18 years of age): 40 mg/kg in 3 or 4 divided doses for 7 to 10 days. The total daily dosage should not exceed 2 g. (2.2) $$EndUnorderedlist 2.1 Adults Vancomycin hydrochloride 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 (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, 125 mg (equivalent to vancomycin) 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. Vancomycin Hydrochloride Capsules USP, 250 mg (equivalent to vancomycin) 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. 125 mg capsules and 250 mg capsules ( 3 )

4 CONTRAINDICATIONS Vancomycin Hydrochloride Capsules are contraindicated in patients with known hypersensitivity to vancomycin. Hypersensitivity to vancomycin ( 4 )

6 ADVERSE REACTIONS The most common adverse reactions (≥ 10%) were nausea (17%), abdominal pain (15%) , and hypokalemia (13%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact PAI Pharma at 1-800-845-8210 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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 capsule 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 capsule 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 capsule (≥ 10%) were nausea, abdominal pain, and hypokalemia. Table 1: Common (≥ 5%) Adverse Reactions a for Vancomycin Hydrochloride Capsule Reported in Clinical Trials for Treatment of Diarrhea Associated with C. difficile System / Organ Class Adverse Reaction Vancomycin Hydrochloride Capsule % ( 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 a Adverse reaction rates were derived from the incidence of treatment-emergent adverse events. Nephrotoxicity (e.g., reports of renal failure, renal impairment, blood creatinine increased) occurred in 5% of subjects treated with vancomycin hydrochloride capsule. Nephrotoxicity following vancomycin hydrochloride capsule typically first occurred within one week after completion of treatment (median day of onset was Day 16). Nephrotoxicity following vancomycin hydrochloride capsule 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 capsule. The most common adverse events leading to discontinuation of vancomycin hydrochloride capsule 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 hydrochloride capsule. 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 ( 5.4 )]. Vertigo, dizziness, and tinnitus have been reported. Skin and Subcutaneous Tissue Disorders: 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 (AG …

7 DRUG INTERACTIONS No drug interaction studies have been conducted. No drug interaction studies have been conducted. ( 7 )

8 USE IN SPECIFIC POPULATIONS Geriatrics: 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. ( 5.3 ) ( 6.1 ) ( 8.5 ) ( 14.1 ) 8.1 Pregnancy Risk Summary Systemic absorption of vancomycin is low following oral administration of Vancomycin Hydrochloride Capsules; however, absorption may vary depending on various factors [see Clinical Pharmacology (12.3) ]. There are no available data on vancomycin use in pregnant women to assess a risk of major birth defects or miscarriage. Available published data on intravenous vancomycin use in pregnancy during the second and third trimesters have not shown an association with adverse maternal or fetal outcomes (see Data ). Vancomycin did not show adverse developmental effects when administered intravenously to pregnant rats and rabbits during organogenesis at doses less than or equal to the recommended maximum human dose (see Data ). Data Human Data There are no available data on first trimester use of vancomycin in pregnant women to assess a risk of major birth defects or miscarriage. A published study evaluated hearing loss and nephrotoxicity in infants of 10 pregnant intravenous drug users treated with intravenous vancomycin for suspected or documented methicillin-resistant Staphylococcal aureus in the second or third trimester. The comparison groups were 10 uninfected non-intravenous drug-dependent patients who received no treatment and 10 uninfected untreated intravenous drug-dependent patients. No infant in the vancomycin exposed group had abnormal sensorineural hearing at 3 months of age or nephrotoxicity. A published prospective study assessed outcomes in 55 pregnant women with a positive Group B streptococcus culture and a high-risk penicillin allergy with resistance to clindamycin or unknown sensitivity who were administered intravenous vancomycin at the time of delivery. Vancomycin dosing ranged from the standard dose of 1 g intravenously every 12 hours to a dose of 20 mg/kg intravenously every 8 hours (maximum individual dose 2 g). No major adverse reactions were recorded either in the mothers or their newborns. None of the newborns had sensorineural hearing loss. Neonatal renal function was not examined, but all of the newborns were discharged in good condition. Animal Data Vancomycin did not cause fetal malformation when administered intravenously during organogenesis to pregnant rats (gestation days 6 to 15) and rabbits (gestation days 6 to 18) at the equivalent recommended maximum human dose of 200 mg/kg/day to rats or 120 mg/kg/day to rabbits. No effects on fetal weight or development were seen in rats at the highest dose tested or in rabbits given 80 mg/kg/day (approximately 1 and 0.8 times the recommended maximum human dose based on body surface area). Maternal toxicity was observed in rats (at doses 120 mg/kg and above) and rabbits (at 80 mg/kg and above). 8.2 Lactation Risk Summary There are no data on the presence of vancomycin in human milk, the effects on the breastfed infant, or the effect on milk production following oral administration. Systemic absorption of vancomycin is low following oral administration of Vancomycin Hydrochloride Capsules [see Clinical Pharmacology (12.3) ]; therefore, it is unlikely to result in clinically relevant exposure in breastfeeding infants. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Vancomycin Hydrochloride Capsules and any potential adverse effects on the breastfed infant from Vancomycin Hydrochloride Capsules or from the underlying maternal condition. 8.4 Pediatric Use Vancomycin Hydrochloride Capsules are indicated in pediatric patients less than 18 years of age for the treatment of C. difficile associated diarrhea and enterocolitis caused by S. aureus (includ …

12.1 Mechanism of Action Vancomycin is an antibacterial drug [see Microbiology ( 12.4 )] .

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 C 66 H 75 Cl 2 N 9 O 24 •HCl. The molecular weight of vancomycin hydrochloride is 1,485.73; 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). Inactive ingredient includes polyethylene glycol. The 125 mg capsule shell contains gelatin, FD&C Blue No. 1, D & C Red No. 28, D & C Yellow No.10, titanium dioxide, iron oxide red and iron oxide yellow. The capsules are printed with black ink. The black imprinting ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide and potassium hydroxide. The 250 mg capsule shell contains gelatin, black iron oxide, iron oxide red, iron oxide yellow and titanium dioxide. The capsules are printed with white ink. The white imprinting ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, potassium hydroxide and titanium dioxide. Vancomycin hydrochloride has the structural formula: structure

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Vancomycin Hydrochloride Capsules, USP are available in: The 125 mg* capsules have an opaque blue cap and opaque brown body imprinted with "1032" on the cap and "125 mg" on the body in white ink. The 250 mg* capsules have an opaque blue cap and opaque lavender body imprinted with "1033" on the cap and "250 mg" on the body in white ink. *Equivalent to vancomycin Strength Pack NDC Number Vancomycin 125 mg A carton contains 2 blister packs. Each blister pack contains 10 capsules for a total of 20 capsules per carton. NDC 0121-1032-20 Each bottle contains 50 capsules. NDC 0121-1032-50 Vancomycin 250 mg A carton contains 2 blister packs. Each blister pack contains 10 capsules for a total of 20 capsules per carton. NDC 0121-1033-20 Each bottle contains 50 capsules. NDC 0121-1033-50 STORAGE: Store at Controlled Room Temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].