Vancomycin Hydrochloride for Oral Solution

1 INDICATIONS AND USAGE Vancomycin hydrochloride is indicated for the treatment of Clostridium difficil e‐associated diarrhea in adults and pediatric patients less than 18 years of age. Vancomycin hydrochloride is also indicated for the treatment of enterocolitis caused by Staphylococcus aureus (including methicillin‐resistant strains) in adults and pediatric patients less than 18 years of age. Important Limitations of Use Parenteral administration of vancomycin is not effective for the above infections; therefore, vancomycin must be given orally for these infections. Orally administered vancomycin hydrochloride is not effective for treatment of other types of infections. To reduce the development of drug‐resistant bacteria and maintain the effectiveness of vancomycin hydrochloride and other antibacterial drugs, vancomycin hydrochloride 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 is a glycopeptide antibacterial indicated in adults and pediatric patients less than 18 years of age for the treatment of: ( 1 ) Clostridium difficile ‐associated diarrhea Enterocolitis caused by Staphylococcus aureus (including methicillin‐resistant strains) Important Limitations of Use: ( 1 ) ( 5.1 ) Orally administered vancomycin hydrochloride is not effective for treatment of other types of infections. To reduce the development of drug‐resistant bacteria and maintain the effectiveness of vancomycin hydrochloride and other antibacterial drugs, vancomycin hydrochloride 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: Adult Patients (18 years of age and older): 125 mg orally 4 times daily for 10 days. ( 2.2 ) 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. ( 2.3 ) Staphylococcal enterocolitis: Adult Patients (18 years of age and older): 500 mg to 2 g orally in 3 or 4 divided doses for 7 to 10 days. ( 2.2 ) 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. ( 2.3 ) See Full Prescribing Information for preparation and important administration information. ( 2.1 ) 2.1 Important Administration Instructions Prior to oral administration, the supplied vancomycin hydrochloride powder must be reconstituted by the healthcare provider (i.e., a pharmacist) to produce the oral solution [ see Dosage and Administration ( 2.4 ) ]. 2.2 Adults 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. 2.3 Pediatric Patients (less than 18 years of age) For both C. difficile ‐associated diarrhea and staphylococcal enterocolitis, the usual daily dosage of vancomycin hydrochloride is 40 mg/kg in 3 or 4 divided doses for 7 to 10 days. The total daily dosage should not exceed 2 g. 2.4 Preparation and Storage of Solutions of Vancomycin Hydrochloride Each vancomycin hydrochloride for oral solution kit contains 1 bottle of vancomycin hydrochloride USP powder and 1 bottle of pre‐measured Grape‐Flavored Diluent to be added to the vancomycin bottle. A healthcare provider (i.e., a pharmacist) must reconstitute vancomycin hydrochloride USP powder with the Grape‐Flavored Diluent provided in the kit. Vancomycin hydrochloride for oral solution is available in various strengths and volumes in the kit as shown in Table 1 . Table 1: Vancomycin Concentration and Volume after Reconstitution Vancomycin Concentration after Reconstitution Final Volume of Vancomycin Hydrochloride after Reconstitution Vancomycin Strength per Bottle Diluent for Vancomycin Hydrochloride 25 mg/mL 150 mL 3.75 g 147 mL 300 mL 7.5 g 295 mL 50 mg/mL 150 mL 7.5 g 145 mL 300 mL 15.0 g 289 mL Steps for the Preparation of Solutions of Vancomycin Hydrochloride Hold the neck of the bottle containing the vancomycin hydrochloride USP powder for oral solution (see Table 1 ), and tap the bottom edges on a hard surface to loosen the powder. Remove the cap from the vancomycin hydrochloride USP powder for oral solution bottle (“Powder Bottle”). Tap the top of the induction seal liner to loosen any powder that may have adhered to the liner. Carefully and slowly peel back the inner foil seal liner from the Powder Bottle. Shake the Grape‐Flavored Diluent (see ) for a few seconds. Remove the cap from the diluent bottle. Carefully and slowly peel back the inner foil seal from the diluent bottle. Transfer approximately one-half the contents of Grape-Flavored Diluent into the Powder Bottle. Replace the Powder Bottle cap, tighten onto the Powder Bottle, and shake the Powder Bottle vertically for approximately 45 seconds. NOTE: DO NOT use the diluent cap on the Powder Bottle as it may cause the solution to leak from the bottle. Re-open the Powder Bottle and add the remaining Grape‐Flavored Diluent into the Powder Bottle. Replace the Powder Bottle cap, tighten onto the Powder Bottle, and shake the Powder Bottle for approximately 30 seconds. NOTE: DO NOT use the diluent cap on the Powder Bottle as it may cause the solution to leak from the bottle. Dispense the Powder Bottle containing reconstituted solution of vancomycin hydrochloride oral solution to the patient [ see Patient Counseling Information ( 17 ) ]. Instruct the patient to shake the reconstituted solution of vancomycin hydrochloride well before …

3 DOSAGE FORMS AND STRENGTHS Each vancomycin hydrochloride for oral solution kit contains vancomycin hydrochloride USP as white to almost white or tan to brown powder for oral solution, equivalent to 3.75 g, 7.5 g or 15.0 g vancomycin, and Grape‐Flavored Diluent for reconstitution. Each vancomycin hydrochloride for oral solution kit contains: vancomycin hydrochloride USP, powder for oral solution, equivalent to 3.75 g, 7.5 g or 15.0 g vancomycin, and Grape‐Flavored Diluent. ( 3 )

4 CONTRAINDICATIONS Vancomycin hydrochloride is 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 Wilshire Pharmaceuticals at 1-877-495-6856, 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 in 260 adult subjects in two Phase 3 clinical trials for the treatment of C. difficile ‐associated diarrhea. In both trials, subjects received vancomycin hydrochloride 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 2 . The most common adverse reactions associated with vancomycin hydrochloride (≥ 10%) were nausea, abdominal pain, and hypokalemia. Table 2: Common (≥ 5%) Adverse Reactions* for Vancomycin Hydrochloride Reported in Clinical Trials for Treatment of C. difficile Associated Diarrhea * 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 site conditions Pyrexia 9 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 over 65 years of age and 3% of subjects 65 years of age and younger [ see Warnings and Precautions ( 5.3 ) ]. Nephrotoxicity can also occur during oral vancomycin administration. The incidences of hypokalemia, urinary tract infection, peripheral edema, insomnia, constipation, anemia, depression, vomiting, and hypotension were higher among subjects over 65 years of age than in subjects 65 years of age and younger [ 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%). 6.2 Postmarketing Experience The following adverse reactions have been identified during post‐approval use of vancomycin hydrochloride. 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 exanthem …

7 DRUG INTERACTIONS No drug interaction studies have been conducted using orally administered vancomycin hydrochloride products.

8 USE IN SPECIFIC POPULATIONS Geriatrics : In patients over 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 to detect potential vancomycin induced nephrotoxicity. ( 5.3 ) ( 6.1 ) ( 8.5 ) ( 14.1 ) 8.1 Pregnancy Risk Summary There are no available data on vancomycin hydrochloride use in pregnant women to inform a drug-associated risk of major birth defects or miscarriage. Available published data on vancomycin use in pregnancy during the second and third trimesters have not shown an association with adverse pregnancy-related 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 based on body surface area (see Data ) . All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data A published study evaluated hearing loss and nephrotoxicity in infants of pregnant intravenous drug users treated with vancomycin for suspected or documented methicillin‐resistant S. aureus in the second or third trimester. The comparison groups were 10 non‐intravenous drug‐dependent patients who received no treatment, and 10 untreated intravenous drug‐dependent patients served as substance abuse controls. 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 vancomycin at the time of delivery. Vancomycin dosing ranged from the standard 1 g intravenously every 12 hours to 20 mg/kg intravenous 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 malformations when administered during organogenesis to pregnant rats (gestation days 6 to 15) and rabbits (gestation days 6 to 18) at the equivalent recommended maximum human dose (based on body surface area comparisons) of 200 mg/kg/day IV to rats or 120 mg/kg/day IV 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, respectively). 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 insufficient data to inform the levels of vancomycin in human milk. However, systemic absorption of vancomycin following oral administration is expected to be minimal [ see Clinical Pharmacology ( 12.3 ) ]. There are no data on the effects of vancomycin hydrochloride on the breastfed infant or milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for vancomycin hydrochloride and any potential adverse effects on the breastfed infant from vancomycin hydrochloride or from the underlying maternal condition. 8.4 Pediatric Use Vancomycin hydrochloride is indicated in pediatric patients less than 18 years of age for the treatment of C. difficile ‐associated diarrhea and enterocolitis caused by S. aureus (including methicillin‐resistant strains) [ see Indications and Usage ( 1 ) and Dosage and Administration ( 2.3 ) ]. 8.5 Geriatric Use In clinical …

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

11 DESCRIPTION Vancomycin hydrochloride for oral administration contains the hydrochloride salt of vancomycin, 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 1485.71 g/mol. Vancomycin hydrochloride has the structural formula: Each vancomycin hydrochloride for oral solution kit contains a bottle of vancomycin hydrochloride USP, as white to almost white or tan to brown powder for oral solution, and a bottle of pre‐measured Grape‐Flavored Diluent, in the strengths and volumes listed in Table 3 . Table 3: Vancomycin Strength, Diluent Volume and Vancomycin Concentration after Reconstitution Vancomycin Strength per Bottle Equivalent Amount of Vancomycin Hydrochloride per Bottle Diluent Volume for Vancomycin hydrochloride Vancomycin Concentration after Reconstitution 3.75 g 3.84 g 147 mL 25 mg/mL 7.5 g 7.7 g 295 mL 7.5 g 7.7 g 145 mL 50 mg/mL 15.0 g 15.4 g 289 mL The Grape‐Flavored Diluent used to reconstitute the oral solution contains: artificial grape flavor, citric acid (anhydrous), D&C Yellow No. 10, FD&C Red No. 40, purified water, sodium benzoate and sucralose. Vancomycin hydrochloride structural formula

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. For current information on the management of overdosage, contact the National Poison Control Center at 1‐800‐222‐1222 or www.poison.org .

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Each vancomycin hydrochloride for oral solution kit contains a bottle of vancomycin hydrochloride USP, as white to almost white or tan to brown powder for oral solution, and a bottle of pre‐measured Grape‐Flavored Diluent, in the strengths and volumes listed in . Table 5: Vancomycin Strength, Diluent Volume and National Drug Code (NDC) Numbers Vancomycin Strength per Bottle Diluent Volume for Vancomycin Hydrochloride NDC Numbers 3.75 g 147 mL 52536-104-05 7.5 g 295 mL 52536-107-10 7.5 g 145 mL 52536-106-05 15.0 g 289 mL 52536-108-10 Storage and Handling Store the vancomycin hydrochloride for oral solution kit at refrigerated conditions, 2°C to 8°C (36°F to 46°F). Store reconstituted solutions of vancomycin hydrochloride at 2°C to 8°C [ see Dosage and Administration ( 2.4 ) ]. Do not freeze. Keep container tightly closed. Protect from light.