VANCOMYCIN HYDROCHLORIDE

Vancomycin hydrochloride for oral solution, USP 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, USP 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 for oral solution, USP 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: citric Acid (anhydrous), D&C Yellow 10, FD & C Red No 40, Grape Flavor 501417C, Methyl Paraben, Propylene Glycol, Propyl Paraben, Purified Water, Sucralose. structure

Vancomycin hydrochloride for oral solution is indicated for the treatment of Clostridium difficile-associated diarrhea in adults and pediatric patients less than 18 years of age. Vancomycin hydrochloride for oral solution 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 for oral solution and other antibacterial drugs, vancomycin hydrochloride for oral solution 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 for oral solution 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 for oral solution and other antibacterial drugs, vancomycin hydrochloride for oral solution should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1 )

• 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 for oral solution 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 for oral solution 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 for oral solution 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 for oral solution after reconstitution Vancomycin strength per bottle Diluent for vancomycin hydrochloride for oral solution 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 for oral solution 1. 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. 2. Remove the cap from the vancomycin hydrochloride USP powder for oral solution bottle (“Powder Bottle”). 3. Tap the top of the induction seal liner to loosen any powder that may have adhered to the liner. 4. Carefully and slowly peel back the inner foil seal liner from the bottle. 5. Shake the Grape-Flavored Diluent (see Table 1) for a few seconds. 6. Remove the cap from the diluent bottle. 7. Carefully and slowly peel back the inner foil seal from the diluent bottle. 8. Transfer approximately one-half the contents of Grape-Flavored Diluent into the powder bottle. 9. Replace the powder bottle cap, tighten on to 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. 10. Re-open the powder bottle and add the remaining Grape-Flavored Diluent into the powder bottle. 11. 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. 12. Dispense the Powder Bottle containing reconstituted solution of vancomycin hydrochloride for oral solution to the patient [see Patient Counseling Information ( 17 )]. 13. Instruct the patient to shake the reconstituted solution of vancomycin hydrochloride for oral solution well before each use and to use an oral dosing device that measures the appropriate volume of the oral solution in milliliters. 14. Store reconstituted solutions of vancomycin hydrochloride for oral solution in the refrigerator, 2°C to 8°C (36°F to 46°F) when not in use 15. Discard the reconstituted solution of vancomycin hydrochloride for oral solution after 14 days, or if it appears hazy or contains particulates.

Vancomycin hydrochloride for oral solution is contraindicated in patients with known hypersensitivity to vancomycin. Hypersensitivity to vancomycin

The most common adverse reactions (≥ 10%) were nausea (17%), abdominal pain (15%) and hypokalemia (13%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-ASC-RX01 (877-272-7901); 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 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 * 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. 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 exanthematous pustulosis (AGEP), and linear lgA bullous dermatosis (LABD) [see Warnings and Precautions ( 5.5 )] , rashes (including exfoliative dermatitis). 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. Neutropenia appears to be promptly reversible when vancomycin is discontinued. Thrombocytopenia has been reported. Miscellaneous: Anaphylaxis, drug fever, chills, nausea, eosinophilia, and vasculitis have been reported with the administration of vancomycin. A condition has been reported with oral vancomycin 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.

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