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 each use and to use an oral dosing device that measures the appropriate volume of the oral solution in milliliters. Store the reconstituted solution of vancomycin hydrochloride at refrigerated conditions, 2°C to 8°C (36°F to 46°F) when not in use. Discard the reconstituted solution of vancomycin hydrochloride after 14 days, or if it appears hazy or contains particulates.

4 CONTRAINDICATIONS Vancomycin hydrochloride is contraindicated in patients with known hypersensitivity to vancomycin. Hypersensitivity to vancomycin ( 4 )

5 WARNINGS AND PRECAUTIONS Vancomycin hydrochloride must be given orally for treatment of C. difficile ‑associated diarrhea and staphylococcal enterocolitis. Orally administered vancomycin hydrochloride is not effective for treatment of other types of infections. ( 5.1 ) Clinically significant serum concentrations have been reported in some patients who have taken multiple oral doses of vancomycin hydrochloride for C. difficile ‑associated diarrhea. Monitoring of serum concentrations may be appropriate in some instances. ( 5.2 ) Nephrotoxicity has occurred following oral vancomycin hydrochloride therapy and can occur either during or after completion of therapy. The risk is increased in geriatric patients. Monitor renal function. ( 5.3 ) Ototoxicity has occurred in patients receiving vancomycin hydrochloride. Assessment of auditory function may be appropriate in some instances. ( 5.4 ) Severe Dermatologic Reactions: Discontinue vancomycin hydrochloride at the first appearance of skin rashes, mucosal lesions, or blisters. ( 5.5 ) Prescribing vancomycin hydrochloride 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. ( 5.7 ) 5.1 Oral Use Only Vancomycin hydrochloride must be given orally for treatment of C. difficile ‑associated diarrhea and staphylococcal enterocolitis. Orally administered vancomycin is not effective for treatment of other types of infections. Parenteral administration of vancomycin is not effective for treatment of C. difficile ‑associated diarrhea and staphylococcal enterocolitis. If parenteral vancomycin therapy is desired, use an intravenous preparation of vancomycin and consult the Full Prescribing Information accompanying that preparation. 5.2 Potential for Systemic Absorption Significant systemic absorption has been reported in some patients (e.g., patients with renal insufficiency and/or colitis) who have taken multiple oral doses of vancomycin hydrochloride for C. difficile ‑associated diarrhea. In these patients, serum vancomycin concentrations reached therapeutic levels for the treatment of systemic infections. 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; 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 antibacterial drug. 5.3 Nephrotoxicity Nephrotoxicity (e.g., reports of renal failure, renal impairment, blood creatinine increased) has occurred following oral vancomycin hydrochloride therapy in randomized controlled clinical trials and can occur either during or after completion of therapy. The risk of nephrotoxicity is increased in patients over 65 years of age [ see Adverse Reactions ( 6.1 ) and Use in Specific Populations ( 8.5 ) ]. 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. 5.4 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 high 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 lgA 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 at the first appearance of signs and symptoms of TEN, SJS, DRESS, AGEP, or LABD. 5.6 Potential for Microbial Overgrowth Use of vancomycin hydrochloride may result in the overgrowth of non‑susceptible bacteria. If superinfection occurs during therapy, appropriate measures should be taken. 5.7 Development of Drug-Resistant Bacteria Prescribing vancomycin hydrochloride 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. 5.8 Hemorrhagic Occlusive Retinal Vasculitis (HORV) Hemorrhagic occlusive retinal vasculitis, including permanent loss of vision, occurred in patients receiving intracameral or intravitreal administration of vancomycin during or after cataract surgery. The safety and efficacy of vancomycin administered by the intracameral or intravitreal route have not been established by adequate and well‑controlled studies. Vancomycin is not indicated for prophylaxis of endophthalmitis.

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

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 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 (“vancomycin infusion reaction”), pain and muscle spasm of the chest and back. These reactions usually resolve within 20 minutes but may persist for several hours.

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).