Vancocin

1 INDICATIONS AND USAGE VANCOCIN is indicated for the treatment of Clostridioides difficil e-associated diarrhea. VANCOCIN is 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, VANCOCIN must be given orally for these infections. • Orally administered VANCOCIN is not effective for other types of infections. To reduce the development of drug-resistant bacteria and maintain the effectiveness of VANCOCIN and other antibacterial drugs, VANCOCIN 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. VANCOCIN is 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, vancocin must be given orally for these infections. • Orally administered VANCOCIN is not effective for other types of infections. To reduce the development of drug-resistant bacteria and maintain the effectiveness of VANCOCIN and other antibacterial drugs, VANCOCIN 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 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 ) • Staphylococcal enterocolitis: • 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 ) 2.1 Adults VANCOCIN 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.

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

5 WARNINGS AND PRECAUTIONS • VANCOCIN must be given orally for treatment of staphylococcal enterocolitis and C. difficile -associated diarrhea. Orally administered VANCOCIN is not effective for other types of infections. ( 5.1 ) • Clinically significant serum concentrations have been reported in some patients who have taken multiple oral doses of VANCOCIN for active C. difficile -associated diarrhea. Monitoring of serum concentrations may be appropriate in some instances. ( 5.2 ) • Nephrotoxicity has occurred following oral VANCOCIN therapy and can occur either during or after completion of therapy. The risk is increased in geriatric patients. ( 5.3 ) Monitor renal function. • Ototoxicity has occurred in patients receiving VANCOCIN. ( 5.4 ) Assessment of auditory function may be appropriate in some instances. • Severe Dermatologic Reactions: Discontinue VANCOCIN at the first appearance of skin rashes, mucosal lesions, or blisters. ( 5.5 ) • Prescribing VANCOCIN 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. ( 5.6 ) 5.1 Oral Use Only VANCOCIN for the treatment of colitis is for oral use only and is not systemically absorbed. VANCOCIN must be given orally for treatment of staphylococcal enterocolitis and Clostridioides difficile- associated diarrhea. Orally administered VANCOCIN 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 VANCOCIN 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 VANCOCIN; 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 VANCOCIN 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 VANCOCIN 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 VANCOCIN at the first appearance of signs and symptoms of TEN, SJS, DRESS, AGEP, or LABD. 5.6 Development of Drug-Resistant Bacteria Prescribing VANCOCIN 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.

7 DRUG INTERACTIONS No drug interaction studies have been conducted.

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 ANI Pharmaceuticals, Inc. at 1-855-204-1431 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 VANCOCIN in 260 adult subjects in two Phase 3 clinical trials for the treatment of diarrhea associated with C. difficile. In both trials, subjects received VANCOCIN 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 VANCOCIN-treated subjects are shown in Table 1 . The most common adverse reactions associated with VANCOCIN (≥10%) were nausea, abdominal pain, and hypokalemia. Table 1: Common (≥5%) Adverse Reactions a for VANCOCIN Reported in Clinical Trials for Treatment of Diarrhea Associated with C. difficile a Adverse reaction rates were derived from the incidence of treatment-emergent adverse events. System/Organ Class Adverse Reaction VANCOCIN % (N=260) Gastrointestinal disorders Nausea Abdominal pain Vomiting Diarrhea Flatulence 17 15 9 9 8 General disorders and administration site conditions Pyrexia Edema peripheral Fatigue 9 6 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 VANCOCIN. Nephrotoxicity following VANCOCIN typically first occurred within one week after completion of treatment (median day of onset was Day 16). Nephrotoxicity following VANCOCIN 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 VANCOCIN. The most common adverse events leading to discontinuation of VANCOCIN 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 VANCOCIN. 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 IgA 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 for several dozen patients. Neutropenia appears to be promptly reversible when vancomycin is discontinued. Thrombocytopenia has been reported. Miscellaneous : Patients have been reported to have had anaphylaxis, drug fever, chills, nausea, eosinophilia, and cases of vasculitis in association with the administration of vancomycin. A condition has been reported 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 Systemic absorption of vancomycin is low following oral administration of VANCOCIN; 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 0.8 880 mg/m2 or 0.74 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).