Amoxicillin and Clavulanate Potassium

1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of Amoxicillin and Clavulanate Potassium Tablets and other antibacterial drugs, Amoxicillin and Clavulanate Potassium Tabletsshould be used only to treat 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. Amoxicillin and Clavulanate Potassium Tablets is a combination penicillin-class antibacterial and beta-lactamase inhibitor indicated in the treatment of infections due to susceptible isolates of the designated bacteria in the conditions listed below*: Amoxicillin and Clavulanate Potassium Tablets are a combination penicillin-class antibacterial and beta-lactamase inhibitor indicated for treatment of the following: Lower respiratory tract infections ( 1.1 ) Acute bacterial otitis media ( 1.2 ) Sinusitis ( 1.3 ) Skin and skin structure infections ( 1.4 ) Urinary tract infections ( 1.5 ) 1.1 Lower Respiratory Tract Infections - caused by beta-lactamase-producing isolates of Haemophilus influenzae and Moraxella catarrhalis . 1.2 Acute Bacterial Otitis Media - caused by beta-lactamase-producing isolates of H. influenzae and M. catarrhalis. 1.3 Sinusitis - caused by beta-lactamase-producing isolates of H. influenzae and M. catarrhalis . 1.4 Skin and Skin Structure Infections - caused by beta-lactamase-producing isolates of Staphylococcus aureus , Escherichia coli , and Klebsiella species. 1.5 Urinary Tract Infections - caused by beta-lactamase-producing isolates of E. coli , Klebsiella species, and Enterobacter species. 1.6 Limitations of Use - When susceptibility test results show susceptibility to amoxicillin, indicating no beta-lactamase production, Amoxicillin and Clavulanate Potassium Tablets should not be used.

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Anaphylactic reactions [see W arnings and Precautions ( 5.1 )] Hepatic Dysfunction [see W arnings and Precautions ( 5.2 )] CDAD [see W arnings and Precautions ( 5.3 )] The most frequently reported adverse effects were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%) ( 6.1 ) To REPORT SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-877-233-2001, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most frequently reported adverse reactions were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). Less than 3% of patients discontinued therapy because of drug-related adverse reactions. The overall incidence of adverse reactions, and in particular diarrhea, increased with the higher recommended dose. Other less frequently reported adverse reactions (<1%) include: Abdominal discomfort, flatulence, and headache. In pediatric patients (aged 2 months to 12 years), 1 US/Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of Amoxicillin and Clavulanate Potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of Amoxicillin and Clavulanate Potassium for 10 days in the treatment of acute otitis media. A total of 575 patients were enrolled, and only the suspension formulations were used in this trial. Overall, the adverse reactions seen were comparable to that noted above; however, there were differences in the rates of diarrhea, skin rashes/urticaria, and diaper area rashes. [See Clinical Studies ( 14.2 )] 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following have been identified during postmarketing use of Amoxicillin and Clavulanate Potassium Tablets. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Amoxicillin and Clavulanate Potassium Tablets. Gastrointestinal: Indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis . Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. [see W arnings and Precautions ( 5.3 )] Hypersensitivity Reactions: Pruritus, angioedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), erythema multiforme, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and cases of exfoliative dermatitis (including toxic epidermal necrolysis) have been reported. [see W arnings and Precautions ( 5.1 )] Liver: Hepatic dysfunction, including hepatitis and cholestatic jaundice, increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been reported with Amoxicillin and Clavulanate Potassium Tablets. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, is usually reversible. Deaths have been reported. [see Contraindications ( 4.2 ), W arnings and Precautions ( 5.2 )] Renal: Interstitial nephritis, hematuria, and crystalluria have been reported. [see Overdosage ( 10 )] Hemic and L ymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Thrombocytosis was noted in less than 1% of the patients treated with Amoxicillin and Clavulanate Potassium Tablets. There have been reports of increased prothrombin time in patients receiving Amoxicillin and Clavulanate Potassium Tablets and anticoagulant therapy concomitantly. [see Drug Interactions ( 7.2 )] Central Nervous System: Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported. Miscellaneous: Tooth discoloration (brown, yellow, or gray staining) has been reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases.

4 CONTRAINDICATIONS History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to Amoxicillin and Clavulanate Potassium Tablets or to other beta-lactams (e.g., penicillins or cephalosporins) ( 4 ) History of cholestatic jaundice/hepatic dysfunction associated with Amoxicillin and Clavulanate Potassium Tablets ( 4 ) 4.1 Serious Hypersensitivity Reactions Amoxicillin and Clavulanate Potassium Tablets are contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin, clavulanate or to other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins). 4.2 Cholestatic Jaundice/Hepatic Dysfunction Amoxicillin and Clavulanate Potassium Tablets are contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with Amoxicillin and Clavulanate Potassium Tablets.

11 DESCRIPTION Amoxicillin and Clavulanate Potassium Tablets, USP is an oral antibacterial combination consisting of amoxicillin and the beta-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is C 16 H 19 N 3 O 5 S•3H 2 O, and the molecular weight is 419.46. Chemically, amoxicillin is (2 S, 5 R, 6 R )-6-[( R )-(-)-2-Amino-2-( p- hydroxyphenyl) acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate and may be represented structurally as: Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a beta-lactam structurally related to the penicillins and possesses the ability to inactivate some beta-lactamases by blocking the active sites of these enzymes. The clavulanate potassium molecular formula is C 8 H 8 KNO 5 , and the molecular weight is 237.25. Chemically, clavulanate potassium is potassium (Z) (2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate and may be represented structurally as: Inactive Ingredients: Colloidal silicon dioxide, ethylcellulose, hypromellose, magnesium stearate, microcrystalline cellulose, propylene glycol, sodium starch glycolate, and titanium dioxide. Each tablet of amoxicillin/clavulanate potassium contains 0.63 mEq potassium. Structrual formula structural formula

2 DOSAGE AND ADMINISTRATION Amoxicillin and Clavulanate Potassium Tablets may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when Amoxicillin and Clavulanate Potassium Tablets is administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, Amoxicillin and Clavulanate Potassium Tablets should be taken at the start of a meal. Adults and Pediatric Patients > 40 kg: 875 mg every 12 hours ( 2.1 ) 2.1 Adults For severe infections and infections of the respiratory tract, the dose should be one 875-mg tablet of Amoxicillin and Clavulanate Potassium every 12 hours. 2.3 Patients with Renal Impairment Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Renal impairment patients with a glomerular filtration rate of <30 mL/min should not receive the 875-mg dose.

10 OVERDOSAGE In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. A prospective study of 51 pediatric patients at a poison-control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms 1 . Interstitial nephritis resulting in oliguric renal failure has been reported in patients after overdosage with amoxicillin/clavulanate potassium. Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin/ clavulanate potassium overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin/clavulanate potassium crystalluria. Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of amoxicillin/clavulanate potassium. Amoxicillin/clavulanate potassium may be removed from circulation by hemodialysis. [see Dosage and Administration ( 2.3 )]

7 DRUG INTERACTIONS Co-administration with probenecid is not recommended. ( 7.1 ) Concomitant use of Amoxicillin and Clavulanate Potassium Tablets and oral anticoagulants may increase the prolongation of prothrombin time. ( 7.2 ) Co-administration with allopurinol increases the risk of rash. ( 7.3 ) Amoxicillin and Clavulanate Potassium Tablets may reduce efficacy of oral contraceptives. ( 7.4 ) 7.1 Probenecid Probenecid decreases the renal tubular secretion of amoxicillin but does not delay renal excretion of clavulanic acid. Concurrent use with Amoxicillin and Clavulanate Potassium Tablets may result in increased and prolonged blood concentrations of amoxicillin. Coadministration of probenecid is not recommended. 7.2 Oral Anticoagulants Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been reported in patients receiving amoxicillin and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently with Amoxicillin and Clavulanate Potassium Tablets. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation. 7.3 Allopurinol The concurrent administration of allopurinol and amoxicillin increases the incidence of rashes in patients receiving both drugs as compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients. 7.4 Oral Contraceptives Amoxicillin and Clavulanate Potassium Tablets may affect intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives. 7.5 Effects on Laboratory Tests High urine concentrations of amoxicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST ® , Benedict’s Solution, or Fehling’s Solution. Since this effect may also occur with Amoxicillin and Clavulanate Potassium Tablets, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. Following administration of amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Amoxicillin and Clavulanate Potassium Tablets are antibacterial drugs. [see Microbiology 12.4 ] 12.3 Pharmacokinetics Mean amoxicillin and clavulanate potassium pharmacokinetic parameters in normal adults following administration of Amoxicillin and Clavulanate Potassium Tablets are shown in Table 1 and following administration of Amoxicillin and Clavulanate Potassium Powder for Oral Suspension and Chewable Tablets are shown in Table 2. Table 1: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters a,b with Amoxicillin and Clavulanate Potassium Tablets. Dose and Regimen C max (mcg/mL) AUC 0-24 (mcg*h/mL) Amoxicillin/Clavulanate potassium Amoxicillin Clavulanate potassium Amoxicillin Clavulanate potassium 250/125 mg every 8 hours 3.3 ± 1.12 1.5 ± 0.70 26.7 ± 4.56 12.6 ± 3.25 500/125 mg every 12 hours 6.5 ± 1.41 1.8 ± 0.61 33.4 ± 6.76 8.6 ± 1.95 500/125 mg every 8 hours 7.2 ± 2.26 2.4 ± 0.83 53.4 ± 8.87 15.7 ± 3.86 875/125 mg every 12 hours 11.6 ± 2.78 2.2 ± 0.99 53.5 ± 12.31 10.2 ± 3.04 a Mean (± standard deviation) values of 14 normal adults (N=15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose. b Amoxicillin/clavulanate potassium administered at the start of a light meal. Table 2: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters a,b with Amoxicillin and Clavulanate Potassium Powder for Oral Suspension and Chewable Tablets Dose C max (mcg/mL) AUC 0-24 (mcg*h/mL) Amoxicillin/Clavulanate potassium Amoxicillin Clavulanate potassium Amoxicillin Clavulanate potassium 400/57 mg (5 mL of suspension) 6.94 ± 1.24 1.10 ± 0.42 17.29 ± 2.28 2.34 ± 0.94 400/57 mg (1 chewable tablet) 6.67 ± 1.37 1.03 ± 0.33 17.24 ± 2.64 2.17 ± 0.73 a Mean (± standard deviation) values of 28 normal adults. Peak concentrations occurred approximately 1 hour after the dose. b Amoxicillin/clavulanate potassium administered at the start of a light meal. Oral administration of 5 mL of 250 mg/5 mL suspension of Amoxicillin and Clavulanate Potassium or the equivalent dose of 10 mL of 125 mg/5 mL suspension of Amoxicillin and Clavulanate Potassium provides average peak serum concentrations approximately 1 hour after dosing of 6.9 mcg/mL for amoxicillin and 1.6 mcg/mL for clavulanic acid. The areas under the serum concentration curves obtained during the first 4 hours after dosing were 12.6 mcg*h/mL for amoxicillin and 2.9 mcg*h/mL for clavulanic acid when 5 mL of 250 mg/5 mL suspension of Amoxicillin and Clavulanate Potassium or equivalent dose of 10 mL of 125 mg/5 mL suspension of Amoxicillin and Clavulanate Potassium were administered to normal adults. One 250-mg chewable tablet of Amoxicillin and Clavulanate Potassium or two 125-mg chewable tablets of Amoxicillin and Clavulanate Potassium are equivalent to 5 mL of 250 mg/5 mL suspension of Amoxicillin and Clavulanate Potassium and provide similar serum concentrations of amoxicillin and clavulanic acid. Amoxicillin serum concentrations achieved with Amoxicillin and Clavulanate Potassium Tablets are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. Time above the minimum inhibitory concentration of 1 mcg/mL for amoxicillin has been shown to be similar after corresponding every 12 hour and every 8 hour dosing regimens of Amoxicillin and Clavulanate Potassium Tablets in adults and children. Absorption: Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While Amoxicillin and Clavulanate Potassium Tablets can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In one study, the relative bioavailability of clavulanate was reduced when Amoxicillin and Clavulanate Potassium Tablets was dosed at 30 and 150 minutes after the start of a high-fat breakfast. Distribution: Neither component in Amoxicillin and Clavulanate Potassium Tablets are highly protein- bound; clavulanic acid is approximately 25% bound to human serum and amoxicillin approximately 18% bound. Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. Two hours after oral administration of a single 35 mg/kg dose of suspension of Amoxicillin and Clavulanate Potassium Tablets to fasting children, average concentrations of 3 mcg/mL of amoxicillin and 0.5 mcg/mL of clavulanic acid were detected in middle ear effusions. Metabolism and Excretion: The half-life of amoxicillin after the oral administration of Amoxicillin and Clavulanate Potassium Tablets is 1.3 hours and that of clavulanic acid is 1 hour. Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single 250-mg or 500-mg tablet of Amoxicillin and Clavulanate Potassium Tablets. 12.4 Microbiology Amoxicillin is a semisynthetic antibiotic with in vitro bactericidal activity against Gram-positive and Gram-negative bacteria. Amoxicillin is, however, susceptible to degradation by beta-lactamases, and therefore, the spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a beta-lactam, structurally related to the penicillins, which possesses the ability to inactivate some beta-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid- mediated beta-lactamases frequently responsible for transferred drug resistance. The formulation of amoxicillin and clavulanic acid in Amoxicillin and Clavulanate Potassium Tablets protects amoxicillin from degradation by some beta-lactamase enzymes and extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin. Amoxicillin/clavulanic acid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive bacteria Staphylococcus aureus Gram-negative bacteria Enterobacter species Escherichia coli Haemophilus influenza e Klebsiella species Moraxella catarrhalis The following in vitro data are available, but their clinical significance is unknown . At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for amoxicillin/clavulanic acid. However, the efficacy of amoxicillin/clavulanic acid in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials. Gram-positive bacteria Enterococcus faecalis Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus pneumoniae Streptococcus pyogenes Viridans group Streptococcus Gram-negative Bacteria Eikenella corrodens Proteus mirabilis Anaerobic Bacteria Bacteroides species including Bacteroides fragilis Fusobacterium species Peptostreptococcus species Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

12.1 Mechanism of Action Amoxicillin and Clavulanate Potassium Tablets are antibacterial drugs. [see Microbiology 12.4 ]

12.3 Pharmacokinetics Mean amoxicillin and clavulanate potassium pharmacokinetic parameters in normal adults following administration of Amoxicillin and Clavulanate Potassium Tablets are shown in Table 1 and following administration of Amoxicillin and Clavulanate Potassium Powder for Oral Suspension and Chewable Tablets are shown in Table 2. Table 1: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters a,b with Amoxicillin and Clavulanate Potassium Tablets. Dose and Regimen C max (mcg/mL) AUC 0-24 (mcg*h/mL) Amoxicillin/Clavulanate potassium Amoxicillin Clavulanate potassium Amoxicillin Clavulanate potassium 250/125 mg every 8 hours 3.3 ± 1.12 1.5 ± 0.70 26.7 ± 4.56 12.6 ± 3.25 500/125 mg every 12 hours 6.5 ± 1.41 1.8 ± 0.61 33.4 ± 6.76 8.6 ± 1.95 500/125 mg every 8 hours 7.2 ± 2.26 2.4 ± 0.83 53.4 ± 8.87 15.7 ± 3.86 875/125 mg every 12 hours 11.6 ± 2.78 2.2 ± 0.99 53.5 ± 12.31 10.2 ± 3.04 a Mean (± standard deviation) values of 14 normal adults (N=15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose. b Amoxicillin/clavulanate potassium administered at the start of a light meal. Table 2: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters a,b with Amoxicillin and Clavulanate Potassium Powder for Oral Suspension and Chewable Tablets Dose C max (mcg/mL) AUC 0-24 (mcg*h/mL) Amoxicillin/Clavulanate potassium Amoxicillin Clavulanate potassium Amoxicillin Clavulanate potassium 400/57 mg (5 mL of suspension) 6.94 ± 1.24 1.10 ± 0.42 17.29 ± 2.28 2.34 ± 0.94 400/57 mg (1 chewable tablet) 6.67 ± 1.37 1.03 ± 0.33 17.24 ± 2.64 2.17 ± 0.73 a Mean (± standard deviation) values of 28 normal adults. Peak concentrations occurred approximately 1 hour after the dose. b Amoxicillin/clavulanate potassium administered at the start of a light meal. Oral administration of 5 mL of 250 mg/5 mL suspension of Amoxicillin and Clavulanate Potassium or the equivalent dose of 10 mL of 125 mg/5 mL suspension of Amoxicillin and Clavulanate Potassium provides average peak serum concentrations approximately 1 hour after dosing of 6.9 mcg/mL for amoxicillin and 1.6 mcg/mL for clavulanic acid. The areas under the serum concentration curves obtained during the first 4 hours after dosing were 12.6 mcg*h/mL for amoxicillin and 2.9 mcg*h/mL for clavulanic acid when 5 mL of 250 mg/5 mL suspension of Amoxicillin and Clavulanate Potassium or equivalent dose of 10 mL of 125 mg/5 mL suspension of Amoxicillin and Clavulanate Potassium were administered to normal adults. One 250-mg chewable tablet of Amoxicillin and Clavulanate Potassium or two 125-mg chewable tablets of Amoxicillin and Clavulanate Potassium are equivalent to 5 mL of 250 mg/5 mL suspension of Amoxicillin and Clavulanate Potassium and provide similar serum concentrations of amoxicillin and clavulanic acid. Amoxicillin serum concentrations achieved with Amoxicillin and Clavulanate Potassium Tablets are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. Time above the minimum inhibitory concentration of 1 mcg/mL for amoxicillin has been shown to be similar after corresponding every 12 hour and every 8 hour dosing regimens of Amoxicillin and Clavulanate Potassium Tablets in adults and children. Absorption: Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While Amoxicillin and Clavulanate Potassium Tablets can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In one study, the relative bioavailability of clavulanate was reduced when Amoxicillin and Clavulanate Potassium Tablets was dosed at 30 and 150 minutes after the start of a high-fat breakfast. Distribution: Neither component in Amoxicillin and Clavulanate Potassium Tablets are highly protein- bound; clavulanic acid is approximately 25% bound to human serum and amoxicillin approximately 18% bound. Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. Two hours after oral administration of a single 35 mg/kg dose of suspension of Amoxicillin and Clavulanate Potassium Tablets to fasting children, average concentrations of 3 mcg/mL of amoxicillin and 0.5 mcg/mL of clavulanic acid were detected in middle ear effusions. Metabolism and Excretion: The half-life of amoxicillin after the oral administration of Amoxicillin and Clavulanate Potassium Tablets is 1.3 hours and that of clavulanic acid is 1 hour. Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single 250-mg or 500-mg tablet of Amoxicillin and Clavulanate Potassium Tablets.

20240618

3

3 DOSAGE FORMS AND STRENGTHS Amoxicillin and Clavulanate Potassium Tablets, USP 875-mg/125-mg T ablets : Each scored white capsule-shaped tablet, debossed with WW949 on the upper side and scored on the other side, contains 875 mg amoxicillin and 125 mg clavulanic acid as the potassium salt. Formulations and amoxicillin/clavulanate content are: Tablets: 875 mg/125 mg. Tablets are scored. ( 3 )

Amoxicillin and Clavulanate Potassium Amoxicillin and Clavulanate Potassium SILICON DIOXIDE ETHYLCELLULOSES HYPROMELLOSES MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE PROPYLENE GLYCOL SODIUM STARCH GLYCOLATE TYPE A POTATO TITANIUM DIOXIDE AMOXICILLIN AMOXICILLIN ANHYDROUS CLAVULANATE POTASSIUM CLAVULANIC ACID WW949

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate carcinogenic potential. Amoxicillin and Clavulanate Potassium Tablets (4:1 ratio formulation of amoxicillin:clavulanate) was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and Clavulanate Potassium Tablets was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. Amoxicillin and Clavulanate Potassium Tablets was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. Amoxicillin and Clavulanate Potassium Tablets (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses of up to 1,200 mg/kg/day was found to have no effect on fertility and reproductive performance in rats. Based on body surface area, this dose of amoxicillin is approximately 4 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, the dose multiple is approximately 9 times higher than the maximum recommended adult human oral dose (125 mg every 8 hours), also based on body surface area.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate carcinogenic potential. Amoxicillin and Clavulanate Potassium Tablets (4:1 ratio formulation of amoxicillin:clavulanate) was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and Clavulanate Potassium Tablets was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. Amoxicillin and Clavulanate Potassium Tablets was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. Amoxicillin and Clavulanate Potassium Tablets (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses of up to 1,200 mg/kg/day was found to have no effect on fertility and reproductive performance in rats. Based on body surface area, this dose of amoxicillin is approximately 4 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, the dose multiple is approximately 9 times higher than the maximum recommended adult human oral dose (125 mg every 8 hours), also based on body surface area.

ANDA203824

Amoxicillin and Clavulanate Potassium

Amoxicillin and Clavulanate Potassium

68071-4967

HUMAN PRESCRIPTION DRUG

ORAL

12.4 Microbiology Amoxicillin is a semisynthetic antibiotic with in vitro bactericidal activity against Gram-positive and Gram-negative bacteria. Amoxicillin is, however, susceptible to degradation by beta-lactamases, and therefore, the spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a beta-lactam, structurally related to the penicillins, which possesses the ability to inactivate some beta-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid- mediated beta-lactamases frequently responsible for transferred drug resistance. The formulation of amoxicillin and clavulanic acid in Amoxicillin and Clavulanate Potassium Tablets protects amoxicillin from degradation by some beta-lactamase enzymes and extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin. Amoxicillin/clavulanic acid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive bacteria Staphylococcus aureus Gram-negative bacteria Enterobacter species Escherichia coli Haemophilus influenza e Klebsiella species Moraxella catarrhalis The following in vitro data are available, but their clinical significance is unknown . At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for amoxicillin/clavulanic acid. However, the efficacy of amoxicillin/clavulanic acid in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials. Gram-positive bacteria Enterococcus faecalis Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus pneumoniae Streptococcus pyogenes Viridans group Streptococcus Gram-negative Bacteria Eikenella corrodens Proteus mirabilis Anaerobic Bacteria Bacteroides species including Bacteroides fragilis Fusobacterium species Peptostreptococcus species Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

PDP

17 PATIENT COUNSELING INFORMATION

14 CLINICAL STUDIES 14.1 Lower Respiratory Tract and Complicated Urinary Tract Infections Data from 2 pivotal trials in 1,191 patients treated for either lower respiratory tract infections or complicated urinary tract infections compared a regimen of 875-mg tablets of Amoxicillin and Clavulanate Potassium every 12 hours to 500-mg tablets of Amoxicillin and Clavulanate Potassium dosed every 8 hours (584 and 607 patients, respectively). Comparable efficacy was demonstrated between the every 12 hours and every 8 hours dosing regimens. There was no significant difference in the percentage of adverse events in each group. The most frequently reported adverse event was diarrhea; incidence rates were similar for the 875-mg every 12 hours and 500-mg every 8 hours dosing regimens (15% and 14%, respectively); however, there was a statistically significant difference (p < 0.05) in rates of severe diarrhea or withdrawals with diarrhea between the regimens: 1% for 875-mg every 12 hours regimen versus 2% for the 500-mg every 8 hours regimen. In one of these pivotal trials, patients with either pyelonephritis (n = 361) or a complicated urinary tract infection (i.e., patients with abnormalities of the urinary tract that predispose to relapse of bacteriuria following eradication, n = 268) were randomized (1:1) to receive either 875-mg tablets of Amoxicillin and Clavulanate Potassium every 12 hours (n=308) or 500-mg tablets of Amoxicillin and Clavulanate Potassium every 8 hours (n=321). The number of bacteriologically evaluable patients was comparable between the two dosing regimens. Amoxicillin and Clavulanate Potassium produced comparable bacteriological success rates in patients assessed 2 to 4 days immediately following end of therapy. The bacteriologic efficacy rates were comparable at one of the follow-up visits (5 to 9 days post-therapy) and at a late post-therapy visit (in the majority of cases, this was 2 to 4 weeks post-therapy), as seen in Table 5. Table 5: Bacteriologic efficacy rates for Amoxicillin and Clavulanate Potassium T ime Post Therapy 875 mg every 12 hours % (n) 500 mg every 8 hours % (n) 2 to 4 days 81% (58) 80% (54) 5 to 9 days 58% (41) 52% (52) 2 to 4 weeks 52% (101) 55% (104) As noted before, though there was no significant difference in the percentage of adverse events in each group, there was a statistically significant difference in rates of severe diarrhea or withdrawals with diarrhea between the regimens. 14.2 Acute Bacterial Otitis Media and Diarrhea in Pediatric Patients One US/Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of Amoxicillin and Clavulanate Potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of Amoxicillin and Clavulanate Potassium for 10 days in the treatment of acute otitis media. Only the suspension formulations were used in this trial. A total of 575 pediatric patients (aged 2 months to 12 years) were enrolled, with an even distribution among the 2 treatment groups and a comparable number of patients were evaluable (i.e., ≥ 84%) per treatment group. Otitis media-specific criteria were required for eligibility and a strong correlation was found at the end of therapy and follow-up between these criteria and physician assessment of clinical response. The clinical efficacy rates at the end of therapy visit (defined as 2-4 days after the completion of therapy) and at the follow-up visit (defined as 22-28 days post-completion of therapy) were comparable for the 2 treatment groups, with the following cure rates obtained for the evaluable patients: At end of therapy, 87% (n = 265) and 82% (n = 260) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. At follow-up, 67% (n = 249) and 69% (n = 243) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. Diarrhea was defined as either: (a) 3 or more watery or 4 or more loose/watery stools in 1 day; OR (b) 2 watery stools per day or 3 loose/watery stools per day for 2 consecutive days. The incidence of diarrhea was significantly lower in patients who received the every 12 hours regimen compared to patients who received the every 8 hours regimen (14% and 34%, respectively). In addition, the number of patients with either severe diarrhea or who were withdrawn with diarrhea was significantly lower in the every 12 hours treatment group (3% and 8% for the every 12 hours/10 day and every 8 hours/10 day, respectively). In the every 12 hours treatment group, 3 patients (1%) were withdrawn with an allergic reaction, while 1 patient in the every 8 hours group was withdrawn for this reason. The number of patients with a candidal infection of the diaper area was 4% and 6% for the every 12 hours and every 8 hours groups, respectively. It is not known if the finding of a statistically significant reduction in diarrhea with the oral suspensions dosed every 12 hours, versus suspensions dosed every 8 hours, can be extrapolated to the chewable tablets. The presence of mannitol in the chewable tablets may contribute to a different diarrhea profile. The every 12 hour oral suspensions (200 mg/5 mL and 400 mg/5 mL) are sweetened with aspartame.

15 REFERENCES 1. Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and cephalosporin ingestions in children less than six years of age.Vet Hum Toxicol. 1988; 30: 66-67.

8.5 Geriatric Use Of the 3,119 patients in an analysis of clinical studies of Amoxicillin and Clavulanate Potassium Tablets, 32% were ≥65 years old, and 14% were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.2 Labor and Delivery Oral ampicillin-class antibiotics are poorly absorbed during labor. It is not known whether use of amoxicillin/clavulanate potassium in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood of the necessity for an obstetrical intervention.

8.3 Nursing Mothers Amoxicillin has been shown to be excreted in human milk. Amoxicillin/clavulanate potassium use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin/ clavulanate potassium is administered to a nursing woman.

8.4 Pediatric Use The safety and effectiveness of Amoxicillin and Clavulanate Potassium Powder for Oral Suspension and Chewable Tablets have been established in pediatric patients. Use of Amoxicillin and Clavulanate Potassium in pediatric patients is supported by evidence from studies of Amoxicillin and Clavulanate Potassium Tablets in adults with additional data from a study of Amoxicillin and Clavulanate Potassium Powder for Oral Suspension in pediatric patients aged 2 months to 12 years with acute otitis media. [ see Clinical Studies ( 14.2 ) ] Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed; clavulanate elimination is unaltered in this age group. Dosing of Amoxicillin and Clavulanate Potassium Tablets should be modified in pediatric patients aged <12 weeks (<3 months). [see Dosage and Administration (2.2)]

8.1 Pregnancy Teratogenic Effects: Pregnancy Category B. Reproduction studies performed in pregnant rats and mice given Amoxicillin and Clavulanate Potassium Tablets (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses up to 1200 mg/kg/day revealed no evidence of harm to the fetus due to Amoxicillin and Clavulanate Potassium Tablets. The amoxicillin doses in rats and mice (based on body surface area) were approximately 4 and 2 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, these dose multiples were approximately 9 and 4 times the maximum recommended adult human oral dose (125 mg every 8 hours). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8 USE IN SPECIFIC POPULATIONS Pediatric Use: Modify dose in patients 12 weeks or younger. ( 8.4 ) Renal impairment; Dosage adjustment is recommended for severe renal impairment (GFR< 30mL/min). ( 2.3 , 8.6 ) 8.1 Pregnancy Teratogenic Effects: Pregnancy Category B. Reproduction studies performed in pregnant rats and mice given Amoxicillin and Clavulanate Potassium Tablets (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses up to 1200 mg/kg/day revealed no evidence of harm to the fetus due to Amoxicillin and Clavulanate Potassium Tablets. The amoxicillin doses in rats and mice (based on body surface area) were approximately 4 and 2 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, these dose multiples were approximately 9 and 4 times the maximum recommended adult human oral dose (125 mg every 8 hours). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 8.2 Labor and Delivery Oral ampicillin-class antibiotics are poorly absorbed during labor. It is not known whether use of amoxicillin/clavulanate potassium in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood of the necessity for an obstetrical intervention. 8.3 Nursing Mothers Amoxicillin has been shown to be excreted in human milk. Amoxicillin/clavulanate potassium use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin/ clavulanate potassium is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of Amoxicillin and Clavulanate Potassium Powder for Oral Suspension and Chewable Tablets have been established in pediatric patients. Use of Amoxicillin and Clavulanate Potassium in pediatric patients is supported by evidence from studies of Amoxicillin and Clavulanate Potassium Tablets in adults with additional data from a study of Amoxicillin and Clavulanate Potassium Powder for Oral Suspension in pediatric patients aged 2 months to 12 years with acute otitis media. [ see Clinical Studies ( 14.2 ) ] Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed; clavulanate elimination is unaltered in this age group. Dosing of Amoxicillin and Clavulanate Potassium Tablets should be modified in pediatric patients aged <12 weeks (<3 months). [see Dosage and Administration (2.2)] 8.5 Geriatric Use Of the 3,119 patients in an analysis of clinical studies of Amoxicillin and Clavulanate Potassium Tablets, 32% were ≥65 years old, and 14% were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Dosing in Renal Impairment Amoxicillin is primarily eliminated by the kidney and dosage adjustment is usually required in patients with severe renal impairment (GFR <30 mL/min). See Patients with Renal Impairment (2.3) for specific recommendations in patients with renal impairment.

16 HOW SUPPLIED/STORAGE AND HANDLING Amoxicillin and Clavulanate Potassium Tablets, USP 875mg/125mg : Each scored white capsule-shaped tablet, debossed with WW949 on the upper side and scored on the other side, contains 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt. NDC 68071-4967-2 BOTTLES OF 20 Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP, with a child-resistant closure (as required). Advise patients to keep in a closed container. KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.