Amoxicillin And Clavulanate Potassium

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

2 DOSAGE AND ADMINISTRATION Adults and Pediatric Patients greater than 40 kg: 500 or 875 mg every 12 hours or 250 or 500 mg every 8 hours, based on the amoxicillin component. ( 2.2 , 2.3 ) Pediatric patients aged 12 weeks (3 months) and older: 25 to 45 mg/kg/day every 12 hours or 20 to 40 mg/kg/day every 8 hours, up to the adult dose. ( 2.3 ) Neonates and infants less than 12 weeks of age: 30 mg/kg/day divided every 12 hours, based on the amoxicillin component. Use of the 125 mg/5 mL oral suspension is recommended. ( 2.3 ) 2.1 Important Administration Instructions Amoxicillin and Clavulanate Potassium may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when Amoxicillin and Clavulanate Potassium is administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, Amoxicillin and Clavulanate Potassium should be taken at the start of a meal. 2.2 Adult Patients See dosing regimens of Amoxicillin and Clavulanate Potassium (based on the amoxicillin component) provided in Table 1 below. Table 1. Dosing Regimens of Amoxicillin and Clavulanate Potassium in Adult Patients TYPE OF INFECTION DOSING REGIMEN OF Amoxicillin and Clavulanate Potassium Severe infections and infections of the respiratory tract one 875 mg tablet a of Amoxicillin and Clavulanate Potassium every 12 hours or one 500 mg tablet b,c of Amoxicillin and Clavulanate Potassium every 8 hours Less severe infections one 500 mg tablet b,c of Amoxicillin and Clavulanate Potassium every 12 hours or one 250 mg tablet d of Amoxicillin and Clavulanate Potassium every 8 hours a Adults who have difficulty swallowing may be given the Amoxicillin and Clavulanate Potassium 200 mg/28.5 mg per 5 mL suspension or the Amoxicillin and Clavulanate Potassium 400 mg/57 mg per 5 mL suspension may be used in place of the 875 mg/125 mg tablet. b Adults who have difficulty swallowing may be given the Amoxicillin and Clavulanate Potassium 125 mg/31.25 mg per 5 mL or Amoxicillin and Clavulanate Potassium 250 mg/62.5 mg per 5 mL suspension in place of the 500 mg/125 mg tablet. c Two Amoxicillin and Clavulanate Potassium 250 mg/125 mg tablets are NOT substitutable with one 500 mg/125 mg Amoxicillin and Clavulanate Potassium tablet [see Dosage and Administration ( 2.6 )] . d Amoxicillin and Clavulanate Potassium 250 mg/125 mg tablet is NOT substitutable with Amoxicillin and Clavulanate Potassium 250 mg/62.5 mg chewable tablet [see Dosage and Administration ( 2.6 )] 2.3 Pediatric Patients Based on the amoxicillin component, Amoxicillin and Clavulanate Potassium should be dosed as follows: Neonates and Infants Aged less than 12 weeks (less than 3 months) : See dosing regimens of Amoxicillin and Clavulanate Potassium provided in Table 2 below. Table 2: Dosing Regimens of Amoxicillin and Clavulanate Potassium in Neonates and Infants Aged Less than 12 Weeks (Less than 3 Months) PATIENT POPULATION DOSING REGIMEN Amoxicillin and Clavulanate Potassium 125 mg/31.25 mg per 5 mL for oral suspension a Neonates and Infants aged less than 12 weeks (less than 3 months) 30 mg/kg/day every 12 hours a Experience with the Amoxicillin and Clavulanate Potassium 200 mg/28.5 mg per 5 mL formulation in this age group is limited, and thus, use of the Amoxicillin and Clavulanate Potassium 125 mg/31.25 mg per 5 mL for oral suspension is recommended. Patients Aged 12 weeks (3 months) and Older and Weighing Less than 40 kg : See dosing regimens provided in Table 3 below. The every 12 hour regimen is recommended as it is associated with significantly less diarrhea [see Clinical Studies ( 14.2 )] . The Amoxicillin and Clavulanate Potassium 200 mg/28.5 mg per 5 mL and Amoxicillin and Clavulanate Potassium 400 mg/57 mg per 5 mL) for oral suspension and Amoxicillin and Clavulanate Potassium 200 mg/28.5 mg and Amoxicillin and Clavulanate Potassium 400 mg/57 mg chewable tablets contain aspartame and should not be used by phenylketonurics. [see Warnings and Precautions ( 5.7 )]. Table 3: Dosing in Patients Aged 12 Weeks (3 Months) and Older and Weighing Less than 40 kg a Each strength of Amoxicillin and Clavulanate Potassium oral suspension is available as a chewable tablet for use by older children. b Duration of therapy studied and recommended for acute otitis media is 10 days. INFECTION DOSING REGIMEN Every 12 hours Every 8 hours Amoxicillin and Clavulanate Potassium 200 mg/28.5 mg per 5 mL or Amoxicillin and Clavulanate Potassium 400 mg/57 mg per 5 mL oral suspension a Amoxicillin and Clavulanate Potassium 125 mg/31.25 mg per 5 mL or Amoxicillin and Clavulanate Potassium 250 mg/62.5 mg per 5 mL oral suspension a Otitis media b , sinusitis, lower respiratory tract infections, and more severe infections 45 mg/kg/day every 12 hours 40 mg/kg/day every 8 hours Less severe infections 25 mg/kg/day every 12 hours 20 mg/kg/day every 8 hours Patients Weighing 40 kg or More : Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations. The 250 mg/125 mg tablet of Amoxicillin and Clavulanate Potassium should NOT be used until the child weighs at least 40 kg, due to the different amoxicillin to clavulanic acid ratios in the 250 mg/125 mg tablet of Amoxicillin and Clavulanate Potassium versus the 250 mg/62.5 mg chewable tablet of Amoxicillin and Clavulanate Potassium. 2.4 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 (GFR) of less than 30 mL/min should NOT receive the 875 mg dose (based on the amoxicillin component) of Amoxicillin and Clavulanate Potassium. See dosing regimens in patients with severe renal impairment provided in Table 4. Table 4. Dosing Regimens of Amoxicillin and Clavulanate Potassium in Patients with Severe Renal Impairment Patients with Renal Impairment Dosing Regimen GFR 10 mL/min to 30 mL/min 500 mg or 250 mg every 12 hours, depending on the severity of the infection GFR less than 10 mL/min 500 mg or 250 mg every 24 hours, depending on severity of the infection Hemodialysis 500 mg or 250 mg every 24 hours, depending on severity of the infection Administer an additional dose both during and at the end of dialysis 2.5 Directions for Mixing Amoxicillin and Clavulanate Potassium for Oral Suspension Prepare Amoxicillin and Clavulanate Potassium for oral suspension at time of dispensing as follows: Tap bottle until all powder flows freely. Measure a total (see Table 5 below for total amount of water for reconstitution) OF WATER. Add approximately 2/3 of the water to the powder. Replace cap and shake VIGOROUSLY. Add remaining water. Replace cap and shake VIGOROUSLY. Table 5: Amount of Water for Mixing Amoxicillin and Clavulanate Potassium for Oral Suspension Strength of Amoxicillin and Clavulanate Potassiumfor Oral Suspension Bottle Size Amount of Water for Reconstitution Contents of Each Teaspoonful (5 mL) 125 mg/31.25 mg per 5 mL 75 mL 100 mL 150 mL 67 mL 90 mL 134 mL 125 mg of amoxicillin and 31.25 mg of clavulanic acid as the potassium salt 200 mg/28.5 mg per 5 mL 50 mL 75 mL 100 mL 50 mL 75 mL 95 mL 200 mg of amoxicillin and 28.5 mg of clavulanic acid as the potassium salt 250 mg/62.5 mg per 5 mL 75 mL 100 mL 150 mL 65 mL 87 mL 130 mL 250 mg of amoxicillin and 62.5 mg of clavulanic acid as the potassium salt 400 mg/57 mg per 5 mL 50 mL 75 mL 100 mL 50 mL 70 mL 90 mL 400 mg of amoxicillin and 57 mg of clavulanic acid as the potassium salt Shake oral suspension well before using. Reconstituted suspension must be stored under refrigeration and discarded after 10 days. Some color change is normal during dosing period. 2.6 Switching between Dosage Forms and between Strengths Amoxicillin and Clavulanate Potassium 250 mg/125 mg Tablet is NOT Substitutable with Amoxicillin and Clavulanate Potassium 250 mg/62.5 mg Chewable Tablet The 250 mg/125 mg tablet of Amoxicillin and Clavulanate Potassium and the 250 mg/62.5 mg chewable tablet of Amoxicillin and Clavulanate Potassium should NOT be substituted for each other and the 250 mg/125 mg tablet of Amoxicillin and Clavulanate Potassium should NOT be used in pediatric patients weighing less than 40 kg [see Dosage and Administration ( 2.3 )] . The 250 mg tablet of Amoxicillin and Clavulanate Potassium and the 250 mg chewable tablet of Amoxicillin and Clavulanate Potassium do not contain the same amount of clavulanic acid. The 250 mg tablet of Amoxicillin and Clavulanate Potassium contains 125 mg of clavulanic acid whereas the 250 mg chewable tablet of Amoxicillin and Clavulanate Potassium contains 62.5 mg of clavulanic acid. Two Amoxicillin and Clavulanate Potassium 250 mg/125 mg Tablets are NOT Substitutable with One 500 mg/125 mg Amoxicillin and Clavulanate Potassium Tablet Two 250 mg/125 mg tablets of Amoxicillin and Clavulanate Potassium should NOT be substituted for one 500 mg/125 mg tablet of Amoxicillin and Clavulanate Potassium. Since both the 250 mg and 500 mg tablets of Amoxicillin and Clavulanate Potassium contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250 mg tablets of Amoxicillin and Clavulanate Potassium are not equivalent to one 500 mg tablet of Amoxicillin and Clavulanate Potassium.

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Anaphylactic reactions [see Warnings and Precautions (5.1) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.2 )] Hepatic Dysfunction [see Warnings and Precautions (5.3) ] Clostridioides difficile Associated Diarrhea (CDAD) [see Warnings and Precautions (5.4) ] 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 USAntibiotics, LLC at 1-844-454-5532 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial 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 (less than 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. 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. 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 antibacterial treatment. [see Warnings and Precautions ( 5.4 )] . Immune: Hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock), angioedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), hypersensitivity vasculitis [see Warnings and Precautions ( 5.1 )] . Skin and Appendages: Rashes, pruritus, urticaria, erythema multiforme, SJS, TEN, DRESS, AGEP, exfoliative dermatitis [see Warnings and Precautions ( 5.2 )] . 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. 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 ), Warnings and Precautions ( 5.3 )] . Renal: Interstitial nephritis, hematuria, and crystalluria have been reported [see Overdosage ( 10 )] . Hemic and Lymphatic 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. There have been reports of increased prothrombin time in patients receiving Amoxicillin and Clavulanate Potassium and anticoagulant therapy concomitantly [see Drug Interactions ( 7.2 )] . Central Nervous System: Agitation, anxiety, behavioral changes, aseptic meningitis, 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.

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 6 and following administration of Amoxicillin and Clavulanate Potassium for Oral Suspension and Chewable Tablets are shown in Table 7. Table 6: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters a,b with Amoxicillin and Clavulanate Potassium Tablets a Mean (± standard deviation) values of 14 normal adults (N equals15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose. b Amoxicillin and clavulanate potassium administered at the start of a light meal. Dose and Regimen of Amoxicillin and Clavulanate C max (mcg/mL) AUC 0-24 (mcg*h/mL) Amoxicillin and Clavulanate potassium Amoxicillin Clavulanate potassium Amoxicillin Clavulanate potassium 250 mg/125 mg every 8 hours 3.3 ± 1.12 1.5 ± 0.70 26.7 ± 4.56 12.6 ± 3.25 500 mg/125 mg every 12 hours 6.5 ± 1.41 1.8 ± 0.61 33.4 ± 6.76 8.6 ± 1.95 500 mg/125 mg every 8 hours 7.2 ± 2.26 2.4 ± 0.83 53.4 ± 8.87 15.7 ± 3.86 875 mg/125 mg every 12 hours 11.6 ± 2.78 2.2 ± 0.99 53.5 ± 12.31 10.2 ± 3.04 Table 7: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters a,b with Amoxicillin and Clavulanate Potassium for Oral Suspension and Chewable Tablets a Mean (± standard deviation) values of 28 normal adults. Peak concentrations occurred approximately 1 hour after the dose. b Amoxicillin and clavulanate potassium administered at the start of a light meal. Dose of Amoxicillin and Clavulanate C max (mcg/mL) AUC 0-24 (mcg*h/mL) Amoxicillin and Clavulanate potassium Amoxicillin Clavulanate potassium Amoxicillin Clavulanate potassium 400 mg/57 mg (5 mL of suspension) 6.94 ± 1.24 1.10 ± 0.42 17.29 ± 2.28 2.34 ± 0.94 400 mg/57 mg (1 chewable tablet) 6.67 ± 1.37 1.03 ± 0.33 17.24 ± 2.64 2.17 ± 0.73 Oral administration of 5 mL of the 250 mg/62.5 mg suspension of Amoxicillin and Clavulanate Potassium or the equivalent dose of 10 mL of the 125 mg/31.25 mg 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 the 250 mg/62.5 mg suspension of Amoxicillin and Clavulanate Potassium or equivalent dose of 10 mL of the 125 mg/31.25 mg suspension of Amoxicillin and Clavulanate Potassium were administered to normal adults. One 250 mg/62.5 mg chewable tablet of Amoxicillin and Clavulanate Potassium or two 125 mg/31.25 mg chewable tablets of Amoxicillin and Clavulanate Potassium are equivalent to 5 mL of the 250 mg/62.5 mg 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 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 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 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 was dosed at 30 and 150 minutes after the start of a high‑fat breakfast. Distribution : Neither component in Amoxicillin and Clavulanate Potassium is 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 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 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/125 mg or 500 mg/125 mg tablet of Amoxicillin and Clavulanate Potassium.