AMOXICILLIN AND CLAVULANATE POTASSIUM

Amoxicillin and clavulanate potassium tablets, USP are an oral antibacterial combination consisting of amoxicillin and the beta-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin USP 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: • 250 mg/125 mg: Each tablet contains 250 mg of amoxicillin USP as the trihydrate, and 125 mg of clavulanic acid (equivalent to 149 mg of clavulanate potassium). • 500 mg/125 mg: Each tablet contains 500 mg of amoxicillin USP as the trihydrate, and 125 mg of clavulanic acid (equivalent to 149 mg of clavulanate potassium). • 875 mg/125 mg: Each tablet contains 875 mg of amoxicillin USP as the trihydrate, and 125 mg of clavulanic acid (equivalent to 149 mg of clavulanate potassium). Inactive Ingredients: Colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, surelease clear (aqueous ethyl cellulose dispersion), and titanium dioxide. Each tablet of amoxicillin and clavulanate contains 0.63 mEq potassium. Chemical Structure1 chemical structure

Amoxicillin and clavulanate potassium tablets are 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. 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. 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 tablets 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. Amoxicillin and clavulanate potassium tablets are 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 tablets should not be used. ( 1 ) 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 tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1 )

• Adults and Pediatric Patients greater than 40 kg: 500 mg/125 mg or 875 mg/125 mg every 12 hours or 250 mg/125 mg or 500 mg/125 mg every 8 hours, based on 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/31.25 mg per 5 mL oral suspension is recommended. ( 2.3 ) 2.1 Important Administration Instructions 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 are 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. 2.2 Adult Patients See dosing regimens of amoxicillin and clavulanate potassium tablets (based on the amoxicillin component) provided in Table 1 below. Table 1. Dosing Regimens of Amoxicillin and Clavulanate Potassium Tablets in Adult Patients TYPE OF INFECTION DOSING REGIMEN OF AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS Severe infections and infections of the respiratory tract one 875 mg/125 mg tablet a of amoxicillin and clavulanate potassium tablets every 12 hours or one 500 mg/125 mg tablet b,c of amoxicillin and clavulanate potassium tablets every 8 hours Less severe infections one 500 mg/125 mg tablet b,c of amoxicillin and clavulanate potassium tablets every 12 hours or one 250 mg/125 mg tablet d of amoxicillin and clavulanate potassium tablets 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 tablets 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 tablets provided in Table 2 below. Table 2: Dosing Regimens of Amoxicillin and Clavulanate Potassium Tablets 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) ] . Table 3: Dosing in Patients Aged 12 Weeks (3 Months) and Older and Weighing Less than 40 kg 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 tablets 400 mg/57 mg per 5 mL for oral suspension a Amoxicillin and clavulanate potassium 125 mg/31.25 mg per 5 mL or Amoxicillin and clavulanate potassium tablets 250 mg/62.5 mg per 5 mL for 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 a Each strength of amoxicillin and clavulanate potassium for 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. 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 tablet. See dosing regimens in patients with severe renal impairment provided in Table 4. Table 4. Dosing Regimens of Amoxicillin and Clavulanate Potassium Tablets 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 2.6 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/125 mg tablet of amoxicillin and clavulanate potassium and the 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium do not contain the same amount of clavulanic acid. The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium contains 125 mg of clavulanic acid whereas the 250 mg/62.5 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/125 mg and 500 mg/125 mg tablets of amoxicillin and clavulanate potassium contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250 mg/125 mg tablets of amoxicillin and clavulanate potassium are not equivalent to one 500 mg/125 mg tablet of amoxicillin and clavulanate potassium.

• 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). ( 4.1 ) • History of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium tablets. ( 4.2 ) 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.

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) ] • Drug-Induced Enterocolitis Syndrome (DIES) [see Warnings and Precautions (5.3) ] • Hepatic Dysfunction [see Warnings and Precautions (5.4) ] • Clostridioides difficile Associated Diarrhea (CDAD) [see Warnings and Precautions (5.5) ] The most frequently reported adverse reactions 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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 U.S./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: Drug-induced enterocolitis syndrome (DIES), 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 (5.5) ] . 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, and linear IgA bullous dermatosis. 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 (5.4) ] . 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.

• Co-administration with probenecid is not recommended. (7.1) • Concomitant use of amoxicillin and clavulanate potassium 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 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 may result in increased and prolonged blood concentrations of amoxicillin. Co-administration 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. 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 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, 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.