AMOXICILLIN AND CLAVULANATE POTASSIUM

Amoxicillin and clavulanate potassium extended-release tablets for oral use is an antibacterial combination consisting of the semisynthetic antibacterial amoxicillin (present as amoxicillin trihydrate and amoxicillin sodium) and the β-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 trihydrate molecular formula is C16H19N3O5S•3H2O, and the molecular weight is 419.45. Chemically, amoxicillin trihydrate 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: The amoxicillin sodium molecular formula is C16H18N3NaO5S, and the molecular weight is 387.39. Chemically, amoxicillin sodium is [2 -[2α,5α,6β(S*)]]-6-[[Amino(4‑ hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1- azabicyclo[3.2.0]heptane-2‑ carboxylic acid monosodium salt and may be represented structurally as: Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus . It is a β‑lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of β-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. The clavulanate potassium molecular formula is C8H8KNO5, and the molecular weight is 237.25. Chemically, clavulanate potassium is potassium (Z)-(2 R ,5 R )-3-(2-hydroxy ethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate, and may be represented structurally as: Each tablet of amoxicillin and clavulanate potassium extended-release contains 1,000 mg of amoxicillin (437.5 mg as amoxicillin sodium and 562.5 mg as amoxicillin trihydrate), and 62.5 mg of clavulanic acid (equivalent to 74.5 mg of clavulanate potassium). Inactive Ingredients: Anhydrous citric acid, colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, titanium dioxide, and xanthan gum. Each tablet of amoxicillin and clavulanate potassium extended-release tablets contains approximately 12 mg of potassium and 29 mg of sodium. Meets USP Dissolution Test 2. amoxicillin-trihydrate-chemical-structure amoxicillin-sodium-chemical-structure clavulanic-acid-chemical-structure

Amoxicillin and clavulanate potassium extended-release tablets is indicated for the treatment of infections in adults and pediatric patients weighing greater than or equal to 40 kg who are able to swallow tablets with: community-acquired pneumonia or acute bacterial sinusitis due to confirmed, or suspected β-lactamase-producing pathogens (i.e., H. influenzae, M. catarrhalis, H. parainfluenzae, K. pneumoniae , or methicillin-susceptible S. aureus ) and S. pneumoniae with reduced susceptibility to penicillin (i.e., penicillin MICs equal to 2 mcg/mL). Limitations of Use Amoxicillin and clavulanate potassium extended-release tablets is not indicated for the treatment of infections due to S. pneumoniae with penicillin MICs greater than or equal to 4 mcg/mL. Data are limited with regard to infections due to S. pneumoniae with penicillin MICs greater than or equal to 4 mcg/mL [see Clinical Studies ( 14 )] . Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium extended-release tablets and other antibacterial drugs, amoxicillin and clavulanate potassium extended-release 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. In patients with community-acquired pneumonia in whom penicillin-resistant S. pneumoniae is suspected, bacteriological studies should be performed to determine the causative organisms and their susceptibility when amoxicillin and clavulanate potassium extended-release tablets are prescribed. Acute bacterial sinusitis or community-acquired pneumonia due to a penicillin-susceptible strain of S. pneumoniae plus a β-lactamase-producing pathogen can be treated with another amoxicillin and clavulanate potassium product containing lower daily doses of amoxicillin (i.e., 500 mg every 8 hours or 875 mg every 12 hours). Acute bacterial sinusitis or community-acquired pneumonia due to S. pneumoniae alone can be treated with amoxicillin. Amoxicillin and clavulanate potassium extended-release tablets is a combination of amoxicillin, a penicillin-class antibacterial and clavulanate potassium, a β-lactamase inhibitor, indicated for treatment of adults and pediatric patients weighing greater than or equal to 40 kg who are able to swallow tablets with: community-acquired pneumonia or acute bacterial sinusitis due to confirmed, or suspected β-lactamase-producing pathogens (i.e., H. influenzae, M. catarrhalis, H. parainfluenzae, K. pneumoniae , or methicillin-susceptible S. aureus ) and S. pneumoniae with reduced susceptibility to penicillin (i.e., penicillin MICs equal to 2 mcg/mL). ( 1 ) Limitations of Use Amoxicillin and clavulanate potassium extended-release tablets is not indicated for the treatment of infections due to S. pneumoniae with penicillin MICs greater than or equal to 4 mcg/mL. Data are limited with regard to infections due to S. pneumoniae with penicillin MICs greater than or equal to 4 mcg/mL. ( 1 ) Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium extended-release tablets and other antibacterial drugs, amoxicillin and clavulanate potassium extended-release 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 weighing greater than or equal to 40 kg who are able to swallow tablets: The recommended dosage of amoxicillin and clavulanate potassium extended-release tablets is 4,000 mg/250 mg daily in divided doses at the start of a meal according to the following table ( 2 ): Indication Dose Duration Acute bacterial sinusitis Two (1,000 mg/62.5 mg) tablets every 12 hours 10 days Community-acquired pneumonia Two (1,000 mg/62.5 mg) tablets every 12 hours 7 to 10 days 2.1 Important Administration Instructions Amoxicillin and clavulanate potassium extended-release tablets should be taken at the start of a meal to enhance the absorption of amoxicillin and to minimize the potential for gastrointestinal intolerance. Amoxicillin and clavulanate potassium extended-release tablets is not recommended to be taken with a high-fat meal because clavulanate absorption is decreased [see Clinical Pharmacology ( 12.3 )] . 2.2 Dosage in Adult Patients The recommended dosage of amoxicillin and clavulanate potassium extended-release tablets is 4,000 mg/250 mg daily in divided doses according to the following table: Table 1: Recommended Dosage of Amoxicillin and Clavulanate Potassium Extended-Release Tablets in Adult Patients Indication Dose Duration Acute bacterial sinusitis Two (1,000 mg/62.5 mg) tablets every 12 hours 10 days Community-acquired pneumonia Two (1,000 mg/62.5 mg) tablets every 12 hours 7 to 10 days Amoxicillin and clavulanate potassium extended-release tablets can be split in half along the score line for patients with difficulty swallowing the tablets whole. Both halves of the tablet must be taken immediately. 2.3 Dosage in Pediatric Patients Pediatric patients who weigh 40 kg or more and can swallow tablets should receive the adult dose [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.4 )] . 2.4 Dosage in Patients with Hepatic Impairment Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals [see Warnings and Precautions ( 5.4 )]. 2.5 Switching between Dosage Forms and between Strengths Amoxicillin and clavulanate potassium extended-release tablet is NOT substitutable on a mg-to-mg basis with other formulations of amoxicillin and clavulanate potassium. In addition, the extended-release tablets provide an extended time course of plasma amoxicillin concentrations compared to immediate-release tablets. Thus, two amoxicillin and clavulanate potassium 500 mg tablets are not equivalent to one amoxicillin and clavulanate potassium extended-release 1,000 mg tablet.

History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin and clavulanate potassium extended-release tablets or to other β‑lactams (e.g., penicillins or cephalosporins). ( 4.1 ) History of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium extended-release tablets. ( 4.2 ) In patients with severe renal impairment (creatinine clearance less than 30 mL/min) and in hemodialysis patients. ( 4.3 ) 4.1 Serious Hypersensitivity Reactions Amoxicillin and clavulanate potassium extended-release tablets is contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin, clavulanate or to other β-lactam antibacterial drugs (e.g., penicillins and cephalosporins). 4.2 Cholestatic Jaundice/Hepatic Dysfunction Amoxicillin and clavulanate potassium extended-release tablets is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with treatment with amoxicillin/clavulanate potassium. 4.3 Renal Impairment Amoxicillin and clavulanate potassium extended-release tablets is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min) and in hemodialysis patients.

The following clinically significant adverse reactions are described elsewhere in the labeling: Anaphylactic reactions [se e 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) [se e Warnings and Precautions ( 5.5 )] Skin Rash in Patients with Mononucleosis [see Warnings and Precautions ( 5.6 )] The most frequently reported adverse reactions were (incidence > 2%), diarrhea, vaginal mycosis, nausea, and loose stools. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 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. In clinical trials, 5,643 patients have been treated with amoxicillin and clavulanate potassium extended-release tablets. The most frequently reported adverse reactions which were suspected or probably drug- related were diarrhea (15%), vaginal mycosis (3%), nausea (2%), and loose stools (2%). Amoxicillin and clavulanate potassium extended-release tablets had a higher rate of diarrhea which required corrective therapy (4% versus 3% for amoxicillin and clavulanate potassium extended-release tablets and all comparators, respectively). Two percent of patients discontinued therapy because of drug-related adverse reactions. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-marketing use of amoxicillin and clavulanate potassium products, including amoxicillin and clavulanate potassium extended-release tablets. 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. Gastrointestinal : Drug-induced enterocolitis syndrome (DIES), diarrhea, nausea, vomiting, 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 ( 5.3 , 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 [see Warnings and Precautions ( 5.1 , 5.2 , 5.6 )] . Liver : A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted in patients treated with ampicillin-class antibacterials, but the significance of these findings is unknown. Hepatic dysfunction, including hepatitis and cholestatic jaundice, [see Contraindications ( 4.2 )], increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been reported with amoxicillin and clavulanate potassium or amoxicillin and clavulanate potassium extended-release 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 ), 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 during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. There have been reports of increased prothrombin time in patients receiving amoxicillin and clavulanate potassium and anticoagulant therapy concomitantly. Central Nervous System : Agitation, anxiety, behavioral changes, aseptic meningitis, confusion, convulsions, dizziness, headache, 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 extended-release 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 extended-release tablets may reduce efficacy of oral contraceptives. ( 7.4 ) 7.1 Probenecid Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with amoxicillin and clavulanate potassium extended-release tablets may result in increased and prolonged blood levels 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. 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 substantially 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. In controlled clinical trials of amoxicillin and clavulanate potassium extended-release tablets, 25 patients received concomitant allopurinol and amoxicillin and clavulanate potassium extended-release tablets. No rashes were reported in these patients. However, this sample size is too small to allow for any conclusions to be drawn regarding the risk of rashes with concomitant amoxicillin and clavulanate potassium extended-release tablets and allopurinol use. 7.4 Oral Contraceptives Amoxicillin and clavulanate potassium extended-release 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 extended release 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