Amoxicillin

1 INDICATIONS AND USAGE Amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL is indicated for the treatment of pediatric patients aged 3 months to 12 years weighing less than or equal to 40 kg with: Recurrent or persistent acute otitis media due to S. pneumoniae (penicillin MICs less than or equal to 2 mcg/mL), H. influenzae (including beta-lactamase-producing strains), or M. catarrhalis (including beta-lactamase-producing strains) characterized by the following risk factors: Antibacterial drug exposure for acute otitis media within the preceding 3 months, and either of the following: 1) age 2 years, or younger or 2) day care attendance [see Microbiology (12.4) ] . Limitations of Use Amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL is not indicated for the treatment of acute otitis media due to S. pneumoniae with penicillin MIC greater than or equal to 4 mcg/mL. Acute otitis media due to S. pneumoniae alone can be treated with amoxicillin. Therapy may be instituted prior to obtaining the results from bacteriological studies when there is reason to believe the infection may involve both S . pneumoniae (penicillin MIC less than or equal to 2 mcg/mL) and the beta-lactamase-producing organisms listed above. Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL and other antibacterial drugs, amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL 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 for oral suspension, 600 mg/42.9 mg per 5 mL is a combination of amoxicillin, a penicillin-class antibacterial and clavulanate potassium, a beta-lactamase inhibitor, indicated for the treatment of pediatric patients aged 3 months to 12 years weighing less than or equal to 40 kg with Recurrent or persistent acute otitis media due to S. pneumoniae (penicillin MICs less than or equal to 2 mcg/mL), H. influenzae (including beta-lactamase-producing strains), or M. catarrhalis (including beta-lactamase-producing strains) characterized by the following risk factors (1): Antibacterial exposure for acute otitis media within the preceding 3 months, and either of the following: 1) age 2 years, or younger or 2) daycare attendance. Limitations of Use Amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL is not indicated for the treatment of acute otitis media due to S. pneumoniae with penicillin MIC greater than or equal to 4 mcg/mL. Acute otitis media due to S. pneumoniae alone can be treated with amoxicillin. Therapy may be instituted prior to obtaining the results from bacteriological studies when there is reason to believe the infection may involve both S. pneumoniae (penicillin MIC less than or equal to 2 mcg/mL) and the beta-lactamase-producing organisms listed above. ( 1 ) Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL and other antibacterial drugs, amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL is an antibacterial drug [see Microbiology (12.4) ]. 12.3 Pharmacokinetics The pharmacokinetics of amoxicillin and clavulanate were determined in a study of 19 pediatric patients, 8 months to 11 years, given amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL at an amoxicillin dose of 45 mg/kg q12h with a snack or meal. The mean plasma amoxicillin and clavulanate pharmacokinetic parameter values are listed in Table 3. Table 3. Mean (±SD) Plasma Amoxicillin and Clavulanate Pharmacokinetic Parameter Values Following Administration of 45 mg/kg of Amoxicillin and Clavulanate Potassium for Oral Suspension, 600 mg/42.9 mg per 5 mL Every 12 Hours to Pediatric Patients Parameter Amoxicillin Clavulanate C max (mcg/mL) 15.7 ± 7.7 1.7 ± 0.9 T max (hr) 2.0 (1.0 to 4.0) 1.1 (1.0 to 4.0) AUC 0-T (mcg * hr/mL) 59.8 ± 20.0 4.0 ± 1.9 T 1/2 (hr) 1.4 ± 0.3 1.1 ± 0.3 CL/F (L/hr/kg) 0.9 ± 0.4 1.1 ± 1.1 * Arithmetic mean ± standard deviation, except T max values which are medians (ranges). The effect of food on the oral absorption of amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL has not been studied. 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 10 mL of amoxicillin and clavulanate potassium, 250 mg/62.5 mg per 5 mL suspension. Neither component in amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL is highly protein-bound; clavulanic acid has been found to be approximately 25% bound to human serum and amoxicillin approximately 18% bound. Oral administration of a single dose of amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL at 45 mg/kg (based on the amoxicillin component) to pediatric patients, 9 months to 8 years, yielded the following pharmacokinetic data for amoxicillin in plasma and middle ear fluid (MEF): Table 4. Amoxicillin Concentrations in Plasma and Middle Ear Fluid Following Administration of 45 mg/kg of Amoxicillin and Clavulanate Potassium for Oral Suspension, 600 mg/42.9 mg per 5 mL to Pediatric Patients * Timepoint Amoxicillin concentration in plasma (mcg/mL) Amoxicillin concentration in MEF (mcg/mL) 1 hour mean median range 7.7 9.3 1.5 to 14.0 (n = 5) 3.2 3.5 0.2 to 5.5 (n = 4) 2 hour mean median range 15.7 13.0 11.0 to 25.0 (n = 7) 3.3 2.4 1.9 to 6 (n = 5) 3 hour mean median range 13.0 12.0 5.5 to 21.0 (n = 5) 5.8 6.5 3.9 to 7.4 (n = 5) * Dose administered immediately prior to eating. Amoxicillin diffuses readily into most body tissues and fluids, with the exception of the brain and spinal fluid. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like amoxicillin, is well distributed in body tissue

2 DOSAGE AND ADMINISTRATION Pediatric Patients aged 3 months to 12 years weighing less than or equal to 40 kg: 90 mg/kg/day divided every 12 hours, administered for 10 days. ( 2 ) 2.1 Important Administration Instructions To minimize the potential for gastrointestinal intolerance, amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL should be taken at the start of a meal. Absorption of clavulanate potassium may be enhanced when amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL is administered at the start of a meal. 2.2 Dosage in Pediatric Patients Pediatric patients aged 3 months to 12 years weighing less than or equal to 40 kg : Based on the amoxicillin component (600 mg/5 mL), the recommended dose of amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL is 90 mg/kg/day divided every 12 hours, administered for 10 days (see Table 1 as a general example guideline for attainment of this dosage). This dose provides 6.4 mg/kg/day of the clavulanic acid component. Table 1: General Dosage Guidelines for Amoxicillin and Clavulanate Potassium for Oral Suspension, 600 mg/42.9 mg per 5 mL in Pediatric Patients Body Weight (kg) Volume of Amoxicillin and Clavulanate Potassium for Oral Suspension, ​​​​​​​600 mg/42.9 mg per 5 mL providing 90 mg/kg/day 8 3 mL twice daily 12 4.5 mL twice daily 16 6 mL twice daily 20 7.5 mL twice daily 24 9 mL twice daily 28 10.5 mL twice daily 32 12 mL twice daily 36 13.5 mL twice daily 40 15 mL twice daily ​​​​​​​ Pediatric patients weighing greater than 40 kg : Experience with amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL in this group is not available. 2.3 Dosage in Adult Patients Experience with amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL in adults is not available and adults who have difficulty swallowing should not be given amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL in place of the amoxicillin and clavulanate potassium 500 mg or 875 mg tablet. 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 Preparation of the Oral Suspension Prepare the suspension at time of dispensing as follows: Tap bottle until all powder flows freely. Measure the total amount of water (see Table 2) to be added in two parts. Add approximately 2/3 of the total amount of water for reconstitution, replace cap and shake vigorously to suspend powder. Add remainder of the water (that had been measured), replace cap and again shake vigorously. Table 2: Volume of Water for Reconstituting Amoxicillin and Clavulanate Potassium for Oral Suspension, 600 mg/42.9 mg per 5 mL Bottle Size Amount of Water Required for Reconstitution 75 mL 68 mL 125 mL 108 mL 200 mL 170 mL ​​​​​​​​​​​​​​Each 5 mL will contain 600 mg of amoxicillin as the trihydrate, and 42.9 mg of clavulanic acid as the potassium salt. Shake oral suspension well before each use. Suspension must be refrigerated. Discard after 10 days. Suspension is off-white at time of reconstitution; some color change is normal during the dosing period. Flavoring Information : For patients who wish to alter the taste of amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL, immediately after reconstitution, 1 drop of FLAVORx ® (apple, banana cream, bubble gum, cherry, or watermelon flavor) may be added for every 5 mL of amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL. The resulting suspension is stable for 10 days under refrigeration. Stability of amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL when mixed with other flavors other than the 5 flavors listed above has not been evaluated. 2.6 Switching between Dosage Forms and between Strengths Amoxicil

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Anaphylactic reactions [see Warnings and Precautions (5.1) ] Severe Cutaneous Adverse Reactions (SCAR) [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) ] Skin Rash in Patients with Mononucleosis [see Warnings and Precautions (5.6) ] The most frequently reported adverse reactions (incidence rate > 4 %) were coughing, vomiting, contact dermatitis (i.e., diaper rash), fever, upper respiratory tract infection, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC. at 1-845-232-1683 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. Two clinical trials evaluated the safety of a 10-day treatment course of amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL 90/6.4 mg/kg/day, divided every 12 hours, in pediatric patients with acute otitis media [see Clinical Studies (14)] . The first trial involved 521 pediatric patients (3 months to 50 months) and the second trial involved 450 pediatric patients (3 months to 12 years). In the intent-to-treat population of the first trial of 521 patients, the most frequently reported adverse events were vomiting (7%), fever (6%), contact dermatitis (i.e., diaper rash) (6%), upper respiratory tract infection (4%), and diarrhea (4%). Protocol-defined diarrhea (i.e., 3 or more watery stools in one day or 2 watery stools per day for 2 consecutive days as recorded on diary cards) occurred in 13% of patients. The primary objective of the second study was to compare the safety of amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL (90/6.4 mg/kg/day, divided every 12 hours) to amoxicillin and clavulanate potassium (45/6.4 mg/kg/day, divided every 12 hours) for ten days. There was no statistically significant difference between treatments in the proportion of patients with 1 or more adverse events. The most frequently reported adverse reactions for amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL and the comparator of amoxicillin and clavulanate potassium were coughing (12% versus 7%), vomiting (7% versus 8%), contact dermatitis (i.e., diaper rash, 6% versus 5%), fever (6% versus 4%), and upper respiratory infection (3% versus 9%), respectively. The frequencies of protocol-defined diarrhea with amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL (11%) and amoxicillin and clavulanate potassium (9%) were not statistically different. Two patients in the group treated with amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL and one patient in the group treated with amoxicillin and clavulanate potassium were withdrawn due to diarrhea. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of amoxicillin and clavulanate potassium products, including amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL. Because these reactions are reported voluntarily from a population of unknown 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.

5 WARNINGS AND PRECAUTIONS Serious (including fatal) hypersensitivity reactions: Discontinue amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL if a reaction occurs and institute appropriate therapy. ( 5.1 ) Severe cutaneous adverse reactions (SCAR): Monitor closely. Discontinue if rash progresses. ( 5.2 ) Drug-induced enterocolitis syndrome (DIES) has been reported with use of amoxicillin, a component of amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL. If this occurs, discontinue amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL and institute appropriate therapy. ( 5.3 ) Hepatic dysfunction and cholestatic jaundice: Discontinue if signs/symptoms of hepatitis occur. Monitor liver function tests in patients with hepatic impairment. ( 5.4 ) Clostridioides difficile - associated diarrhea (CDAD) (ranging from mild diarrhea to fatal colitis): Evaluate patients if diarrhea occurs. ( 5.5 ) Patients with mononucleosis who receive amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL develop skin rash. Avoid amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL use in these patients. ( 5.6 ) 5.1 Serious Allergic Reactions, including Anaphylaxis Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Before initiating therapy with amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, discontinue amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL and institute appropriate therapy. 5.2 Severe Cutaneous Adverse Reactions Amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL may cause severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). If patients develop a skin rash, they should be monitored closely, and amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL discontinued if lesions progress. 5.3 Drug-Induced Enterocolitis Syndrome (DIES) Drug-induced enterocolitis syndrome (DIES) has been reported with use of amoxicillin, a component of amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL, [see Adverse Reactions (6.2) ] , with most cases occurring in pediatric patients ≤18 years of age. DIES is a non-IgE mediated hypersensitivity reaction characterized by protracted vomiting occurring 1 to 4 hours after drug ingestion in the absence of skin or respiratory symptoms. DIES may be associated with pallor, lethargy, hypotension, shock, diarrhea within 24 hours after ingesting amoxicillin, and leukocytosis with neutrophilia. If DIES occurs, discontinue amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL and institute appropriate therapy. 5.4 Hepatic Dysfunction Use amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL with caution in patients with evidence of hepatic dysfunction. Hepatic toxicity associated with the use of amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL is usually reversible. Deaths have been reported (fewer than one death reported per estimated four million prescriptions worldwide). These have generally been cases associated with serious underlying diseases or conco

4 CONTRAINDICATIONS History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL or any other beta-lactams (e.g., penicillins or cephalosporins). ( 4.1 ) History of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL. ( 4.2 ) 4.1 Serious Hypersensitivity Reactions Amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL is 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 for oral suspension, 600 mg/42.9 mg per 5 mL is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with treatment with amoxicillin and clavulanate potassium.

10 OVERDOSAGE Following overdosage, patients have experienced primarily gastrointestinal symptoms including stomach and abdominal pain, vomiting, and diarrhea. Rash, hyperactivity, or drowsiness have also been observed in a small number of patients. In the case of overdosage, discontinue amoxicillin and clavulanate potassium for oral suspension, 600 mg/42.9 mg per 5 mL, treat symptomatically, and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. 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 and do not require gastric emptying.1 Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin. Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin 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 both amoxicillin and clavulanate. Both amoxicillin and clavulanate are removed from the circulation by hemodialysis [see Dosage and Administration (2) ].