Amoxicillin and Clavulanate Potassium

Warnings and Precautions ( 5 ) 6/2022 Indications and Usage ( 1 ) 12/2024 Dosage and Administration, Dosage in Pediatric Patients ( 2.2 ) 12/2024 Warnings and Precautions, Drug-Induced Enterocolitis Syndrome (DIES) ( 5.3 ) 5/2024

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 Acute otitis media due to S. pneumoniae alone can be treated with amoxicillin. 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. 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 Acute otitis media due to S. pneumoniae alone can be treated with amoxicillin. 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. 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 )

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 500 mg or 875 mg tablet of amoxicillin and clavulanate potassium. 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 66 mL 125 mL 110 mL 200 mL 176 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 Amoxicillin and clavulanate potassium for oral …

3 DOSAGE FORMS AND STRENGTHS Amoxicillin and Clavulanate Potassium for Oral Suspension USP, 600 mg/42.9 mg per 5 mL: orange-flavored powder for oral suspension (each 5 mL of reconstituted suspension contains 600 mg of amoxicillin as the trihydrate, and 42.9 mg of clavulanic acid as the potassium salt). For oral suspension: 600 mg/42.9 mg per 5 mL. ( 3 )

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.

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 Hikma Pharmaceuticals USA Inc. at 1-877-233-2001, or the 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 Stud ies ( 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/pseudom …

7 DRUG INTERACTIONS • Co-administration with probenecid is not recommended. ( 7.1 ) • Concomitant use of amoxicillin and clavulanate potassium for oral suspension 600 mg/42.9 mg per 5 mL with 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 for oral suspension 600 mg/42.9 mg per 5 mL 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 for oral suspension 600 mg/42.9 mg per 5 mL may result in increased and prolonged blood levels 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. 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 substantially 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. There are no data with amoxicillin and clavulanate potassium for oral suspension 600 mg/42.9 mg per 5 mL and allopurinol administered concurrently. 7.4 Oral Contraceptives Amoxicillin and clavulanate potassium for oral suspension 600 mg/42.9 mg per 5 mL 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 for oral suspension 600 mg/42.9 mg per 5 mL, 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from published epidemiologic studies and pharmacovigilance case reports over several decades of use with amoxicillin and clavulanate during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal outcomes. A study in women with preterm prelabor rupture of membranes (PPROM) reported that prophylactic treatment with amoxicillin and clavulanate may be associated with an increased risk of necrotizing enterocolitis in neonates (see Data) . Reproduction studies performed in pregnant rodents, given up to approximately 2 times the amount of amoxicillin and 15 times the amount of clavulanate in the Maximum Human Recommended Dose (MHRD) of amoxicillin and clavulanate potassium for oral suspension 600 mg/42.9 mg per 5 mL, revealed no evidence of harm to the fetus (see Data). The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data One randomized, controlled trial included 4,826 pregnant women with premature rupture of fetal membranes who were randomly assigned to 250 mg erythromycin (n=1,197), 250 mg amoxicillin and 125 mg clavulanic acid (amoxicillin and clavulanate, n=1,212), amoxicillin and clavulanate and erythromycin (n=1,192), or placebo (n=1,225) four times daily for 10 days or until delivery. Amoxicillin and clavulanate was associated with a significantly increased rate of proven neonatal necrotizing enterocolitis: 1.9% (n = 24) in the amoxicillin and clavulanate only group versus 0.5% (n = 6) in the placebo group (p = 0.001), and 1.8% (n = 44) in the any amoxicillin and clavulanate group versus 0.7% (n =17) in the no amoxicillin and clavulanate group (p = 0.0005). Animal Data Reproduction studies performed in pregnant rats and mice given amoxicillin and clavulanate (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. The amoxicillin doses in rodents (based on body surface area and assuming a 20 kg child) were approximately 2 times (rats) or equal to (mice) the recommended clinical amoxicillin and clavulanate potassium for oral suspension 600 mg/42.9 mg per 5 mL, dose of 90/6.4 mg/kg/day. For clavulanate, these dose multiples were approximately 15 times and 7.5 times the recommended daily dose of amoxicillin and clavulanate potassium for oral suspension 600 mg/42.9 mg per 5 mL. 8.2 Lactation Risk Summary Data from a published clinical lactation study report that amoxicillin is present in human milk. There are reports of diarrhea, irritability, and rash in infants exposed to amoxicillin and clavulanate through breast milk; therefore, infants exposed to amoxicillin and clavulanate potassium for oral suspension 600 mg/42.9 mg per 5 mL should be monitored for these symptoms. There are no data on the effects of amoxicillin and clavulanate on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for amoxicillin and clavulanate potassium for oral suspension 600 mg/42.9 mg per 5 mL and any potential adverse effects on the breastfed child from amoxicillin and clavulanate potassium for oral suspension 600 mg/42.9 mg per 5 mL or from the underlying maternal condition. 8.4 Pediatric Use Acute Otitis Media The safety and effectiveness of amoxicillin and clavulanate potassium for oral suspension 600 mg/42.9 mg per 5 mL have been established in pediatric patients aged 3 months to 12 years weighing less than or equal to 40 kg, for the treatment of acute otitis media, and the information on this use is discussed thro …

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 ( Error! Hyperlink reference not valid. )].

11 DESCRIPTION Amoxicillin and clavulanate potassium for oral suspension, USP is an oral antibacterial combination consisting of the semisynthetic antibacterial 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 0 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 a wide variety of beta-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid-mediated beta-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. 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 )-(2 R ,5 R )-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate and may be represented structurally as: Inactive Ingredients Caramel flavor, carboxymethyl cellulose sodium, citric acid, colloidal silicon dioxide, microcrystalline cellulose, orange flavor, raspberry flavor, saccharin sodium, silicon dioxide, sodium citrate, and xanthan gum. Each 5 mL of reconstituted amoxicillin and clavulanate potassium for oral suspension 600 mg/42.9 mg per 5 mL contains 600 mg amoxicillin as the trihydrate and 42.9 mg clavulanic acid as the potassium salt (clavulanate potassium). The potassium content per 5 mL is 0.23 mEq (equivalent to 9 mg). Color and appearance of the dry powder White to yellowish white crystalline powder. Color and appearance of the suspension Almost white to yellow, homogeneous suspension. amoxicillin structure clavulanate potassium structure

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 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 ( Error! Hyperlink reference not valid. )].

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Amoxicillin and Clavulanate Potassium for Oral Suspension, USP 600 mg/42.9 mg per 5 mL Amoxicillin and Clavulanate Potassium for Oral Suspension is a Caramel-orange-raspberry-flavored powder for oral suspension. Following constitution, each 5 mL of oral suspension contains 600 mg of amoxicillin as the trihydrate and 42.9 mg of clavulanic acid as the potassium salt (equivalent to 51.1 mg of clavulanate potassium). NDC 0781-6139-57 75 mL bottle NDC 0781-6139-54 125 mL bottle NDC 0781-6139-48 200 mL bottle Storage Store reconstituted suspension under refrigeration. Discard unused suspension after 10 days. Store dry powder for oral suspension at 20oC to 25°C (68oF to 77°F) [see USP Controlled Room Temperature]. Dispense in original container.