AMOXICILLIN AND CLAVULANATE POTASSIUM

1 INDICATIONS AND USAGE Amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) 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, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) 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 tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) 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, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) are 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, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) should not be used. ( 1 ) Usage To reduce the development of drug–resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) and other antibacterial drugs, amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) 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 Adults and Pediatric Patients greater than 40 kg: 500 mg or 875 mg every 12 hours or 250 mg or 500 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. ( 2.3 ) 2.1 Important Administration Instructions Amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) are administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) should be taken at the start of a meal. 2.2 Adult Patients See dosing regimens of amoxicillin/clavulanate potassium (based on the amoxicillin component) provided in Table 1 below. Table 1. Dosing Regimens of Amoxicillin/Clavulanate Potassium in Adult Patients TYPE OF INFECTION DOSING REGIMEN OF AMOXICILLIN/CLAVULANATE POTASSIUM Severe infections and infections of the respiratory tract one 875 mg tablet a of amoxicillin/clavulanate potassium every 12 hours or one 500 mg tablet b,c of amoxicillin/clavulanate potassium every 8 hours Less severe infections one 500 mg tablet b,c of amoxicillin/clavulanate potassium every 12 hours or one 250 mg tablet d of amoxicillin/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 for oral suspension or the amoxicillin and clavulanate potassium 400 mg/57 mg per 5 mL for oral 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 for oral suspension or amoxicillin and clavulanate potassium 250 mg/62.5 mg per 5 mL for oral 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 for oral suspension should be dosed as follows: Neonates and Infants Aged less than 12 Weeks (less than 3 Months) : See dosing regimens of amoxicillin/clavulanate potassium provided in Table 2 below. Table 2: Dosing Regimens of Amoxicillin and Clavulanate Potassium for Oral Suspension 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 for oral suspension 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 tablets (chewable) 400 mg/57 mg contain aspartame and should not be used by phenylketonurics [see Warnings and Precautions ( 5.8 )] . Table 3: Dosing in Patients Aged 12 Weeks (3 Months) and Older and Weighing Less than 40 kg INFECTION DOSING REGIMEN Every 12 hours Amoxicillin/Clavulanate Potassium 200 mg/28.5 mg per 5 mL for Oral Suspension or Amoxicillin/Clavulanate Potassium 400 mg/57 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 Less severe infections 25 mg/kg/day every 12 hours Each strength of amoxicillin and clavulanate potassium for oral suspension is available as a chewable tablet for use by older children. 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 tablets 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 tablets versus the 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium tablets (chewable). 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 tablets. 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 2.5 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 Potassium for Oral Suspension Bottle Size Amount of Water for Reconstitution Contents of Each Teaspoonful (5 mL) 200 mg/28.5 mg per 5 mL 100 mL 92 mL 200 mg of amoxicillin and 28.5 mg of clavulanic acid as the potassium salt 400 mg/57 mg per 5 mL 100 mL 87 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 Tablet, 250 mg/125 mg are NOT Substitutable with Amoxicillin and Clavulanate Potassium Chewable Tablet, 250 mg/62.5 mg The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium tablets and the 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium tablets (chewable) should NOT be substituted for each other and the tablet of 250 mg/125 mg amoxicillin and clavulanate potassium tablets 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 tablets and the tablet of 250 mg amoxicillin and clavulanate potassium tablets (chewable) do not contain the same amount of clavulanic acid. The 250 mg tablet of amoxicillin and clavulanate potassium tablets contain 125 mg of clavulanic acid whereas the 250 mg tablet of amoxicillin and clavulanate potassium tablets (chewable) contain 62.5 mg of clavulanic acid. Two Amoxicillin and Clavulanate Potassium Tablets, 250 mg/125 mg are NOT Substitutable with One Amoxicillin and Clavulanate Potassium Tablet, 500 mg/125 mg Two 250 mg/125 mg amoxicillin and clavulanate potassium tablets should NOT be substituted for one 500 mg/125 mg amoxicillin and clavulanate potassium tablet. Since both the 250 mg and 500 mg tablets of amoxicillin and clavulanate potassium tablets contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250 mg tablets of amoxicillin and clavulanate potassium tablets are not equivalent to one 500 mg tablet of amoxicillin and clavulanate potassium tablet.

4 CONTRAINDICATIONS History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens–Johnson syndrome) to amoxicillin/clavulanate potassium or to other beta–lactams (e.g., penicillins or cephalosporins). ( 4.1 ) History of cholestatic jaundice/hepatic dysfunction associated with amoxicillin/clavulanate potassium. ( 4.2 ) 4.1 Serious Hypersensitivity Reactions Amoxicillin/clavulanate potassium 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/clavulanate potassium is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with amoxicillin/clavulanate potassium.

5 WARNINGS AND PRECAUTIONS Serious (including fatal) hypersensitivity reactions: Discontinue amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) if a reaction occurs. ( 5.1 ) Severe Cutaneous Adverse Reactions (SCAR): Monitor closely. Discontinue if rash progresses. ( 5.2 ) Drug-induced enterocolitis syndrome (DIES) has been reported with the use of amoxicillin, a component of amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable). If this occurs, discontinue amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) 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): Evaluate patients if diarrhea occurs. ( 5.5 ) Patients with mononucleosis who receive amoxicillin/clavulanate potassium develop skin rash. Avoid amoxicillin/clavulanate potassium use in these patients. ( 5.6 ) Overgrowth: The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. ( 5.7 ) 5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including amoxicillin/clavulanate potassium. 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 tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable), careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) should be discontinued, and appropriate therapy instituted. 5.2 Severe Cutaneous Adverse Reactions Amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) 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 tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) discontinued if lesions progress. 5.3 Drug-Induced Enterocolitis Syndrome (DIES) Drug-induced enterocolitis syndrome (DIES) has been reported with the use of amoxicillin, a component of amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable), [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 tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) and institute appropriate therapy. 5.4 Hepatic Dysfunction Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of amoxicillin/clavulanate potassium. Hepatic toxicity is usually reversible; however, deaths have been reported. Hepatic function should be monitored at regular intervals in patients with hepatic impairment. 5.5 Clostridioides difficile Associated Diarrhea (CDAD) Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin/clavulanate potassium, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. 5.6 Skin Rash in Patients with Mononucleosis A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus, amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, and amoxicillin and clavulanate potassium tablets (chewable) should not be administered to patients with mononucleosis. 5.7 Potential for Microbial Overgrowth The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfection occurs, amoxicillin/clavulanate potassium should be discontinued and appropriate therapy instituted. 5.8 Phenylketonurics Amoxicillin and clavulanate potassium tablets (chewable) and amoxicillin and clavulanate potassium for oral suspension contain aspartame which contains phenylalanine. Each 200 mg/28.5 mg chewable tablet of amoxicillin/clavulanate potassium contains 3.4 mg phenylalanine. Each 400 mg/57 mg chewable tablet contains 6.7 mg phenylalanine. Each 5 mL of the 200 mg/28.5 mg per 5 mL oral suspension contains 0.67 mg phenylalanine. Each 5 mL of the 400 mg/57 mg per 5 mL oral suspension contains 1.12 mg phenylalanine. The other formulations of amoxicillin/clavulanate potassium do not contain phenylalanine. 5.9 Development of Drug-Resistant Bacteria Prescribing amoxicillin and clavulanate potassium tablets, amoxicillin and clavulanate potassium for oral suspension, or amoxicillin and clavulanate potassium tablets (chewable) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug–resistant bacteria.

7 DRUG INTERACTIONS Coadministration with probenecid is not recommended. ( 7.1 ) Concomitant use of amoxicillin/clavulanate potassium and oral anticoagulants may increase the prolongation of prothrombin time. ( 7.2 ) Coadministration with allopurinol increases the risk of rash. ( 7.3 ) Amoxicillin/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/clavulanate potassium may result in increased and prolonged blood concentrations 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 with amoxicillin/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/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/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.

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 )] 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 Teva at 1-888-838-2872 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/clavulanate potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxicillin/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/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/clavulanate potassium. Gastrointestinal: Indigestion, gastritis, stomatitis, glossitis, Drug-induced enterocolitis syndrome (DIES), 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/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/clavulanate potassium. There have been reports of increased prothrombin time in patients receiving amoxicillin/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.

8.1 Pregnancy Teratogenic Effects : Reproduction studies performed in pregnant rats and mice given amoxicillin/clavulanate potassium (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/clavulanate potassium. The amoxicillin doses in rats and mice (based on body surface area) were approximately 4 and 2 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, these dose multiples were approximately 9 and 4 times the maximum recommended adult human oral dose (125 mg every 8 hours). There are, however, no adequate and well–controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.