Amoxicillin and clavulanate potassium tablets are indicated for the treatment of infections in adults and pediatric patients, due to susceptible isolates of the designated bacteria in the conditions listed below:

• Lower Respiratory Tract Infections- caused by beta‑lactamase‑producing isolates of Haemophilus influenzaeand Moraxella catarrhalis.
• Acute Bacterial Otitis Media- caused by beta‑lactamase‑producing isolates of H. influenzaeand M. catarrhalis.
• Sinusitis- caused by beta‑lactamase‑producing isolates of H. influenzaeand M. catarrhalis.
• Skin and Skin Structure Infections- caused by beta‑lactamase‑producing isolates of Staphylococcus aureus, Escherichia coli,and Klebsiellaspecies.
• Urinary Tract Infections- caused by beta‑lactamase‑producing isolates of E. coli, Klebsiellaspecies, and Enterobacterspecies.
Limitations of Use
When susceptibility test results show susceptibility to amoxicillin, indicating no beta-lactamase production, amoxicillin and clavulanate potassium tablets should not be used.
Usage
To reduce the development of drug‑resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium tablets and other antibacterial drugs, amoxicillin and clavulanate potassium tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Amoxicillin and clavulanate potassium tablets are a combination of amoxicillin, a penicillin-class antibacterial and clavulanate potassium, a beta‑lactamase inhibitor indicated for treatment of the following infections in adults and pediatric patients: ( 1)

• Lower respiratory tract infections
• Acute bacterial otitis media
• Sinusitis
• Skin and skin structure infections
• Urinary tract infections 

Limitations of Use

When susceptibility test results show susceptibility to amoxicillin, indicating no beta-lactamase production, amoxicillin and clavulanate potassium tablets should not be used. ( 1)

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium tablets and other antibacterial drugs, amoxicillin and clavulanate potassium tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1)

• Adults and Pediatric Patients greater than 40 kg: 500 or 875 mg every 12 hours or 250 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. Use of the 125 mg/5 mL oral suspension is recommended. ( 2.3)

Amoxicillin and clavulanate potassium tablets may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when amoxicillin and clavulanate potassium tablets are administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, amoxicillin and clavulanate potassium tablets should be taken at the start of a meal.

See dosing regimens of amoxicillin and clavulanate potassium (based on the amoxicillin component) provided in Table 1 below.
Table 1. Dosing Regimens of Amoxicillin and Clavulanate Potassium in Adult Patients

^a   Adults who have difficulty swallowing may be given the amoxicillin and clavulanate potassium 200 mg/28.5 mg per 5 mL suspension or the amoxicillin and clavulanate potassium 400 mg/57 mg per 5 mL suspension may be used in place of the 875 mg/125 mg tablet.

^b  Adults who have difficulty swallowing may be given the amoxicillin and clavulanate potassium 125 mg/31.25 mg per 5 mL suspension or amoxicillin and clavulanate potassium 250 mg/62.5 mg per 5 mL suspension in place of the 500 mg/125 mg tablet.

^c  Two amoxicillin and clavulanate potassium 250 mg/125 mg tablets are NOTsubstitutable 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 NOTsubstitutable with amoxicillin and clavulanate potassium 250 mg/62.5 mg chewable tablet [see Dosage and Administration ( 2.6)] . 

Based on the amoxicillin component, amoxicillin and clavulanate potassium should be dosed as follows:
Neonates and Infants Aged less than 12 weeks (less than 3 months): See dosing regimens of amoxicillin and clavulanate potassium provided in Table 2 below.
Table 2: Dosing Regimens of Amoxicillin and Clavulanate Potassium in Neonates and Infants Aged Less than 12 Weeks (Less than 3 Months)

^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)] .   Table 3: Dosing in Patients Aged 12 Weeks (3 Months) and Older and Weighing Less than 40 kg

^a  Each strength of amoxicillin and clavulanate potassium for oral suspension is available as a chewable tablet for use by older children.

^b  Duration of therapy studied and recommended for acute otitis media is 10 days.

Patients Weighing 40 kg or More: Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations.

 • The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium should NOTbe used until the child weighs at least 40 kg, due to the different amoxicillin to clavulanic acid ratios in the 250 mg/125 mg tablet of amoxicillin and clavulanate potassium versus the 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium.  

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 NOTreceive the 875 mg dose (based on the amoxicillin component) of amoxicillin and clavulanate potassium tablet. See dosing regimens in patients with severe renal impairment provided in Table 4.
Table 4. Dosing Regimens of Amoxicillin and Clavulanate Potassium in Patients with Severe Renal Impairment

Amoxicillin and Clavulanate Potassium 250 mg/125 mg Tablet is NOTSubstitutable with Amoxicillin and Clavulanate Potassium 250 mg/62.5 mg Chewable Tablet

The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium and the 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium should NOTbe substituted for each other and the 250 mg/125 mg tablet of amoxicillin and clavulanate potassium should NOTbe used in pediatric patients weighing less than 40 kg [see Dosage and Administration ( 2.3)]. The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium and the 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium do not contain the same amount of clavulanic acid. The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium contains 125 mg of clavulanic acid whereas the 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium contains 62.5 mg of clavulanic acid.

Two Amoxicillin and Clavulanate Potassium 250 mg/125 mg Tablets are NOTSubstitutable with One 500 mg/125 mg Amoxicillin and Clavulanate Potassium Tablet

Two 250 mg/125 mg tablets of amoxicillin and clavulanate potassium should NOTbe substituted for one 500 mg/125 mg tablet of amoxicillin and clavulanate potassium. Since both the 250 mg/125 mg and 500 mg/125 mg tablets of amoxicillin and clavulanate potassium contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250 mg/125 mg tablets of amoxicillin and clavulanate potassium are not equivalent to one 500 mg/125 mg tablet of amoxicillin and clavulanate potassium.

• History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin and clavulanate potassium or to other beta‑lactams (e.g., penicillins or cephalosporins). ( 4.1)
• History of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium. ( 4.2)

Amoxicillin and clavulanate potassium tablets are contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin, clavulanate or to other beta‑lactam antibacterial drugs (e.g., penicillins and cephalosporins).

Amoxicillin and clavulanate potassium tablets are contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium.

• Serious (including fatal) hypersensitivity reactions: Discontinue amoxicillin and clavulanate potassium 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 use of amoxicillin, a component of amoxicillin and clavulanate potassium. If this occurs, discontinue amoxicillin and clavulanate potassium 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 and clavulanate potassium develop skin rash. Avoid amoxicillin and 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)

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including amoxicillin and 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, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, amoxicillin and clavulanate potassium should be discontinued, and appropriate therapy instituted.

Amoxicillin and clavulanate potassium 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 discontinued if lesions progress.

Drug-induced enterocolitis syndrome (DIES) has been reported with use of amoxicillin, a component of amoxicillin and clavulanate potassium [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 of ingesting amoxicillin, and leukocytosis with neutrophilia. If DIES occurs, discontinue amoxicillin and clavulanate potassium and institute appropriate therapy.

Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of amoxicillin and 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.

Clostridioides difficileassociated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin and 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. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficilecause 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. difficilemay 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.

A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus, amoxicillin and clavulanate potassium should not be administered to patients with mononucleosis.

The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfection occurs, amoxicillin and clavulanate potassium should be discontinued and appropriate therapy instituted.

Prescribing amoxicillin and clavulanate potassium 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.

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 difficileAssociated 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 Micro Labs USA Inc. at 1-855-839-8195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 US/Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of amoxicillin and clavulanate potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxicillin and clavulanate potassium for 10 days in the treatment of acute otitis media. A total of 575 patients were enrolled, and only the suspension formulations were used in this trial. Overall, the adverse reactions seen were comparable to that noted above; however, there were differences in the rates of diarrhea, skin rashes/urticaria, and diaper area rashes [see Clinical Studies ( 14.2)] .

In addition to adverse reactions reported from clinical trials, the following have been identified during postmarketing use of amoxicillin and clavulanate potassium. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to amoxicillin and clavulanate potassium.

Gastrointestinal:Drug-induced enterocolitis syndrome (DIES), indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment [see Warnings and Precautions ( 5.5)].

Immune:Hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock), angioedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), hypersensitivity vasculitis [see Warnings and Precautions ( 5.1)].

Skin and Appendages:Rashes, pruritus, urticaria, erythema multiforme, SJS, TEN, DRESS, AGEP, exfoliative dermatitis, and linear IgA bullous dermatosis.

Liver:Hepatic dysfunction, including hepatitis and cholestatic jaundice, increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been reported with amoxicillin and clavulanate potassium. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, is usually reversible. Deaths have been reported [see Contraindications ( 4.2), Warnings and Precautions ( 5.4)] .

Renal:Interstitial nephritis, hematuria, and crystalluria have been reported [see Overdosage ( 10)] .

Hemic and Lymphatic Systems:Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Thrombocytosis was noted in less than 1% of the patients treated with amoxicillin and clavulanate potassium. There have been reports of increased prothrombin time in patients receiving amoxicillin and clavulanate potassium and anticoagulant therapy concomitantly [see Drug Interactions ( 7.2)] .

Central Nervous System:Agitation, anxiety, behavioral changes, aseptic meningitis, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported.

Miscellaneous:Tooth discoloration (brown, yellow, or gray staining) has been reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases.