FDA label f95e9c05-74d0-d78a-8560-49b7b8175edb

5 WARNINGS AND PRECAUTIONS Serious (including fatal) hypersensitivity reactions: Discontinue amoxicillin and clavulanate potassium tablets 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 amoxicillin, a component of amoxicillin and clavulanate potassium tablets. If this occurs, discontinue amoxicillin and clavulanate potassium tablets 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: Increased risk of skin rash. Avoid amoxicillin and clavulanate potassium tablets 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. 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, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. Amoxicillin and clavulanate potassium tablets are contraindicated in patients with a history of serious hypersensitivity reactions to amoxicillin, clavulanate, or to other beta-lactam antibacterial drugs [see Contraindications ( 4.1 )] . If an allergic reaction occurs, discontinue amoxicillin and clavulanate potassium tablets and institute appropriate therapy. 5.2 Severe Cutaneous Adverse Reactions (SCAR) Amoxicillin and clavulanate potassium tablets 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 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 tablets [see Adverse Reactions ( 6.2 )] , with most cases occurring in pediatric patients. 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 and institute appropriate therapy. 5.4 Hepatic Dysfunction Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of amoxicillin and clavulanate potassium tablets. Hepato-toxicity is usually reversible; however, deaths have been reported. These cases have generally been associated with serious underlying diseases or concomitant medications. Amoxicillin clavulanate potassium tablets are contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with treatment with amoxicillin and clavulanate potassium [see Contraindications ( 4.2 ), Use in Specific Populations ( 8.7 ), Adverse Reactions ( 6.2 )] . 5.5 Clostridioides difficile Associated Diarrhea (CDAD) Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin and clavulanate potassium tablets, 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 drug 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 drug 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. Avoid amoxicillin and clavulanate potassium tablet use in patients with mononucleosis [see Adverse Reactions ( 6.2 )]. 5.7 Potential for Microbial Overgrowth The possibility of superinfections with mycotic or bacterial pathogens should be considered during therapy. If superinfections occur (commonly involving Pseudomonas spp. or Candida spp.), discontinue amoxicillin and clavulanate potassium tablets and institute appropriate therapy. 5.9 Development of Drug-Resistant Bacteria Prescribing amoxicillin and clavulanate potassium tablets 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Allergic Reactions including Anaphylaxis [ 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 )] Skin Rash in Patients with Mononucleosis [see Warnings and Precautions ( 5.6 )] The most frequently reported adverse reactions with amoxicillin and clavulanate potassium tablets were (incidence ≥3%) diarrhea/loose stools, nausea, skin rash and urticaria ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 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. Amoxicillin and clavulanate potassium tablets The most frequently reported adverse reactions in clinical trials were diarrhea/loose stools (9%), nausea (3%), skin rash and urticaria (3%), vomiting (1%) and vaginitis (1%). Less than 3% of patients discontinued therapy due to adverse reactions. The overall incidence of adverse reactions, particularly diarrhea, increased with higher recommended doses. Other less frequently reported adverse reactions (< 1%) included: abdominal discomfort, flatulence, and headache. In two pivotal trials in adults with lower respiratory tract or urinary tract infections, the overall incidence of adverse reactions was similar between amoxicillin and clavulanate potassium tablets 875 mg/125 mg Tablets every 12 hours and amoxicillin and clavulanate potassium tablets 500 mg/125 mg Tablets every 8 hours [see Clinical Studies ( 14.1 , 14.2 )] . The most common adverse reaction was diarrhea, reported in 15% of patients receiving amoxicillin and clavulanate potassium tablets 875 mg/125 mg every 12 hours and 14% of patients receiving amoxicillin and clavulanate potassium tablets 500 mg/125 mg every 8 hours. The rate of severe diarrhea or discontinuation due to diarrhea was 1% versus 2%, respectively. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of amoxicillin and clavulanate potassium tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Drug-induced enterocolitis syndrome (DIES), diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment [see Warnings and Precautions ( 5.3 , 5.5 )] . Immune Hypersensitivity reactions, anaphylactic reactions (including shock), angioedema, serum sickness–like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), hypersensitivity vasculitis [ see Warnings and Precautions ( 5.1 ) ]. Skin and Appendages Rashes, pruritus, urticaria, erythema multiforme, SJS, TEN, DRESS, AGEP, exfoliative dermatitis, and linear IgA bullous dermatosis [see Warnings and Precautions ( 5.1 , 5.2 , 5.6 )]. Liver A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted in patients treated with ampicillin-class antibacterials. 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 tablets. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of 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 and hematuria have been reported. Crystalluria has also been reported [ see Overdosage ( 10 ) ]. Hemic and Lymphatic Systems Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. There have been reports of increased prothrombin time in patients receiving amoxicillin and clavulanate potassium tablets 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.