Amoxicillin and Clavulanate Potassium (Page 3 of 7)

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 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.

5.4 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.

5.5 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.

5.6 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.

5.7 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.

5.8 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.

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)]
  • Hepatic Dysfunction [see Warnings and Precautions (5.3)]
  • Clostridioides difficile Associated Diarrhea (CDAD) [see Warnings and Precautions (5.4)]

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, 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 (5.4)].

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 [see Warnings and Precautions (5.2)].

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 (5.3)].

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.

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