What are the side effects of co‑amoxiclav (amoxicillin/clavulanic acid)?

Side Effects of Co-amoxiclav (Amoxicillin/Clavulanic Acid)

Co-amoxiclav is generally well-tolerated, but gastrointestinal side effects—particularly diarrhea—are the most common adverse events, occurring in approximately 9-44% of patients depending on dose and formulation, with the clavulanate component being the primary culprit. 1, 2

Common Side Effects (Mild to Moderate)

Gastrointestinal Effects

• Diarrhea/loose stools occur in 9% of patients at standard doses but can reach 44% with high-dose formulations, compared to only 14% with placebo 1, 2
• The clavulanate component is responsible for most GI toxicity, with diarrhea becoming especially problematic when clavulanate doses exceed 10 mg/kg/day 3
• Twice-daily dosing significantly reduces diarrhea compared to three-times-daily regimens, and higher amoxicillin:clavulanate ratios (14:1 or 16:1) minimize GI side effects 4, 3
• Nausea (3%), vomiting (1%), abdominal discomfort, and flatulence are also reported 1

Dermatologic Reactions

• Skin rashes and urticaria occur in approximately 3% of patients 1
• Italian surveillance data shows 76% of adverse event reports for co-amoxiclav involve skin reactions, though this is lower than amoxicillin alone (82%) 5

Other Common Effects

• Vaginitis (1%), headache, and mucocutaneous candidiasis 1

Serious Adverse Effects (Rare but Important)

Hepatotoxicity

• Cholestatic hepatitis is the most concerning serious adverse effect, with co-amoxiclav having a 9-fold higher reporting rate for hepatitis compared to amoxicillin alone 5
• Drug-induced cholestatic hepatitis has been documented in 208 reported cases, predominantly affecting males (106 of 153 evaluable patients) with mean age 60 years 6
• Hepatic dysfunction typically manifests 25.2 days after starting treatment (average), with normalization occurring 11.5 weeks after onset 6
• Liver injury patterns include hepatocellular (35 patients), cholestatic (24 patients), and mixed (83 patients) presentations 6
• Three deaths have been reported among 153 patients with hepatotoxicity, though deaths overall are rare (less than 1 per 4 million prescriptions) 6, 1
• Elevated AST/ALT, serum bilirubin, and alkaline phosphatase may occur, reported more commonly in elderly patients, males, and those on prolonged treatment 1

Severe Allergic Reactions

• Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme (rare) 1
• Co-amoxiclav shows higher risk of Stevens-Johnson syndrome and purpura compared to amoxicillin alone 5
• Anaphylactic reactions can occur but are rare 1
• Hypersensitivity vasculitis, serum sickness-like reactions (urticaria/rash with arthritis, arthralgia, myalgia, and fever), and angioedema 1

Hematologic Effects

• Hematological reactions occur in 2% of co-amoxiclav cases versus 1% with amoxicillin alone 5
• Interstitial nephritis and hematuria (rare) 1

Gastrointestinal Complications

• Pseudomembranous colitis and Clostridium difficile infection, with recent antibiotic exposure being an important risk factor 1, 2
• Hemorrhagic/pseudomembranous colitis symptoms may occur during or after treatment 1

Special Population Considerations

Pregnancy

• Co-amoxiclav is not recommended in women at risk of preterm delivery due to very low risk of necrotizing enterocolitis in the fetus 2
• Otherwise compatible during pregnancy when clinically indicated, though diarrhea and dermatitis rates may be higher 2

Pediatrics

• Antibiotics cause over 150,000 unplanned medical visits annually in children for medication-related adverse events 2
• Diaper area rashes are more common in pediatric patients 1
• Emerging evidence suggests early-life antibiotic exposure may contribute to long-term effects including inflammatory bowel disease, obesity, eczema, and asthma 2

Comparative Tolerability

• Ciprofloxacin is better tolerated than co-amoxiclav, with only 12.4% reporting adverse events versus 25% with co-amoxiclav (p=0.012) 3
• Co-amoxiclav has significantly higher rates of gastrointestinal (13% vs 7%), hepatic (4% vs 1%), and hematological (2% vs 1%) reactions compared to amoxicillin alone 5

Clinical Monitoring Recommendations

• Obtain transaminase, alkaline phosphatase, and bilirubin tests within the first two weeks and at 4-5 weeks after starting treatment to detect hepatic side effects early 6
• Less than 3% of patients discontinue therapy due to drug-related side effects 1
• Discontinue immediately if hypersensitivity reactions occur unless physician determines continuation is essential 1