What are the side effects of nitrofurantoin and which patients (those with impaired renal function, the elderly, a history of lung or liver disease, or pregnant women) require special monitoring or should avoid it?

Nitrofurantoin Side Effects and Special Population Considerations

Nitrofurantoin causes serious pulmonary, hepatic, and neurologic toxicity that can be fatal, particularly with prolonged use, and should be avoided in patients with creatinine clearance below 30 mL/min due to both reduced efficacy and increased toxicity risk. 1

Major Adverse Effects

Pulmonary Toxicity

• Acute pulmonary reactions occur most commonly within the first week of treatment and manifest as fever, chills, cough, chest pain, dyspnea, pulmonary infiltration with consolidation or pleural effusion on x-ray, and eosinophilia 1
• These acute reactions are reversible with immediate cessation of therapy, often with dramatic resolution 1
• Chronic pulmonary fibrosis can develop with long-term use, causing end-stage interstitial fibrosis with diffuse alveolar damage that may be irreversible and fatal 2
• Patients on long-term nitrofurantoin require regular monitoring for pulmonary symptoms and chest imaging 2

Hepatotoxicity

• Hepatic reactions include hepatitis, cholestatic jaundice, chronic active hepatitis, and hepatic necrosis, all of which occur rarely but can be severe 1
• Chronic active hepatitis from nitrofurantoin can progress to cirrhosis and death if the drug is not discontinued 3
• Liver function tests should be monitored during prolonged therapy 3

Neurologic Toxicity

• Peripheral neuropathy may become severe or irreversible, with fatalities reported 1
• Risk factors for peripheral neuropathy include renal impairment (creatinine clearance under 60 mL/min), anemia, diabetes mellitus, electrolyte imbalance, vitamin B deficiency, and debilitating diseases 1
• Other neurologic effects include asthenia, vertigo, nystagmus, dizziness, headache, drowsiness, benign intracranial hypertension, confusion, depression, optic neuritis, and psychotic reactions 1

Hematologic Effects

• Cyanosis secondary to methemoglobinemia has been reported rarely 1
• Laboratory abnormalities include agranulocytosis, leukopenia, granulocytopenia, hemolytic anemia, thrombocytopenia, and megaloblastic anemia 1
• Glucose-6-phosphate dehydrogenase deficiency anemia and aplastic anemia (rare) can occur 1

Gastrointestinal Effects

• Nausea, emesis, and anorexia occur most frequently and are dose-related 1
• Abdominal pain and diarrhea are less common 1
• Sialadenitis, pancreatitis, and pseudomembranous colitis have been reported 1

Hypersensitivity Reactions

• Hypersensitivity reactions represent the most frequent spontaneously-reported adverse events in worldwide postmarketing experience 1
• A lupus-like syndrome associated with pulmonary reactions has been reported 1
• Other allergic manifestations include angioedema, maculopapular/erythematous/eczematous eruptions, pruritus, urticaria, anaphylaxis, arthralgia, myalgia, drug fever, and vasculitis 1

Dermatologic Effects

• Exfoliative dermatitis and erythema multiforme (including Stevens-Johnson syndrome) occur rarely 1
• Transient alopecia has been reported 1

Special Population Considerations

Patients with Renal Impairment

Nitrofurantoin is contraindicated in patients with creatinine clearance below 60 mL/min according to FDA labeling 1, though recent evidence suggests this may be overly restrictive:

• The original contraindication was based on limited 1968 data showing reduced urinary drug recovery, not clinical efficacy endpoints 4
• More recent studies demonstrate that nitrofurantoin remains effective for acute uncomplicated cystitis in patients with CrCl 30-60 mL/min 5
• In patients with CrCl below 30 mL/min, nitrofurantoin should be avoided due to both inadequate urinary concentrations for efficacy and markedly increased risk of peripheral neuropathy 1, 5
• The 2015 Beers Criteria revised its recommendation to avoid nitrofurantoin only when CrCl is below 30 mL/min rather than below 60 mL/min 6

Clinical approach for renal impairment:

• CrCl ≥60 mL/min: Use standard dosing 4
• CrCl 30-60 mL/min: May use with caution for short-term treatment (5-7 days) of acute uncomplicated cystitis with susceptible organisms, avoiding prolonged therapy 5
• CrCl <30 mL/min: Avoid use 1, 5

Elderly Patients

• Elderly patients are at higher risk for adverse effects due to age-related decline in renal function 1
• Peripheral neuropathy risk is substantially elevated in elderly patients, particularly those with unrecognized renal insufficiency 1
• The revised Beers Criteria allow use in elderly patients with CrCl ≥30 mL/min for short-term treatment 6
• Monitor renal function before initiating therapy in all elderly patients 6

Patients with History of Lung Disease

• Nitrofurantoin should be avoided or used with extreme caution in patients with pre-existing pulmonary disease 2
• Patients with any history of pulmonary reactions to nitrofurantoin should never be re-exposed 1
• If use is necessary, baseline chest imaging and pulmonary function testing should be obtained, with regular monitoring during therapy 2

Patients with History of Liver Disease

• Use with caution in patients with underlying liver disease, as nitrofurantoin can cause severe hepatotoxicity 3
• Baseline and periodic liver function tests are essential when treating patients with pre-existing hepatic disease 3
• Discontinue immediately if signs of hepatitis develop (jaundice, elevated transaminases, hepatomegaly) 3

Pregnant Women

• Nitrofurantoin is generally considered safe during most of pregnancy, though data are limited 1
• Avoid use at term (38-42 weeks gestation) and during labor/delivery due to risk of hemolytic anemia in the newborn, particularly in infants with G6PD deficiency 1
• The risk-benefit ratio should be carefully considered, especially in the first trimester 1

Critical Monitoring Parameters

For All Patients on Nitrofurantoin:

• Baseline: Complete blood count, renal function (creatinine clearance), liver function tests 3
• During therapy: Monitor for pulmonary symptoms (cough, dyspnea, chest pain), neurologic symptoms (numbness, tingling, weakness), and hepatic symptoms (jaundice, right upper quadrant pain) 1, 3
• Long-term use (>6 months): Regular pulmonary function testing, chest imaging, and liver function monitoring 2

Red Flags Requiring Immediate Discontinuation:

• Any pulmonary symptoms developing during treatment 1
• Signs of peripheral neuropathy 1
• Elevated liver enzymes or clinical hepatitis 3
• Hemolytic anemia or other severe hematologic reactions 1

Common Pitfalls to Avoid

• Do not use for prolonged prophylaxis without regular monitoring, as chronic pulmonary fibrosis and hepatotoxicity are associated with long-term use 2, 3
• Do not prescribe in patients with CrCl <30 mL/min regardless of indication 5
• Do not ignore early pulmonary symptoms (fever, cough, dyspnea in first week), as failure to discontinue can lead to severe reactions 1
• Do not use in patients with diabetes, anemia, or vitamin B deficiency without careful consideration of peripheral neuropathy risk 1
• Do not combine with other nephrotoxic or neurotoxic agents when avoidable 1