Common Side Effects of Rifabutin, Ethambutol, and Azithromycin
The most common side effects are gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain) for all three drugs, with rifabutin additionally causing fever/flu-like illness and leukopenia, ethambutol causing ocular toxicity, and azithromycin causing reversible hearing impairment. 1
Rifabutin Side Effects
Most Common Toxicities
- Fever, chills, and flu-like illness are the most frequent adverse effects of rifabutin, occurring commonly and typically resolving with dose reduction 1
- Gastrointestinal symptoms (nausea, vomiting, diarrhea) occur in approximately 42% of patients receiving high-dose rifabutin 2
- Leukopenia is common, with total white blood cell counts frequently dropping below 5,000 cells/μL at doses of 300-600 mg/day, though severe reductions below 2,000 cells/μL are unusual 1
Serious Dose-Related Toxicities
- Uveitis occurs particularly at higher doses (450-600 mg/day) when combined with clarithromycin, which more than doubles rifabutin serum levels 1
- Polyarthralgia syndrome is a severe adverse event occurring in approximately 19% of patients on high-dose rifabutin, always requiring dosage adjustment 2
- Rifabutin toxicity is dose-related and frequently requires adjustment to 150 mg/day, especially in elderly patients with low body weight when combined with clarithromycin 1
Additional Effects
- Orange discoloration of body fluids (urine, tears, sweat) and potential permanent staining of soft contact lenses 1
- Hepatotoxicity can occur but is less common than with rifampin 1
Ethambutol Side Effects
Ocular Toxicity (Most Significant)
- Optic neuritis is the primary concern, presenting with blurred vision, decreased visual acuity, central scotomas, and impaired red-green color discrimination 1
- Daily dosing carries higher risk than intermittent administration: 6% of patients on daily therapy developed ocular toxicity compared to 0% on three-times-weekly therapy in one study of 229 patients 1
- Risk is greater in MAC lung disease than tuberculosis due to longer treatment duration 1
- Ethambutol excretion is reduced in renal dysfunction, increasing toxicity risk 1
Monitoring Requirements
- Visual acuity and red-green color discrimination must be monitored monthly when receiving 25 mg/kg/day 1
- Discontinue immediately with any subjective visual loss 1
- Ophthalmology evaluation required for symptomatic patients 1
Azithromycin Side Effects
Gastrointestinal Effects
- Diarrhea is the primary gastrointestinal symptom, occurring more frequently than with other macrolides 1
- Nausea, vomiting, and abdominal pain occur in 5-18% of patients depending on dose 3
- Most adult patients with MAC lung disease cannot tolerate doses greater than 300 mg/day due to gastrointestinal symptoms 1
Ototoxicity
- Reversible hearing impairment and tinnitus occur particularly with higher doses in elderly patients 1
- Maximum recommended doses are 250 mg/day or 500 mg three times weekly to minimize this risk 1
Other Common Effects
- Headache and dizziness occur in approximately 1% of patients 1, 3
- Abdominal discomfort occurs commonly across all dosing regimens 1, 3
Critical Drug Interaction Warning
Rifabutin combined with clarithromycin significantly increases rifabutin toxicity risk, particularly uveitis, because clarithromycin more than doubles rifabutin serum levels by inhibiting hepatic metabolism 1, 2. When these drugs are used together, rifabutin dosage must be reduced to 150 mg/day, especially in elderly patients 1.