Can isoniazid, rifampicin, pyrazinamide, and ethambutol cause pancytopenia?

Pancytopenia Risk with Tuberculosis Medications

Yes, rifampicin is the most likely agent in the isoniazid, rifampicin, pyrazinamide, and ethambutol regimen to cause pancytopenia, though all these drugs can potentially contribute to hematologic abnormalities. 1

Hematologic Effects of First-Line TB Medications

Rifampicin

• Most commonly associated with hematologic abnormalities among first-line TB drugs 1
• Can cause thrombocytopenia (particularly with high-dose intermittent therapy), leukopenia, hemolytic anemia, and decreased hemoglobin 1
• In severe cases, can lead to disseminated intravascular coagulation and cerebral hemorrhage 1
• Vitamin K-dependent coagulation disorders with abnormal prolongation of prothrombin time have been reported 1
• Agranulocytosis, though very rare, has been documented with rifampicin use 1

Isoniazid

• Less commonly associated with hematologic abnormalities compared to rifampicin 2
• Can occasionally contribute to anemia, particularly in patients with G6PD deficiency 3
• Hematologic side effects are not among the most common adverse reactions 4

Pyrazinamide

• Primarily known for hepatotoxicity and hyperuricemia rather than hematologic effects 4, 2
• Less frequently associated with blood dyscrasias compared to rifampicin 2
• May contribute to cumulative risk when used in combination with other agents 2

Ethambutol

• Rarely associated with hematologic abnormalities 5
• Primarily known for optic neuritis rather than blood dyscrasias 3

Risk Factors and Monitoring

• Age ≥60 years increases risk of adverse effects, particularly with pyrazinamide 2
• History of hepatitis increases risk of drug intolerance 2
• Baseline laboratory testing is recommended for patients at higher risk of adverse effects 5
• Monthly clinical and laboratory monitoring is essential during treatment 3

Management of Hematologic Abnormalities

• If pancytopenia develops, the suspected medication should be immediately discontinued 3
• Sequential reintroduction of drugs may help identify the offending agent 3
• Alternative regimens should be considered if a drug must be permanently excluded:
  • If rifampicin cannot be used, treatment with pyrazinamide, ethambutol, and a fluoroquinolone for 9-12 months is recommended 6
  • If isoniazid cannot be used, treatment with rifampicin and ethambutol for at least 12 months, supplemented with pyrazinamide for the initial two months 3

Clinical Approach

1. Obtain complete blood count at baseline and monitor regularly during treatment 5
2. If pancytopenia develops, immediately stop all medications 3
3. After blood counts normalize, consider sequential reintroduction of drugs (starting with ethambutol, then isoniazid, then pyrazinamide, with rifampicin last) 3
4. If a specific drug is identified as the cause, permanently exclude it and adjust the regimen accordingly 3
5. Consult with a specialist experienced in TB management for complex cases 6

Important Caveats

• Hematologic abnormalities may be more common with intermittent dosing regimens 1
• Resumption of treatment after interruption increases risk of adverse reactions 1
• Drug interactions may potentiate hematologic toxicity, particularly in HIV-positive patients 6
• Severe reactions like agranulocytosis require immediate and permanent discontinuation of the offending drug 1