What medications can cause leukopenia or neutropenia?

Medications That Can Lower WBCs or Neutrophils

Numerous medication classes can cause leukopenia or neutropenia, with chemotherapy agents, certain antibiotics, antiepileptics, immunosuppressants, and antithyroid drugs being the most common culprits.

Chemotherapy Agents

Chemotherapy drugs are among the most frequent causes of leukopenia due to direct myelosuppressive effects on bone marrow 1, 2:

• Gemcitabine + cisplatin causes leukopenia in 21.5-78.8% of patients depending on the regimen 1
• MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) causes leukopenia in 14.3-62% of patients 1
• Paclitaxel + gemcitabine + cisplatin causes leukopenia in 49-60% of patients 1
• Larotaxel + cisplatin causes leukopenia in 16% of patients 1
• Cyclophosphamide has increased leukopenic activity when combined with CYP3A4 inducers like carbamazepine 3

Antibiotics

Beta-lactam antibiotics and other antimicrobials are well-documented causes of neutropenia 4, 5, 6:

• Beta-lactam antibiotics (penicillins, cephalosporins) cause neutropenia through immunologic reactions, with penicillinase-resistant penicillins most frequently implicated, especially at dosages ≥150 mg/kg/day in pediatric patients 4, 5
• Ticarcillin can cause rapid neutropenia, typically resolving within 3 days of discontinuation 5
• Moxalactam has been associated with neutropenia developing after approximately 2 weeks of therapy 5
• Trimethoprim-sulfamethoxazole is associated with leukopenia 2, 7, 4
• Vancomycin is among drugs most often associated with neutropenia 4

Antiepileptic Drugs

Antiepileptic medications commonly cause chronic leukopenia 3, 8:

• Carbamazepine causes leukopenia and requires monitoring with baseline and periodic CBC; discontinuation should be considered if significant bone marrow depression develops 3, 4, 8
• Phenytoin is associated with leukopenia 8
• Valproate can cause leukopenia 8
• Phenobarbital and primidone have been associated with leukopenia 8

The FDA label for carbamazepine specifically warns that patients exhibiting low or decreased WBC counts should be monitored closely, and discontinuation should be considered if evidence of significant bone marrow depression develops 3.

Immunosuppressants

Immunosuppressive medications frequently cause leukopenia 2, 7:

• Tacrolimus itself does not directly cause leukocytosis but increases infection risk through immunosuppression 7
• Methotrexate typically causes leukopenia rather than leukocytosis and requires regular CBC monitoring 7
• Azathioprine typically causes leukopenia 7
• Cyclosporine is mentioned in drug interaction contexts with potential hematologic effects 1

Other High-Risk Medications

Additional medications with significant neutropenia risk include 4:

• Antithyroid drugs (propylthiouracil) are among the most common causes 4
• Clozapine is well-documented to cause agranulocytosis 4
• Ticlopidine is frequently associated with neutropenia 4
• Dipyrone and diclofenac are among the most common causes globally 4
• Spironolactone has been associated with neutropenia 4
• Levamisole is a known cause of drug-induced neutropenia 4
• Ganciclovir is associated with leukopenia 2, 7
• Vorinostat causes leukopenia in 20-42% of patients 2

Monitoring and Management Considerations

For patients on high-risk medications, baseline CBC before starting therapy is essential, with frequency of monitoring depending on the specific agent 2, 3:

• Carbamazepine requires baseline and periodic CBC monitoring; discontinue if significant bone marrow depression develops 3
• Vorinostat requires CBC monitoring weekly during initial therapy, then every 2-4 weeks once stable 2
• For chemotherapy-induced neutropenia with fever, G-CSF should be considered for high-risk patients 2, 9
• Chemotherapy should be held until adequate recovery: ANC ≥1000-1500/mm³ 9

Common pitfall: Antiepileptic drug-related chronic leukopenia (WBC <4,000/μL) often stabilizes and may not require discontinuation if the absolute neutrophil count remains >1,000/μL and bone marrow examination is normal 8. However, caution is warranted if absolute PMN count is consistently <1,000/μL 8.

Risk Factors

Patients at higher risk for medication-induced leukopenia include those with 2:

• Advanced age
• Renal or hepatic dysfunction
• Concurrent use of multiple myelosuppressive agents

The incidence of severe neutropenia or agranulocytosis from nonchemotherapy drugs ranges from 1.6 to 15.4 cases per million population per year 4.