What medications contribute to macrocytosis (large red blood cell condition)?

From the Guidelines

Medications such as methotrexate, sulfasalazine, azathioprine, and 6-mercaptopurine are known to contribute to macrocytosis, primarily through interference with folate metabolism or myelosuppressive activity, as highlighted in the most recent guideline from 2023 1.

Causes of Macrocytosis

The causes of macrocytosis can be multifactorial, including:

• Medications that interfere with DNA synthesis, such as anticonvulsants, chemotherapeutic agents, and immunosuppressants
• Folate deficiency, which can be exacerbated by certain medications like methotrexate and sulfasalazine
• Vitamin B12 deficiency, which can also contribute to macrocytosis
• Other factors such as alcoholism, liver disease, and myelodysplastic syndromes

Medications Contributing to Macrocytosis

Specific medications that contribute to macrocytosis include:

• Methotrexate, which directly antagonizes folate metabolism 1
• Sulfasalazine, which can cause folate malabsorption 1
• Azathioprine and 6-mercaptopurine, which induce macrocytosis through myelosuppressive activity 1
• Other medications such as trimethoprim, sulfamethoxazole, and certain antibiotics, which can also interfere with folate metabolism or DNA synthesis

Management Approach

When evaluating macrocytosis, it is essential to consider medication history alongside other common causes, as the condition is usually reversible upon discontinuation of the offending medication, though this should only be done under medical supervision 1.

Key Considerations

• Folate supplementation may be necessary for patients taking certain medications, such as methotrexate and sulfasalazine, to prevent folate deficiency 1
• Vitamin B12 deficiency should be treated immediately, especially in cases with possible neurological involvement, and folate supplementation should not mask severe vitamin B12 depletion 1

From the FDA Drug Label

Macrocytosis was reported in the majority of pediatric subjects receiving zidovudine 180 mg per m2 every 6 hours in open-label trials.

Zidovudine can contribute to macrocytosis, as it was reported in the majority of pediatric subjects receiving the medication in open-label trials 2.

From the Research

Medications Contributing to Macrocytosis

• Macrocytosis is a condition characterized by larger than normal red blood cells, and it can be caused by various medications, including:
  • Methotrexate: a study published in the Journal of rheumatic diseases 3 found that methotrexate can cause macrocytosis in patients with rheumatoid arthritis, and that this condition is associated with an increased risk of hematologic toxicity.
  • Zidovudine: studies published in the American journal of clinical pathology 4 and AIDS patient care and STDs 5 found that zidovudine, a medication used to treat HIV infection, can cause macrocytosis in patients.
  • Stavudine: a study published in AIDS patient care and STDs 5 found that stavudine, another medication used to treat HIV infection, can also cause macrocytosis.
• Other medications that can cause macrocytosis include:
  • Certain drugs used to treat myelodysplastic syndrome (MDS) and myeloid neoplasms, as mentioned in a study published in the Journal of general and family medicine 6.
  • Medications that can cause folate deficiency, such as methotrexate, as mentioned in a study published in Arthritis and rheumatism 7.

Clinical Implications

• Macrocytosis can be a predictor of hematologic toxicity due to methotrexate therapy, as mentioned in a study published in Arthritis and rheumatism 7.
• Macrocytosis can also be used as a clinical indicator of zidovudine adherence in patients with HIV infection, as mentioned in a study published in AIDS patient care and STDs 5.
• It is essential to differentiate nonmegaloblastic from megaloblastic anemia, as mentioned in a study published in the Journal of general and family medicine 6, to provide appropriate treatment for macrocytic anemias.