To reduce toxicity, patients treated with pemetrexed must be instructed to take a folic acid preparation or a multivitamin with folic acid

• as a daily oral low-dose
• initiated during the 7-day period preceding the first dose of pemetrexed, and for at least 5 doses, and
• during the full course of therapy and for 21 days after the last dose of pemetrexed.1
  

In clinical trials, the dose of folic acid studied ranged from 350 to 1000 μg. The most commonly used dose of oral folic acid in clinical trials was 400 μg.2

Patients must also receive vitamin B₁₂

• as an IM injection
• initiated the week preceding the first dose of pemetrexed, and
• every 3 cycles thereafter.1

Subsequent vitamin B₁₂ injections may be given the same day as pemetrexed.1 In clinical trials, the dose of vitamin B₁₂ received was 1000 μg.2

In the phase 3 malignant pleural mesothelioma (MPM) registration trial, pretreatment with folic acid and vitamin B₁₂ led to overall less toxicity and reduction in grade 3/4 hematologic and nonhematologic toxicities such as

• neutropenia
• febrile neutropenia, and
• infection with grade 3/4 neutropenia.2,3

Therefore, patients treated with pemetrexed must be instructed to take folic acid and vitamin B₁₂ as a prophylactic measure to reduce treatment-related toxicity.2

The pharmacokinetics (PK) of pemetrexed is not influenced by oral folic acid and IM vitamin B₁₂ supplementation.2