Folate Antagonists Flashcards
What drugs are in the Folate Antagonist class?
Drugs in this class are:
- Methotrexate
- Pemetrexed
What are the main cancer-related indications for use of Methotrexate?
The main cancer-related indications of this drug are:
- ALL
- Non-Hodgkin Lymphoma
- GVHD
- Bladder Cancer
- Head and Neck Cancer
- Osteosarcoma
- Soft Tissue Sarcoma
What are the main indications for use of Pemetrexed?
The main indications of this drug are:
- Bladder Cancer
- Mesothelioma
- NSCLC
What is the class and MOA of Methotrexate?
This drug in the following class:
- Folate antagonist
This drug’s MOA is as follows:
- Inhibits dihydrofolate reductase thus inhibiting the formation of reduced folates.
- Inhibits thymidylate synthetase thus inhibiting synthesis of purines and thymidylic acid.
- All this leads to inhibition of DNA synthesis, repair, and cellular replication
What is the class and MOA of Pemetrexed?
This drug in the following class:
- Folate antagonist
This drug’s MOA is as follows:
- Inhibits dihydrofolate reductase thus inhibiting the formation of reduced folates.
- Inhibits thymidylate synthetase thus inhibiting synthesis of purines and thymidylic acid.
- All this leads to inhibition of DNA synthesis, repair, and cellular replication
What are the notable monitoring parameters for Methotrexate?
The notable monitoring parameters for this drug are:
- Methotrexate levels with high dose (>500 mg/m2) - monitor daily until cleared
- Urine pH with high dose
What drug(s) notably require monitoring for urine pH?
Drug(s) notably requiring this monitoring are:
- Methotrexate
What drug(s) notably require monitoring for drug levels daily until cleared?
Drug(s) notably requiring this monitoring are:
- Methotrexate
Describe the administration of Methotrexate.
The administration of this drug is described as follows:
- Most methotrexate protocols will require the urine pH to be >7 before starting methotrexate.
- Alkalization protocols vary per institution but often include IV fluids, sodium bicarbonate (either IV or oral) and/or acetazolamide.
What is the emetic potential of Methotrexate?
The emetic potential of this drug is:
- Minimal with low lose (<50 mg/m2)
- Low with low-moderate doses (50-250 mg/m2)
- High with moderate-high doses (>250 mg/m2)
What is the emetic potential of Pemetrexed?
The emetic potential of this drug is:
- Low
Describe the extravasation risk and management strategies for Methotrexate.
The extravasation risk and management strategies for this drug are as follows:
- None; N/A
Describe the extravasation risk and management strategies for Pemetrexed.
The extravasation risk and management strategies for this drug are as follows:
- None; N/A
Describe the metabolism of Methotrexate.
The metabolism of this drug is as follows:
- Minimal metabolism; excreted primarily (90%) in the urine as unchanged drug
- Urine clearance is pH dependant and improved when the urine is alkalized
- High dose methotrexate may “third space” or accumulate in fluid collections leading to prolonged methotrexate clearance and increased toxicity. Patients with ascites. pericardial effusions. pleural effusions or other fluid collections should not receive high
dose methotrexate until those have been drained.
Describe the metabolism of Pemetrexed.
The metabolism of this drug is as follows:
- Minimal metabolism; excreted primarily (90%) in the urine as unchanged drug
What are the notable ADRs of Methotrexate?
The notable ADRs of this drug are:
- Methotrexate toxicity
- Renal dysfunction
- Bone marrow suppression
- Mucositis
What are the notable ADRs of Pemetrexed?
The notable ADRs of this drug are:
- Main one is that serious and occasionally fatal dermatologic toxicity may occur
- Others are myelosuppression, renal dysfunction, and GI toxicities (especially with concomitant Ibuprofen use)
Describe the strategy and rationale for management of Methotrexate toxicity.
The strategy and rationale for management of this condition caused by this drug are:
- Ensure urine is adequate alkalized before starting methotrexate
- Administer leucovorin rescue with doses greater than >500 mg/m2
- Glucarpidase can be administered as an antidote.
How does Glucarpidase work as a antidote with Methotrexate?
This drug works as follows when used as a Methotrexate antidote:
- Glucarpidase is an enzyme that hydrolyzes the methotrexate into inactive metabolites rapidly reducing the methotrexate concentration.
How is Glucarpidase given when used as a Methotrexate antidote?
This drug is given as follows when use as a Methotrexate rescue:
- The typical dose is 50 units/kg and it should ideally be given within 48-60 hours of methotrexate infusion (beyond this point, life threating toxicities may not be preventable).
Describe the strategy and rationale for management of dermatologic toxicity with Pemetrexed.
The strategy and rationale for management of this condition caused by this drug are:
- Pretreat with dexamethasone 4 mg orally twice daily for 3 days to reduce the incidence and severity of cutaneous reactions.
What are the clinical pearls of Methotrexate?
The clinical pearls of this drug are as follows:
- Most methotrexate protocols will require the urine pH to be >7 before starting methotrexate
- Doses >500 mg/m2 require leucovorin “rescue” and inpatient monitoring of levels to ensure appropriate methotrexate clearance
- High dose methotrexate may “third space” or accumulate in fluid collections leading to prolonged methotrexate clearance and increased toxicity. Patients with ascites. pericardial effusions. pleural effusions or other fluid collections should not receive high
dose methotrexate until those have been drained.
- Methotrexate has many drug interactions which can cause delayed clearance. Medications that must be stopped prior to high dose methotrexate include:
- Bactrim, PPIs, Penicillins, Salicylates, Probenecid, NSAIDs, Tetracyclines, and Ciprofloxacin.
- Many of these agents can be stopped 1-2 days prior to high dose methotrexate and can be resumed after adequate clearance.
- Intrathecal methotrexate or low oral doses of methotrexate do not have the same drug interaction concerns.
- When checking doses on oral methotrexate, only oncologic indications will have daily dosing options. If a prescription for lupus, psoriasis, arthritis, etc. is written for daily (instead of weekly) it’s likely an error!
What drugs must be stopped prior to high dose methotrexate?
Medications that must be stopped prior to administration of this drug include:
- Bactrim
- PPIs
- Penicillins
- Salicylates
- Probenecid
- NSAIDs
- Tetracyclines
- Ciprofloxacin
How does Leucovorin work as a “rescue” with Methotrexate?
This drug works as follows when used as a Methotrexate rescue:
- It is folinic acid (an active form of folate) that does not need to be processed by dihydrofolate reductase. It is given to rescue healthy cells from the toxicity of methotrexate and replenish the supply of folate metabolites depleted by methotrexate.