Folate Antagonists

Question 1

What drugs are in the Folate Antagonist class?

Answer 1

Drugs in this class are:
- Methotrexate
- Pemetrexed

Question 2

What are the main cancer-related indications for use of Methotrexate?

Answer 2

The main cancer-related indications of this drug are:
- ALL
- Non-Hodgkin Lymphoma
- GVHD
- Bladder Cancer
- Head and Neck Cancer
- Osteosarcoma
- Soft Tissue Sarcoma

Question 3

What are the main indications for use of Pemetrexed?

Answer 3

The main indications of this drug are:
- Bladder Cancer
- Mesothelioma
- NSCLC

Question 4

What is the class and MOA of Methotrexate?

Answer 4

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

Question 5

What is the class and MOA of Pemetrexed?

Answer 5

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

Question 6

What are the notable monitoring parameters for Methotrexate?

Answer 6

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

Question 7

What drug(s) notably require monitoring for urine pH?

Answer 7

Drug(s) notably requiring this monitoring are:
- Methotrexate

Question 8

What drug(s) notably require monitoring for drug levels daily until cleared?

Answer 8

Drug(s) notably requiring this monitoring are:
- Methotrexate

Question 9

Describe the administration of Methotrexate.

Answer 9

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.

Question 10

What is the emetic potential of Methotrexate?

Answer 10

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)

Question 11

What is the emetic potential of Pemetrexed?

Answer 11

The emetic potential of this drug is:
- Low

Question 12

Describe the extravasation risk and management strategies for Methotrexate.

Answer 12

The extravasation risk and management strategies for this drug are as follows:
- None; N/A

Question 13

Describe the extravasation risk and management strategies for Pemetrexed.

Answer 13

The extravasation risk and management strategies for this drug are as follows:
- None; N/A

Question 14

Describe the metabolism of Methotrexate.

Answer 14

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.

Question 15

Describe the metabolism of Pemetrexed.

Answer 15

The metabolism of this drug is as follows:
- Minimal metabolism; excreted primarily (90%) in the urine as unchanged drug

Question 16

What are the notable ADRs of Methotrexate?

Answer 16

The notable ADRs of this drug are:
- Methotrexate toxicity
- Renal dysfunction
- Bone marrow suppression
- Mucositis

Question 17

What are the notable ADRs of Pemetrexed?

Answer 17

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)

Question 18

Describe the strategy and rationale for management of Methotrexate toxicity.

Answer 18

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.

Question 19

How does Glucarpidase work as a antidote with Methotrexate?

Answer 19

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.

Question 20

How is Glucarpidase given when used as a Methotrexate antidote?

Answer 20

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).

Question 21

Describe the strategy and rationale for management of dermatologic toxicity with Pemetrexed.

Answer 21

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.

Question 22

What are the clinical pearls of Methotrexate?

Answer 22

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!

Question 23

What drugs must be stopped prior to high dose methotrexate?

Answer 23

Medications that must be stopped prior to administration of this drug include:
- Bactrim
- PPIs
- Penicillins
- Salicylates
- Probenecid
- NSAIDs
- Tetracyclines
- Ciprofloxacin

Question 24

How does Leucovorin work as a “rescue” with Methotrexate?

Answer 24

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.

Question 25

How is Leucovorin given when used as a Methotrexate rescue?

Answer 25

This drug is given as follows when use as a Methotrexate rescue:
- Usually started 12-24 hours post high dose methotrexate and given until serum methotrexate levels are below a certain threshold (often 0.05 mM).
- Dosing varies per protocol but oral absorption is saturable at doses >25 mg, so doses >25 mg are often given IV.
- Typical dosing frequency is orally every 6 hours, although dose and frequency may be increased if a patient is experiencing methotrexate toxicity.

Question 26

What are the clinical pearls of Pemetrexed?

Answer 26

The clinical pearls of this drug are as follows:
- Patients receiving pemetrexed require vitamin supplementation with folic acid and B12.
- Give folic acid 400 to 1,000 mcg daily starting 7 days before initial pemetrexed dose and continue daily during treatment and for 21 days after last pemetrexed dose.
- Give Vitamin B12 1,000 mcg IM starting 7 days prior to treatment initiation and then every 3 cycles.
- To prevent dermatologic toxicity, pretreat with dexamethasone
- Patients with a CrCl 45 to 79 mL/min must avoid ibuprofen for 2 days before, the day of, and for 2 days following a dose of pemetrexed. Monitor more frequently for myelosuppression, renal dysfunction, and GI toxicities if concomitant Ibuprofen administration cannot be avoided.