European Medicines Agency warns of new adverse reactions to methotrexate!

The European Medicines Agency (EMA) website recently published revised information on the drug labeling of methotrexate, adding information about adverse reactions in progressive multifocal leukoencephalopathy (PML)
.

The European Medicines Agency (EMA) website recently published revised information on the drug labeling of methotrexate, adding information about adverse reactions in progressive multifocal leukoencephalopathy (PML)
.

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Modifications to the product insert of methotrexate include: 【Special Warnings and Precautions】: Progressive multifocal leukoencephalopathy (PML) has received reports of PML in methotrexate-treated patients, mainly occurring in combination with other immunosuppressed patients.
when the drug is used in combination
.

Immunization to PML can lead to death, and the possibility of PML should be considered in the differential diagnosis in immunosuppressed patients with new or worsening neurologic symptoms .

common toxicitycommon toxicity

1.

Symptoms and signs:

1.
Symptoms and signs: Most patients will have one or more of the following common methotrexate toxicities in some form or form at some point

Gastrointestinal problems, such as nausea, upset stomach, and loose stools;

Gastrointestinal problems, such as nausea, upset stomach, and loose stools;

Gastrointestinal problems, such as nausea, upset stomach, and loose stools;

• stomatitis or mouth pain;

stomatitis or mouth pain;

stomatitis or mouth pain;

stomatitis or mouth pain;

• Abnormal liver chemistry, usually mildly elevated liver transaminases;

Abnormal liver chemistry, usually mildly elevated liver transaminases;

Abnormal liver chemistry, usually mildly elevated liver transaminases;

Abnormal liver chemistry, usually mildly elevated liver transaminases;

• Spotted rash, usually on the extremities, often involving the elbows and knees, but not the trunk;

Spotted rash, usually on the extremities, often involving the elbows and knees, but not the trunk;

Spotted rash, usually on the extremities, often involving the elbows and knees, but not the trunk;

Spotted rash, usually on the extremities, often involving the elbows and knees, but not the trunk;

• Central nervous system symptoms, including headache, fatigue, malaise, or inability to concentrate;

Central nervous system symptoms, including headache, fatigue, malaise, or inability to concentrate;

Central nervous system symptoms, including headache, fatigue, malaise, or inability to concentrate;

Central nervous system symptoms, including headache, fatigue, malaise, or inability to concentrate;

• hair loss;

hair loss;

hair loss;

hair loss;

• Drug-related fever, but the cause of the fever may also be infection ;

Drug-related fever, but the cause of the fever may also be infection ;

Drug-related fever, but the cause of the fever may also be infection ;

Drug-related fever, but fever can also be caused by infection ; infection

• Hematologic abnormalities, especially megaloblastic anemia, and less common but severe myelosuppression
  .
  

Hematologic abnormalities, especially megaloblastic anemia, and less common but severe myelosuppression
.

Hematologic abnormalities, especially megaloblastic anemia, and less common but severe myelosuppression
.

Hematologic abnormalities, especially megaloblastic anemia, and less common but severe myelosuppression
.

2.
Time node of the emergence of toxicity

2.
Time node of the emergence of toxicity

• Central nervous system and gastrointestinal symptoms usually appear within 24-48 hours of weekly methotrexate use;

Central nervous system and gastrointestinal symptoms usually appear within 24-48 hours of weekly methotrexate use;

Central nervous system and gastrointestinal symptoms usually appear within 24-48 hours of weekly methotrexate use;

Central nervous system and gastrointestinal symptoms usually appear within 24-48 hours of weekly methotrexate use;

• Hair loss usually occurs within a few weeks and is generally not dose-related;

Hair loss usually occurs within a few weeks and is generally not dose-related;

Hair loss usually occurs within a few weeks and is generally not dose-related;

Hair loss usually occurs within a few weeks and is generally not dose-related;

• Macrocytosis may appear several months later (after longer use) and is not necessarily due to folic acid deficiency, as patients on methotrexate typically receive daily folic acid supplementation; macrocytosis may also arise from Macrocytosis may also occur in methotrexate users who have normal serum levels of folic acid and vitamin B12, regardless of etiology, such as vitamin B12 deficiency
  .
  

Macrocytosis may appear several months later (after longer use) and is not necessarily due to folic acid deficiency, as patients on methotrexate typically receive daily folic acid supplementation; macrocytosis may also arise from Macrocytosis may also occur in methotrexate users who have normal serum levels of folic acid and vitamin B12, regardless of etiology, such as vitamin B12 deficiency
.

Macrocytosis may appear several months later (after longer use) and is not necessarily due to folic acid deficiency, as patients on methotrexate typically receive daily folic acid supplementation; macrocytosis may also arise from Macrocytosis may also occur in methotrexate users who have normal serum levels of folic acid and vitamin B12, regardless of etiology, such as vitamin B12 deficiency
.

Macrocytosis may appear several months later (after longer use) and is not necessarily due to folic acid deficiency, as patients on methotrexate typically receive daily folic acid supplementation; macrocytosis may also arise from Macrocytosis may also occur in methotrexate users who have normal serum levels of folic acid and vitamin B12, regardless of etiology, such as vitamin B12 deficiency
.

• The rash can appear within a few days of weekly methotrexate use and subside by the next week of dosing;

The rash can appear within a few days of weekly methotrexate use and subside by the next week of dosing;

The rash can appear within a few days of weekly methotrexate use and subside by the next week of dosing;

The rash can appear within a few days of weekly methotrexate use and subside by the next week of dosing;

• Stomatitis can last for days or weeks and is usually mild, but can occasionally be so painful that it is difficult to eat and cause the patient to want to stop treatment;

Stomatitis can last for days or weeks and is usually mild, but can occasionally be so painful that it is difficult to eat and cause the patient to want to stop treatment;

Stomatitis can last for days or weeks and is usually mild, but can occasionally be so painful that it is difficult to eat and cause the patient to want to stop treatment;

Stomatitis can last for days or weeks and is usually mild, but can occasionally be so painful that it is difficult to eat and cause the patient to want to stop treatment;

3.
Symptomatic treatment measures

3.
Symptomatic treatment measures (1) Nausea: (1) Nausea: use histamine H2 receptor blockers (eg, oral ranitidine 150-300 mg), or proton pump inhibitors (eg, oral omeprazole) azole 20-40 mg)
.

As with weekly methotrexate, these drugs are usually given periodically, the night before, the day, and the morning of the weekly methotrexate dose

Specific recommendations for liver function monitoring are as follows: Specific recommendations for liver function monitoring are as follows:

(a) Blood samples should be collected every 4-8 weeks for transaminases and serum albumin (Note: The 2008 ACR recommendation is: every 8-12 weeks after 3 months of treatment for patients on a stable dose of methotrexate Monitoring once, and monitoring once every 12 weeks after 6 months of treatment);

(a) Blood samples should be collected every 4-8 weeks for transaminases and serum albumin (Note: The 2008 ACR recommendation is: every 8-12 weeks after 3 months of treatment for patients on a stable dose of methotrexate Monitoring once, and monitoring once every 12 weeks after 6 months of treatment);

(b) liver biopsy should be performed if 6 out of 12 examinations in any year are abnormal (or if 5 out of 9 examinations are abnormal every 6 weeks instead of monthly examinations;

(b) liver biopsy should be performed if 6 out of 12 examinations in any year are abnormal (or if 5 out of 9 examinations are abnormal every 6 weeks instead of monthly examinations;

(c) Abnormal transaminases were defined as above the normal range, and low serum albumin levels were defined as less than or equal to 3.

4 g/dL (≤ 34 g/L);

In summary , folic acid therapy (1 mg/d) is recommended for all patients on long-term low-dose methotrexate use
.
Based on reported residual symptoms, folic acid dose can be increased to a maximum of 5 mg/day as needed
.
Leucovorin should only be used in patients with poor response to folic acid (ie, when toxicity persists)
.
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