What Factors Affect a Sufficient Methotrexate Dose?

Methotrexate injection, the indication is that methotrexate has broad-spectrum antitumor activity, and can be used alone or in combination with other chemotherapy drugs. The specific indications are as follows: 1. Antitumor therapy, used alone: breast cancer, pregnancy chorionic carcinoma, hydatidiform mole or hydatidiform mole. 2. Antitumor therapy, combined use: acute leukemia (especially acute lymphocytic leukemia), Burkitts lymphoma, advanced lymphosarcoma (stages III and IV, according to Peter's staging method), and advanced mycosis. 3. Intrathecal injection: treatment of meningeal metastatic cancer (only isotonic preparations can be used). 4. High-dose therapy: Large-dose methotrexate is used alone or in combination with other chemotherapeutics to treat the following tumors: osteosarcoma, acute leukemia, bronchial lung cancer, or head and neck epidermal cancer. For high-dose methotrexate, folinic acid must be used for rescue. Folic acid is a derivative of tetrahydrofolate that competes with methotrexate to enter cells. This "folic acid rescue" protects normal tissue cells from damage during high-dose methotrexate application. 5. Psoriasis chemotherapy: methotrexate can be used to treat severe, stubborn, disabling psoriasis that is not sensitive to conventional therapies. However, because it is more dangerous during use, it should be used after a biopsy and / or dermatologist consultation.

Methotrexate injection, the indication is that methotrexate has broad-spectrum antitumor activity, and can be used alone or in combination with other chemotherapy drugs. The specific indications are as follows: 1. Antitumor therapy, used alone: breast cancer, pregnancy chorionic carcinoma, hydatidiform mole or hydatidiform mole. 2. Antitumor therapy, combined use: acute leukemia (especially acute lymphocytic leukemia), Burkitts lymphoma, advanced lymphosarcoma (stages III and IV, according to Peter's staging method), and advanced mycosis. 3. Intrathecal injection: treatment of meningeal metastatic cancer (only isotonic preparations can be used). 4. High-dose therapy: Large-dose methotrexate is used alone or in combination with other chemotherapeutics to treat the following tumors: osteosarcoma, acute leukemia, bronchial lung cancer, or head and neck epidermal cancer. For high-dose methotrexate, folinic acid must be used for rescue. Folic acid is a derivative of tetrahydrofolate that competes with methotrexate to enter cells. This "folic acid rescue" protects normal tissue cells from damage during high-dose methotrexate application. 5. Psoriasis chemotherapy: methotrexate can be used to treat severe, stubborn, disabling psoriasis that is not sensitive to conventional therapies. However, because it is more dangerous during use, it should be used after a biopsy and / or dermatologist consultation.

Drug Name

Methotrexate injection

Drug type

Prescription drugs, medicines for medical workers' injuries

Use classification

Antimetabolite

Methotrexate injection ingredients

The main ingredient of this product is methotrexate, and its chemical name is: S-(+)-N-2- [4-([(2,4-diamino-6-pteridyl) methyl] methylamino] The structural formula of benzoyl] glutamic acid is:

Molecular formula: C ₂₀ H ₂₂ N ₈ O ₅
Molecular weight: 454.45
Excipients: sodium hydroxide and / or sodium chloride, water for injection

Traits of methotrexate injection

This product is a yellow to orange sterile clear liquid without preservatives, and methotrexate and sodium hydroxide are contained in water for injection. There are 3 specifications. 2ml: 50mg and 20ml: 500mg specifications are added with sodium chloride to make the solution isotonic. Methotrexate injection 10ml: 1000mg Specification is hypertonic solution.

Methotrexate injection specifications

(1) 2ml: 50mg; (2) 20ml: 500mg; (3) 10ml: 1000mg

Methotrexate injection dosage

Antitumor chemotherapy : Methotrexate can be administered by intramuscular, intravenous or intrathecal injection.
10ml: 1000mg methotrexate injection is a hypertonic solution, and it is forbidden to intrathecally.
When used for intrathecal injection, methotrexate injection should be diluted to a concentration of 1 mg / ml with a suitable preservative-free solvent such as 0.9% sodium chloride injection.
For converting mg / kg body weight to mg / m ² body surface area or vice versa, the guidelines recommend a ratio of 1:30. The conversion coefficients selected according to age and physique range between 1:20 and 1:40.
Choriocarcinoma and similar trophoblastic diseases : the usual dose is 15-30mg / day, intramuscular injection for 5 days. Usually after one to several weeks, after all the toxic reactions have disappeared, the next course of treatment is started. It usually takes 3-5 courses.
The efficacy of treatment can be assessed using a 24-hour urine HCG (human chorionic gonadotropin) quantitative analysis. After the third or fourth course of treatment, HCG levels should return to normal or below 50 IU / 24h. Measurable lesions are usually completely eliminated after 4-6 weeks. After HCG levels return to normal, it is recommended to continue with 1 or 2 courses of methotrexate.
A detailed clinical assessment must be performed before each session begins. Methotrexate can be used in combination with other antitumor drugs.
Breast cancer : For patients with lymph node-positive early breast cancer, as an adjuvant treatment after radical mastectomy for breast cancer, methotrexate combined with cyclophosphamide and fluorouracil for long-term periodic chemotherapy can achieve better results. Methotrexate was administered at a dose of 40 mg / m ² intravenously on the first and eighth days.
Leukemia : Children and adolescents with acute lymphoblastic (lymphoblastic) leukemia are the most responsive to current chemotherapy. Clinical remission is more difficult for young and elderly patients, and early relapses are more common. In chronic lymphocytic leukemia, chemotherapy is less sensitive. Methotrexate was used alone or in combination with steroids to initially induce remission therapy for lymphoblastic leukemia. In recent years, multi-cycle treatment of corticosteroids with other anti-leukemia drugs or with combination regimens including methotrexate can cause rapid and effective remission. When used in induction remission therapy, methotrexate is administered at a dose of 3.3 mg / m ² / day combined with prednisone 60 mg / m ² / day. Fifty percent of patients receiving treatment generally respond within 4 to 6 weeks. Not sensitive to chemotherapy for acute myeloid leukemia.
Methotrexate can be used alone or in combination with other drugs to consolidate maintenance therapy. After remission and supportive treatment have improved the general clinical situation, maintenance treatment can be started. The usage is 30mg / m ² intramuscular injection twice weekly, or 2.5 mg / kg intravenously every 14 days. When relapses occur, repetition can be achieved by repeating the initial induction regimen.
Meningeal leukemia:
Leukemia patients have a tendency to invade the central nervous system. It can be characterized by symptoms or signs, or it can be diagnosed only by finding leukemia cells by cerebrospinal fluid examination. Therefore, the cerebrospinal fluid of all patients with leukemia should be examined. Since the amount of methotrexate that enters the cerebrospinal fluid from the serum is very small, this product should be administered intrathecally in order to obtain sufficient treatment.
Today, as a preventive treatment for lymphocytic leukemia, intrathecal methotrexate is a commonly used treatment.
Intrathecal injection allows methotrexate to be distributed in the cerebrospinal fluid, the amount of which is based on age rather than body surface area. Cerebrospinal fluid in newborns is equivalent to about 40% of adults, and can reach adult levels after a few years. The recommended dosage based on age is as follows:
6mg under 1 year
1 mg 8 years old
2mg 10mg
3 years and over 12mg
For adults aged 70 years or older, and infants less than four months old, toxicity may increase, so appropriate reductions can be made.
Dosages should be spaced 2 to 5 days apart. In some indications, doses less than one week apart may lead to increased toxicity. Methotrexate can be continued until the total number of cells in the cerebrospinal fluid returns to normal, and then it is recommended to give another methotrexate.
For the prevention of meningeal leukemia, doctors should consult the medical literature.
Methotrexate administration via intrathecal injection can occur in large quantities in the circulatory system, causing systemic methotrexate toxicity. Therefore, systemic anti-leukemia treatment drugs should be appropriately adjusted, reduced or discontinued.
For intrathecal injection, methotrexate injection should be diluted with a suitable preservative-free solvent such as 0.9% sodium chloride injection. The concentration after dilution was 1 mg / ml.
Large doses of methotrexate can cause convulsions and other difficult side effects, mainly in the nervous system.

Intrathecal chemotherapy may not be effective for focal leukemias involving the central nervous system. The best way is to give radiation therapy.
Lymphoma stage III lymphosarcoma may be effective in combination therapy with methotrexate containing 0.625-2.5 mg / kg / day. Hodgkin's disease has a low response rate to methotrexate and most chemotherapy.

Mycosis fungoides : Methotrexate 50mg once weekly or 25mg twice weekly intramuscular injection can be used as an alternative to oral therapy.

High-dose therapy : See the precautions. The dosing schedule can be adjusted based on the history, severity of the disease, and the clinical experience of the physician. High-dose dosing regimens can only be performed by qualified experts if they have adequate equipment to handle adverse reactions.
Psoriasis chemotherapy : The dosing regimen for psoriasis is mainly based on the nature and severity of the condition and the physician's own experience.
Patients should be informed of all possible dangers in advance, and the patient's condition should be continuously monitored during treatment. Assessments of renal function, liver function, and blood composition should be historically recorded. Physical examination and laboratory tests (such as a complete blood count, a urine test, a serum creatinine test, a liver function test, and a liver function test) are required before starting treatment with methotrexate, periodically during treatment, and before resuming treatment after an interval of time. Liver biopsy if necessary). Appropriate measures should be taken for contraception at least 3 months after receiving and ending methotrexate treatment.
Based on weekly parenteral intermittent high-dose usage, a commonly used injection dose schedule is developed.
The schedule should be continuously adjusted for individual patients. The dosage schedule cited below is for adults with an average weight of 70 kg. It is recommended to use the initial attempted dose to detect any specific constitution one week before starting treatment. The recommended dosage range for parenteral administration is 5-10 mg.
Recommended starting dose < br Weekly intramuscular or intravenous single-dose regimen: 10-25 mg per week until appropriate efficacy appears. In this dosage schedule, the dosage should generally not exceed 50 mg / week.
The dose should be adjusted gradually to achieve the best clinical effect, but the maximum dose cannot be exceeded in each course. Once the best clinical response occurs, the dose schedule should be reduced to the lowest possible dose and the longest rest period. The use of methotrexate should be encouraged to restore routine topical treatment.

Adverse effects of methotrexate injection

The main toxicity of methotrexate occurs in normal and rapidly proliferating tissues, especially the bone marrow and gastrointestinal tract. Oral mucosal ulcers are usually the earliest symptoms of a toxic reaction. The most common adverse reactions include ulcerative stomatitis, leukocytopenia, nausea, and abdominal discomfort. Others include discomfort, fatigue, chills, fever, headache, dizziness, drowsiness, tinnitus, blurred vision, eye discomfort, and decreased resistance to infection. In general, the incidence and severity of adverse reactions are related to the dose and frequency of medication. The adverse reactions of different systems are reported as follows:
Skin and hypersensitivity reactions: dermatitis, erythema rash, pruritus, urticaria, photosensitivity, hypopigmentation / pigmentation, hair loss, vasculitis, petechiae, petechiae, telangiectasia, acne, folliculitis, Nail changes. Psoriasis lesions may show hot and erythema that lasts 1 to 2 days after each dose. At the same time exposure to ultraviolet radiation will worsen the skin damage caused by psoriasis. Skin ulcers have been reported in patients with psoriasis, and a few allergic reactions have been reported. Radiation dermatitis and sunburn may reappear.
Serious and occasionally lethal skin reactions have been reported in children and adult patients within a few days after methotrexate administration, including toxic epidermal necrolysis, Steven-Johnson Syndrome, exfoliative dermatitis, Skin ulcers / necrosis and erythema polymorpha. The above-mentioned toxic reactions are significant in tumor and non-tumor patients after receiving single or multiple doses of methotrexate.
Blood and lymphatic system: bone marrow suppression, leukopenia, neutropenia, thrombocytopenia, serum albumin decrease, anemia (including aplastic anemia), eosinophilia, pancytopenia, agranulocytosis, low Gammaglobulinemia, lymphadenopathy, and hyperplasia. The following clinical manifestations may occur such as fever, infection, bleeding from different sites and sepsis. Megaloblastic anemia has also been reported, mainly in elderly patients receiving long-term methotrexate treatment. Continuous methotrexate treatment should allow folic acid supplementation to reduce anemia.
Gastrointestinal tract: mucositis (gingivitis, pharyngitis, stomatitis, glossitis), loss of appetite, nausea, vomiting, diarrhea, abdominal discomfort, vomiting, melena, gastrointestinal ulcers and bleeding, intestinal perforation, enteritis, acute And chronic hepatocellular toxicity caused by acute liver atrophy, necrosis, steatosis, acute hepatitis, periportal fibrosis, cirrhosis, pancreatitis, elevated liver enzymes, decreased serum albumin, and liver failure. Methotrexate damage to the intestinal mucosa rarely causes malabsorption or toxic megacolon. Changes in liver function test results (increased levels of transaminase and LDH) are often reported, but generally recover within one month after discontinuation.
Urogenital system: renal failure, dysuria, azotemia, cystitis, hematuria, egg production or sperm defect, transient oligospermia, urogenital or menstrual abnormalities, infertility, abortion, fetal malformations, Stillbirth, severe kidney disease, vaginitis, vaginal discharge.
Cardiovascular system: pericarditis, vasculitis, pericardial effusion, hypotension, and thrombotic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolism).
Nervous system: headache, drowsiness, blurred vision, drowsiness, motor dysfunction, cranial nerve palsy, white matter encephalopathy, encephalopathy, and coma are reported. Aphasia, hemiplegia, local paralysis, convulsions, and Guillain-Barre syndrome and increased cerebrospinal fluid pressure may occur after intrathecal injection. After low-dose administration, occasional patients have reported temporary fine cognitive impairment, mood changes, or rare cranial sensory disturbances. Cognitive impairment has been reported in children receiving intrathecal injection of methotrexate with head irradiation. White matter encephalopathy has been reported in patients undergoing cranial spine irradiation following intravenous infusion of high-dose methotrexate.
The central nervous system toxicity that may occur after intrathecal injection or high-dose methotrexate is classified as follows:
(1) Chemical arachnoiditis, manifested as headache, back pain, rigidity and fever;
(2) Generally temporary temporary paralysis, manifested by paraplegia and increased CSF pressure involving one or more spinal nerve roots;
(3) A delayed onset syndrome can occur months to years after treatment, which is characterized by necrotizing leukoencephalopathy, manifested as confusion, stiffness, irritability, lethargy, ataxia, dementia, occasional and rare Seizures and death. The above reactions are dose-dependent, and are prone to occur when intrathecal injection of methotrexate over 50mg combined with head irradiation and systemic methotrexate treatment.
Lungs: Deaths caused by interstitial pneumonia, interstitial fibrosis, and reversible pulmonary eosinophilia have been reported. Chronic interstitial obstructive pulmonary disease and alveolitis have occasionally occurred. The lung toxicity caused by methotrexate is usually manifested by: radiological evidence of fever, cough (especially dry cough without sputum), dyspnea, chest pain, hypoxemia, and / or pulmonary infiltration (usually diffuse and / Or honeycomb).
Eye: Conjunctivitis, severe unexplained changes in vision, including transient blindness.
Carcinogenicity: Cytotoxic drugs have been reported in humans to be associated with an increased risk of secondary tumors. There are reports in the literature that patients receiving methotrexate may develop lymphomas including reversible lymphoma and tumor lysis syndrome. There is evidence of chromosomal disruption in animal somatic cells and human bone marrow cells following methotrexate use.
Infections: Fatal opportunistic infections have been reported in patients receiving methotrexate treatment for tumor and non-tumor diseases. Pneumocystis carinii pneumonia is the most common infection. Other reported infections include pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, shingles, herpes simplex virus hepatitis, diffuse herpes simplex, lethal sepsis, and cytomegalovirus including cytomegalovirus Viral pneumonia.
Others: Others have reported reactions related to or caused by methotrexate: metabolic changes, exacerbation of diabetes, osteoporosis (including aseptic necrosis of the femoral head), abnormal changes in histiocytes, and joint pain / Myalgia, proteinuria, sarcoidosis, stress fractures, weakened libido, impotence and even sudden death.

Methotrexate injection contraindications

Methotrexate is disabled in the following cases: Pregnant women with psoriasis;
lactating women;
Psoriasis patients with severe liver dysfunction;
Patients with severe renal insufficiency;
Psoriasis patients with alcoholism or alcoholic liver disease;
Patients with obvious or laboratory-confirmed immunodeficiency;
Psoriasis patients with bone marrow suppression or preexisting blood cachexia, such as bone marrow dysplasia, leukopenia, thrombocytopenia, or anemia;
Psoriatic patients with severe infections;
Patients known to be allergic to methotrexate or any excipients;
Psoriasis patients with peptic ulcer disease or ulcerative colitis;
Patients receiving central nervous system radiotherapy should not receive methotrexate intrathecal injection at the same time;
Warning <br /> Methotrexate can only be used by physicians with experience in antimetabolite chemotherapy. If it is non-tumorous, it must be used by a professional physician.
Because of the possibility of fatal or severe toxic reactions, physicians must fully inform patients of the risks and should take medication under their supervision.
Deaths have been reported following methotrexate use.
In the treatment of psoriasis, methotrexate is limited to severe, stubborn and disabling cases that are not effective in other treatments and can only be used after a clear diagnosis of tissue biopsy and / or appropriate consultation.
1. Methotrexate can cause significant bone marrow suppression, anemia, aplastic anemia, leukopenia, neutropenia, thrombocytopenia, and bleeding.
2. Methotrexate may be hepatotoxic, especially in the case of large doses or prolonged treatment. Liver atrophy, liver necrosis, cirrhosis, steatosis, and fibrosis around the portal have been reported. Because these reactions can occur without the omen of gastrointestinal or hematological toxicity, liver function must be evaluated before treatment is started and monitored regularly during the course of treatment. Special care should be taken in the case of pre-existing hepatocyte damage or impaired liver function. Concomitant use of other potentially hepatotoxic drugs (including alcohol) must be avoided.
3. Malignant lymphoma may subside after methotrexate is discontinued. The above situation may occur in patients receiving low-dose methotrexate treatment. These patients may not need cytotoxic drugs. Methotrexate should be stopped first. If the lymphoma does not resolve, an appropriate treatment plan must be developed.
4. Potentially lethal opportunistic infections, especially pneumocystis carinii pneumonia, can occur during methotrexate treatment.
5. Concurrent radiation therapy with methotrexate may increase the risk of soft tissue necrosis and osteonecrosis.
6. Renal impairment is a common contraindication.
7. Diarrhea and ulcerative stomatitis are common toxic reactions and need to be discontinued. In addition, hemorrhagic enteritis and fatal bowel perforation may occur.
8. There have been reports of unpredictable severe (sometimes fatal) myelosuppression and aplastic anemia following non-steroidal anti-inflammatory drugs (NSAIDs) infusion with methotrexate (usually large doses). And gastrointestinal toxicity 9. Methotrexate-induced lung disease, including acute or chronic interstitial pneumonia, is a potentially dangerous lesion, and it has been reported that they may have an acute attack at any stage of treatment when used at low doses . Not all of this damage is completely reversible, and deaths have been reported as a result. Pulmonary symptoms (especially sputum-free dry cough and difficulty breathing) may require interruption of treatment and careful examination. Lung injury can occur at any dose as low as 7.5 mg per week. Infection (including pneumonia) needs to be ruled out. Patients' lung symptoms need to be closely monitored.
10. High-dose methotrexate combined with folic acid (calcium folate) rescue experimental treatments for specific neoplastic diseases. The above procedures are still under study and dangerous. Do not attempt to use high-dose methotrexate without facilities that have the necessary expertise and combination of resources. It is necessary to consult the latest published literature.

Precautions for methotrexate injection

Use caution in the following situations. <br /> Methotrexate can only be used by doctors with experience in antimetabolite chemotherapy. If it is non-tumor, it must be used by a specialist. Because of the possibility of fatal or severe toxic reactions, the doctor must fully inform the patient of the risks and should take the drug under his supervision. Possible complications should be handled by appropriate facilities.
In the case of high-dose use or weakened excretion of the drug (impaired renal function, pleural effusion, ascites), the drug toxicity must be closely monitored. There have been reports of deaths following methotrexate treatment of malignancies and psoriasis.
Methotrexate is only used in severe, stubborn and disabling cases where the efficacy of other treatments is not obvious in the treatment of psoriasis, and can only be used after a clear diagnosis of tissue biopsy and / or appropriate consultation.
Methotrexate can cause significant bone marrow suppression, anemia, aplastic anemia, leukopenia, neutropenia, thrombocytopenia, and bleeding. Methotrexate may be hepatotoxic, especially in the case of large doses or prolonged treatment. Liver atrophy, liver necrosis, cirrhosis, steatosis, and portal vein fibrosis have been reported. Because these reactions can occur without the omen of gastrointestinal or hematological toxicity, liver function must be evaluated before treatment is started and monitored regularly during the course of treatment. Special care should be taken in the case of pre-existing hepatocyte damage or impaired liver function. Concomitant use of other potentially hepatotoxic drugs (including alcohol) must be avoided. Impaired renal function is a common contraindication.
Use caution when using methotrexate in frail and pediatric patients. Because elderly patients have weakened liver and kidney functions and reduced folic acid in the body, relatively low doses need to be given, and these patients need to be closely monitored during medication.
In patients with psoriasis, the occurrence of acute hepatitis and chronic hepatotoxicity seems to be related not only to the cumulative dose of the drug, but also to the coexistence of conditions such as alcoholism, obesity, diabetes, old age, and ingestion. Arsenic compounds. Chronic toxicity is potentially lethal and usually occurs with long-term use (usually 2 years or more) and a total cumulative dose of at least 1.5 g.
Patients with malignant tumors with bone marrow dysplasia, leukocytopenia, thrombocytopenia, or anemia need to be cautious with their medication.
Concurrent radiation therapy with methotrexate treatment increases the risk of soft tissue necrosis and osteonecrosis.
High-dose treatment High-dose methotrexate combined with folinic acid rescue experimental treatment for specific neoplastic diseases. The above procedures are still under study and dangerous. Do not attempt to use high-dose methotrexate without facilities that have the necessary expertise and combination of resources. It is necessary to consult the latest published literature. High-dose methotrexate should not be used in patients with renal insufficiency or third interstitial fluid, such as ascites or a large amount of pleural effusion. Because rapid excretion of drugs is important to limit toxicity. In order to be able to detect imminent toxic effects, renal function and methotrexate serum concentrations must be carefully monitored. Calcium folinate must be given when using high-dose methotrexate. Calcium folic acid should be given to rescue, hydrate, and alkalize urine while continuously monitoring for toxic effects and methotrexate clearance.
Check the following items before and during the medication:
Methotrexate can cause renal damage and lead to acute renal failure. Close observation of renal function includes adequate hydration, alkalinization of urine, and determination of methotrexate serum levels, and monitoring of renal function is recommended.
Methotrexate is mainly excreted by the kidneys. When used in the presence of renal impairment, the drug can cause accumulation of poisoning and even worsen renal impairment. Before administration and during methotrexate treatment, the renal function of the patient should be checked. Appropriate examination can find obvious renal damage. The drug should be reduced or discontinued until renal function improves or recovers. Urine should remain alkaline during methotrexate treatment (methotrexate is weakly acidic and precipitation occurs when the urine pH is below 6).
High-dose methotrexate is used in the treatment of osteosarcoma, which can cause renal damage and lead to acute renal failure. Renal toxicity occurs mainly due to the deposition of methotrexate and 7-hydroxymethotrexate in the renal tubules. Close monitoring of renal function including adequate hydration, alkalization, and determination of serum methotrexate and creatinine concentrations are all necessary for safe medication.
Vomiting, diarrhea, and ulcerative stomatitis are common toxic reactions that require treatment interruption. In addition, hemorrhagic enteritis and fatal bowel perforation may occur.
Pulmonary symptoms (especially sputum-free dry cough) or non-specific pneumonia during methotrexate treatment may be a precursor to potentially dangerous injuries. At this time, treatment needs to be interrupted and carefully examined. Despite varying clinical presentations, patients with typical lung lesions caused by methotrexate have fever, cough, chest pain, dyspnea, hypoxemia, and infiltration on X-rays. Lung damage can occur at any dose. When this occurs, infection (including pneumonia) needs to be ruled out.
High systemic doses or intrathecal injection of methotrexate can cause significant central nervous system toxicity. Closely monitor the patient's neurological symptoms. If abnormalities occur during treatment, medications need to be stopped and appropriate treatment given.
Methotrexate is at risk of serious toxic effects. Toxic reactions may be related to dose frequency and intensity or the frequency of injections, but can occur at any drug concentration. Since toxic effects can occur at any time during treatment, it is necessary to monitor patients receiving methotrexate very closely. When the above reaction does occur, it is necessary to reduce the dose or discontinue the drug and give corresponding rescue measures. If the methotrexate treatment is restarted, the medication needs to be extremely cautious, full consideration of the necessity of re-administration, and more attention to the possibility of recurrence of toxic reactions.
Because methotrexate has a common hematopoietic inhibitory effect, manifested as anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia and / or thrombocytopenia, it is necessary to use methotrexate in chemotherapy Perform preventative treatment and regular hematology examinations. It can happen suddenly at a safe dose. Any severe decrease in the number of blood cells indicates that treatment needs to be discontinued immediately and treated accordingly. If a severe decrease in white blood cells occurs during treatment, a bacterial infection may occur and cause danger. Withdrawal and appropriate antibiotic treatment are usually required. In severe bone marrow suppression, transfusion of whole blood or platelets may be necessary.
Methotrexate can cause hepatocellular toxicity, liver fibrosis, and cirrhosis, but it usually only occurs after long-term medication. Elevated liver enzymes are usually observed. These are generally temporary, asymptomatic and are not a sign of subsequent liver disease. A liver biopsy after continuous methotrexate use usually reveals histological changes, and fibrosis and sclerosis have been reported. These advanced lesions may appear before symptoms or abnormal liver function tests in patients with psoriasis. Regular liver biopsy is recommended for patients with long-term treatment of psoriasis.
In psoriasis, hepatic cell damage and its function are measured multiple times before administration, including serum albumin and prothrombin time. In patients with advanced liver fibrosis or cirrhosis, liver function tests are usually normal. These injuries may only be observed by a needle biopsy. It is recommended to perform liver biopsy under the following conditions: 1) before the start of treatment or within 2-4 months after the initial administration; 2) when the total cumulative dose reaches 1.5g; 3) after each addition of 1.0-1.5g. Medication should be discontinued once moderate liver fibrosis or any degree of liver cirrhosis occurs; if mild liver fibrosis is present, repeat liver biopsy is recommended within 6 months. It is relatively easy to see mild histological changes such as steatosis and low-grade portal vein inflammation before treatment begins. Although these minor changes are usually not a factor in avoiding or discontinuing methotrexate treatment, medication must be used with caution.
In general, patients who are or are receiving methotrexate treatment are recommended to perform the following laboratory tests as part of the necessary clinical assessment and appropriate monitoring methods. These tests include: complete blood cell count, hematocrit, urine test, Renal function test and liver function test. A chest X-ray is also recommended. These tests should be performed before, during the appropriate period of treatment, and after the last treatment. More frequent monitoring is recommended when starting or changing doses, or when there is an increased risk of increased methotrexate blood levels (such as dehydration). During the treatment of psoriasis, it is recommended to monitor the following indicators: monthly blood system examination, liver and kidney function examination every 1-2 months. More frequent monitoring is generally recommended during antitumor treatment. A liver biopsy or bone marrow aspiration biopsy can be helpful or important when given in high doses or long-term treatment.
Methotrexate is slowly excreted from the third space (such as pleural effusion or ascites). This can lead to prolonged terminal half-life and unpredictable toxicity. If the patient has significant third-gap accumulation, body fluids can be withdrawn and methotrexate plasma concentrations can be monitored before treatment.
Information for patients :
Patients should be informed of the early signs and symptoms of a toxic reaction, see a doctor immediately if symptoms occur, and follow up closely if necessary, including regular laboratory tests to monitor the toxic reaction.
Patients should be informed of the potential benefits and risks of using methotrexate. The risk of reproductive effects after methotrexate treatment should be discussed with male and female patients.
Because of the possibility of photosensitivity, patients receiving methotrexate should avoid excessive exposure to sunlight or sunlight without protection.
Infection or immune status Methotrexate should be used with caution in the presence of active infections, peptic ulcers, and ulcerative colitis. Methotrexate has immunosuppressive activity and may cause severe or even fatal infections. This factor must be considered when assessing the use of methotrexate when the immune response may be important or necessary for the patient.
Pneumonia may occur (in some cases, it can cause respiratory failure). Potentially lethal opportunistic infections may occur during methotrexate treatment, especially pneumocystis carinii pneumonia. The possibility of Pneumocystis carinii pneumonia should be considered in patients with pulmonary symptoms.
Methotrexate is generally forbidden in patients with obvious or laboratory-confirmed immunodeficiency.
Immunization during methotrexate treatment may be ineffective. A live virus vaccine is generally not recommended. Patients have reported disseminated infection after receiving smallpox vaccine during methotrexate treatment.
Ability to drive or operate machinery <br /> Adverse reactions of methotrexate, such as dizziness and fatigue, can affect the ability to drive or operate machinery.
[u] Precautions for operation [/ u]
As with all anti-tumor drugs, the preparation of methotrexate injections must be performed by a trained professional at a designated location (preferably in a cytotoxic laminar flow cabinet). Wear protective gloves during operation. If the skin or mucous membrane accidentally comes into contact with the methotrexate solution, the contaminated area should be washed thoroughly with soap and water immediately.
Pregnant women are advised not to come in contact with cytotoxic drugs such as methotrexate.
It is recommended to use a syringe equipped with Luer-lock. It is recommended to use large-hole needles to reduce pressure and avoid the formation of aerosols. In the preparation of pharmaceutical liquids, the use of injection needles with vent holes can also reduce the formation of aerosols. All preparations of methotrexate or body-related waste should be placed in double-sealed polyethylene bags and incinerated at 1100 ° C.
[u] Leak and disposal [/ u]
If leaks occur, restrict access to contaminated areas. Wear double latex gloves, breathing mask, protective gown, and goggles. Use paper, "CHUX", sawdust or fine debris to absorb the leak and prevent it from spreading. Leaks can also be treated with 5% sodium hypochlorite. Adsorbent materials and debris collected from the leak area are placed in leak-proof plastic containers and labeled accordingly. As a harmful and toxic substance, cytotoxic waste should be clearly marked with "Cytotoxic waste, burned at 1100 ° C". The waste should be incinerated for at least 1 second at 1100 ° C (the waste medicine bottle decomposes into H ₂ O and CO ₂ ). Rinse the contaminated area with plenty of water.

Methotrexate injection for pregnant and lactating women

Use during pregnancy: Class D drugs <br /> methotrexate can cause stillbirth and / or congenital malformations, so this product is not recommended for women who may become pregnant unless there is appropriate medical evidence that the potential benefits outweigh the benefits Assessed risk. Pregnant patients with psoriasis cannot receive methotrexate. Women with the possibility of pregnancy should not use methotrexate before ruling out pregnancy and should be fully informed that if they become pregnant during treatment there is a serious risk to the fetus.
Although the optimal interval between methotrexate treatment discontinuation and pregnancy has not been determined, either spouse should be receiving methotrexate treatment or at least 3 months after the end of treatment should be contraceptive.
Medications during lactation <br /> Methotrexate can be secreted into breast milk, and it is forbidden during lactation. The ratio of the highest concentration of methotrexate in breast milk to serum concentration can reach 0.08: 1. Due to the potential danger of serious side effects from methotrexate in breast milk when breast-feeding infants, the use of this product is prohibited for breast-feeding women.

Methotrexate injection for children

Methotrexate should be used with caution in patients too young.
Meningeal leukemia: Intrathecal injection enables methotrexate to be distributed in the cerebrospinal fluid, the amount of which is based on age rather than body surface area. Cerebrospinal fluid in newborns is equivalent to about 40% of adults, and can reach adult levels after a few years. The recommended dosage based on age is as follows:
6mg under 1 year
1 mg 8 years old
2mg 10mg
3 years and over 12mg
Infants younger than four months may have increased toxicity, so they can be reduced appropriately.

Methotrexate injection for the elderly

Methotrexate should be used with caution in elderly patients.
Meningeal leukemia: Intrathecal injection can distribute methotrexate in the cerebrospinal fluid. To adults aged 70 years or older, toxicity may increase, so it can be appropriately reduced.

Methotrexate injection drug interactions

After methotrexate is absorbed, it binds to the serum albumin part. Since its binding energy can be replaced by certain drugs such as salicylates, sulfa drugs, sulfonylureas, butazone and phenytoin, the toxicity may increase. Probenecid can reduce renal tubular transport, therefore, methotrexate and probenecid should be carefully monitored. When a hypolipidemic compound (such as cholestyramine) is used in combination with methotrexate, its ability to bind methotrexate is greater than serum proteins.
Penicillin and sulfa drugs may reduce renal clearance of methotrexate; elevated methotrexate serum concentrations have been observed with hematological and gastrointestinal toxicity. Methotrexate should be closely observed when combined with penicillin or sulfa drugs.
Non-steroidal anti-inflammatory drugs should not be used before or concurrently with high-dose methotrexate in the treatment of osteosarcoma. It has been reported that the simultaneous use of NSAIDs with high-dose methotrexate can increase and prolong the serum concentration of methotrexate, resulting in death of patients due to severe hematological and gastrointestinal toxicity.
Use caution when using NSAIDs and salicylate with low-dose methotrexate. These drugs have been reported to reduce the renal tubular secretion of methotrexate and may exacerbate toxic effects in an animal model.
It has been reported that methotrexate (usually in high doses) appears when coadministered with certain NSAIDs including aspirin and other salicylates, azapropion, diclofenac, indomethacin, and ketoprofen Unpredicted severe (sometimes fatal) bone marrow suppression and gastrointestinal toxicity. It has been reported that methotrexate does not affect the pharmacokinetics of methotrexate, but lethal drug interactions have been reported.
Folic acid deficiency may increase the toxicity of methotrexate. Rarely, methotrexate alone or in combination with sulfamethoxazole may increase bone marrow suppression in patients treated with methotrexate by reducing renal tubular secretion and / or an additive antifolate effect. Increased bone marrow suppression has also been reported in patients receiving methotrexate and pyrimethamine. In contrast, multivitamin products, including folic acid or its derivatives, can alter the efficacy of methotrexate and should not be given at the same time.
Methotrexate is often combined with other cytotoxic drugs. If a chemotherapy regimen includes drugs with the same pharmacological effects, toxic effects may increase. At this time, special monitoring of bone marrow suppression, renal, gastrointestinal and pulmonary toxicity is required. The dose of methotrexate needs to be adjusted if it is used in combination with other chemotherapeutic drugs that have cross-toxic effects.
In the treatment of patients with osteosarcoma, if high-dose methotrexate is used in combination with chemotherapy drugs with potential nephrotoxicity (such as cisplatin), caution is required.
Oral antibiotics such as tetracycline, chloramphenicol, and non-absorbable broad-spectrum antibiotics may reduce the intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting intestinal flora and inhibiting drug metabolism by bacteria.
It has been reported to antagonize the efficacy of methotrexate after using asparaginase.
It has been reported that it can increase liver toxicity when methotrexate and other potentially hepatotoxic drugs such as leflunomide, azathioprine, retinoids, and sulfasalazine are given simultaneously with methotrexate. The use of nitrous oxide anesthesia enhances the effect of methotrexate on folate metabolism resulting in severe, unpredictable bone marrow suppression and stomatitis. The use of calcium folate can reduce this effect.
Methotrexate combined with leflunomide may also increase the risk of whole blood cell reduction.
Using amiodarone in patients with psoriasis treated with methotrexate can induce ulcerative skin damage.
Methotrexate increases the plasma concentration of thiopurine. Therefore, the combination of thiopurine and methotrexate may require a dose adjustment.
Some patients with psoriasis or mycosis fungoides (a type of cutaneous T-lymphoma) have been reported to develop skin cancer after receiving methotrexate plus PUVA (methoxan and UV radiation).
Be careful when erythrocyte concentrate and methotrexate are given at the same time. Patients who received blood transfusions after receiving a 24-hour methotrexate infusion experienced an increased toxic response, which may be due to the extended duration of serum-methotrexate concentration.
Methotrexate is an immunosuppressant that reduces the immune response after vaccination. If given a live vaccine at the same time, it can cause a severe antigenic response.
Methotrexate can reduce theophylline clearance rate; theophylline level needs to be monitored when co-administered with methotrexate.
It has been reported that the combination of methotrexate with some drugs can change the cell's uptake rate of methotrexate, so patients can only use other drugs approved by oncologists while receiving methotrexate. These drugs include: hydrocortisone succinate, cefalotin, methylprednisolone, asparaginase, bleomycin, penicillin, kanamycin, vincristine, and vinblastine.
Compatibility contraindications There are reports of incompatibility between methotrexate and cytarabine, fluorouracil, and prednisolone.

Methotrexate injection overdose

Methotrexate should be discontinued when the first ulcer or bleeding occurs, diarrhea or significant suppression of hematopoietic function.
Common symptoms after oral overdose include symptoms and signs at pharmacological dose levels, notably blood system and gastrointestinal reactions such as leukopenia, thrombocytopenia, anemia, whole blood cell reduction, bone marrow suppression, mucositis, oral Ulcers, nausea, vomiting, gastrointestinal ulcers and gastrointestinal bleeding. No symptoms have been reported in some cases. There have been reports of lethal drug overdose. In these cases, adverse events such as sepsis or septic shock, renal failure, and aplastic anemia have also been reported. Fatal symptoms include anorexia, progressive weight loss, bloody diarrhea, leukopenia, depression, and coma.
Once an inadvertent overdose of methotrexate is found, calcium folinate (folate) should be given as soon as possible, 10 mg / m [sup] 2 [/ sup] every 6 hours intravenously or intramuscularly until methotrexate The concentration is below 10 [sup] -2 [/ sup] M. If gastric retention or obstruction is present, folinic acid should be administered parenterally. Hydration (3 L / d) was performed simultaneously and urine was basified with sodium bicarbonate. Adjust the dose of sodium bicarbonate so that the urine pH is 7 or higher. Serum samples should be analyzed at 24 hour intervals for creatinine and methotrexate levels. If 24-hour serum creatinine levels have increased by 50% from baseline or if 24-hour methotrexate levels are greater than 5 x 10 [sup] -6 [/ sup] M or 48-hour methotrexate levels are greater than or equal to 9 x 10 [ sup] -7 [/ sup] M, then the dose of calcium folinate should be increased to 100 mg / m [sup] 2 [/ sup] intravenously every 3 hours until methotrexate level [10 [sup] -8 [ / sup] M. The rate of calcium folic acid infusion cannot exceed 16.0 mL (160 mg calcium folic acid) per minute. Patients with significant third-gap accumulation are at high risk regardless of their 24-hour serum methotrexate level until serum methotrexate level is less than 10 [sup] -8 [/ sup] M.
The doses of calcium folinate mentioned above are not suitable for high-dose methotrexate treatment. The dose of calcium folic acid varies in different studies and published literature. It is recommended to refer to the published literature on high-dose methotrexate administration.
Neither standard hemodialysis nor peritoneal dialysis can significantly improve methotrexate clearance. If the patient is completely anuria, some methotrexate may be cleared by hemodialysis, and there is no alternative treatment option. It has been reported that the use of high-throughput dialyzer for acute intermittent hemodialysis is effective for the clearance of methotrexate.

Pharmacology and toxicology of methotrexate injection

Pharmacology <br /> The main mechanism of action of methotrexate is the competitive inhibition of folate reductase. Folic acid must be reduced to tetrahydrofolate by this enzyme during DNA synthesis and cell replication. Methotrexate inhibits folic acid reduction and interferes with tissue cell replication. Methotrexate is a cell cycle-specific drug that acts primarily on cells during DNA synthesis. Proliferating tissues such as malignant tumor cells, bone marrow, embryonic cells, skin epithelial cells, oral and intestinal mucosa, and bladder cells are often more sensitive to methotrexate effects. Cells in malignant tumors proliferate faster than in most normal tissues, so methotrexate can attenuate the growth of malignant tumors without causing irreversible damage to normal tissues.
The proliferative capacity of skin epithelial cells is much stronger than that of normal skin during psoriasis. The difference in proliferation rates is the basis for using methotrexate to control the progression of psoriasis.
Toxicology < br In vitro, methotrexate caused chromosomal aberrations in Chinese hamster A (T1) C1-3 cells, induced morphological changes in mouse C3H / 10T1 / 2 clone 8 cells, and compared with mouse lymphoma cells L5178Y / The increase of tk ± tk gene mutation rate is related. In vivo, it causes an increase in the rate of polychromatic erythrocytes in mice and a temporary, reversible increase in the number of chromosomal aberrations in human bone marrow cells. The clinical significance of these findings is unclear.
Carcinogenicity and Mutagenicity < br There is no human data on the risk of methotrexate tumorigenesis. Some animal studies evaluating the potential carcinogenicity of methotrexate have no definitive results.

Absorption : Peak plasma concentrations were observed within about 0.5-2.0 hours after parenteral injection. About 50% of absorbed methotrexate reversibly binds to serum proteins, but is still easily exchanged with body fluids and distributed to human tissue cells.
Distribution : Methotrexate is widely distributed in various tissues in the body, and can also be distributed in body fluids accumulated in the third space such as ascites or pleural effusion. Methotrexate can be retained for a long time in some tissues, such as in the kidney for several weeks and in the liver for months. When methotrexate is administered orally or parenterally, it cannot cross the blood-brain barrier. If necessary, intrathecal injection can be used to directly administer high concentrations of the drug.
Metabolism and excretion : Methotrexate is not significantly metabolized in the body at regular doses, but it can be partially metabolized at high doses. Clearance conforms to the three-phase model. The first phase may be distributed into the organs; the second phase is excreted by the kidneys, and the third phase is excreted by methotrexate into the enterohepatic circulation. Excretion is mainly through the kidneys. Approximately 41% are excreted through the urine as a prototype within the first 6 hours, and 90% within 24 hours. A small part may pass through the biliary tract and eventually be excreted by feces. Repeated daily doses result in more persistent serum concentrations and partial drug retention after each 24 hours, which may cause drug accumulation in the tissue. Prolonging the medication cycle or even a single therapeutic dose of the drug can keep a certain amount of the drug in the liver cells. Excretion of methotrexate is reduced during renal impairment, in which case drugs in serum and tissue cells may increase rapidly.

Methotrexate injection storage

Store below 25oC in the dark. Each bottle is for one use only. Discard excess.

Methotrexate injection packaging

This product is packaged with Cytosafe Cytosafe Packaging Bottles Anpan® means that the ready-to-use dosage form of the drug is packaged with a special polypropylene medicine bottle to improve transportation and use safety.

Validity of methotrexate injection

24 months

Methotrexate injection standard

JX20050036 ^[1]