Active ingredients: Methotrexate
METHOTREXATE 50 mg powder for solution for injection
METHOTREXATE 500 mg powder for solution for injection
METHOTREXATE 1 g powder for solution for injection
METHOTREXATE 50 mg / 2 ml solution for injection
METHOTREXATE 500 mg / 20 ml solution for injection
METHOTREXATE 1 g / 10 ml solution for injection
METHOTREXATE 5 g / 50 ml solution for injection
Methotrexate package inserts are available for pack sizes: - METHOTREXATE 50 mg powder for solution for injection, METHOTREXATE 500 mg powder for solution for injection, METHOTREXATE 1 g powder for solution for injection, METHOTREXATE 50 mg / 2 ml solution for injection, METHOTREXATE 500 mg / 20 ml solution for injection, METHOTREXATE 1 g / 10 ml solution for injection , METHOTREXATE 5 g / 50 ml solution for injection
- METHOTREXATE 2.5 mg tablets, METHOTREXATE 5 mg powder for solution for injection, METHOTREXATE 7.5 mg / ml solution for injection, METHOTREXATE 10 mg / 1.33 ml solution for injection, METHOTREXATE 15 mg / 2 ml solution for injection, METHOTREXATE 20 mg / 2 , 66 ml solution for injection.
Why is Methotrexate used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Antineoplastic.
THERAPEUTIC INDICATIONS
Methotrexate is indicated for the antineoplastic chemotherapy treatment of the following forms: breast carcinoma, choriocarcinoma and similar trophoblastic diseases, acute and subacute lymphatic and meningeal leukemia, lymphosarcoma, mycosis fungoides.
Clinical research has shown that it is considerably more effective in childhood leukemia than in adult leukemia. In some cases of acute leukemia it has produced clinical improvement and prolonged survival time for a period ranging from a few weeks to 2 years. The haematological picture, obtained from blood tests and bone marrow smears after administration of Methotrexate, can become almost indistinguishable from normal for variable periods of time. The best effects were observed in acute leukemias characterized by the presence of highly immature forms in the bone marrow and blood. Favorable results obtained with Methotrexate in choriocarcinoma have been reported.
Methotrexate is particularly indicated in mono or polychemotherapy, for the treatment of: osteogenic sarcoma, acute leukemia, bronchogenic carcinoma, epidermoid carcinoma of the head and neck.
Contraindications When Methotrexate should not be used
Hypersensitivity to the active substance or to any of the excipients.
Methotrexate is contraindicated during pregnancy.
Its use can cause teratogenic effects, fetal death, embryotoxicity and abortion when administered to pregnant women. In the treatment of neoplastic diseases it should only be used if the potential benefits outweigh the risk to the fetus.
Women of childbearing age should not initiate Methotrexate therapy until pregnancy has been ruled out; they must be fully informed of the serious risks to the fetus if pregnancy occurs during treatment with Methotrexate. If either partner is being treated with Methotrexate, pregnancy should be avoided. The optimal time interval between either partner ending treatment with Methotrexate and becoming pregnant has not yet been clearly established (see "Special Warnings"). The recommendations regarding the time intervals, taken from the published literature, range from 3 months to a year.
Methotrexate is found in human breast milk. Methotrexate is contraindicated in breastfeeding women due to its potential to produce serious adverse reactions in the infant.
The highest ratio of Methotrexate concentrations in breast milk to plasma was 0.08: 1. Methotrexate formulations and diluents that contain preservatives should not be used for intrathecal administration or for high dose therapy of Methotrexate.
Severe renal insufficiency
Precautions for use What you need to know before taking Methotrexate
Methotrexate has the potential to induce severe toxic reactions, usually related to dosage.
Patients undergoing Methotrexate therapy should be closely monitored in order to identify and evaluate the signs and symptoms of possible toxic or side effects as soon as possible. A pre-treatment check and periodic haematological checks are necessary for the use of Methotrexate in chemotherapy, due to the possible suppressive effect on the hematopoietic function attributable to the drug.
It can occur suddenly at any time and even in low doses.
Any sharp drop in blood cell counts indicates that drug administration should be discontinued immediately and appropriate therapy instituted. In patients with cancer and pre-existing bone marrow aplasia, leukopenia, thrombocytopenia or anemia, the product should be used with caution. and only if strictly necessary. Methotrexate is mainly excreted via the kidneys. Methotrexate therapy in patients with renal insufficiency should be undertaken with extreme caution and at reduced dosage regimens, as impaired renal function decreases the elimination of Methotrexate. In the presence of impaired renal function, methotrexate should be taken with extreme caution and at a reduced dosage, because reduced renal function results in a delayed elimination of methotrexate. The renal function of the patient should be determined before and during therapy with Methotrexate proceeding with great caution if severe renal insufficiency is found. In this case, the dosage should be reduced or the drug suspended until renal function improves.
Methotrexate causes hepatotoxicity, liver fibrosis and cirrhosis, but generally only after prolonged use.
Acute onset increases in liver enzymes have frequently been observed; these are usually transient and asymptomatic and also do not appear to predict a subsequent liver disease. After prolonged use, liver biopsy often shows histological changes and fibrosis and cirrhosis have been reported; the latter may also not be preceded by symptoms or abnormal liver function tests in the psoriasis population.
Periodic liver biopsies are generally recommended for psoriasis patients on long-term treatment. Persistent abnormalities in liver function tests may precede the onset of fibrosis or cirrhosis in the rheumatoid arthritis population.
Methotrexate caused the hepatitis B infection to become reactivated or the hepatitis C infection to worsen, in some cases resulting in death. Some cases of hepatitis B reactivation have occurred after discontinuation of Methotrexate. Clinical and laboratory evaluation should be performed to evaluate pre-existing liver disease in patients with previous hepatitis B and C infections. Based on these evaluations, treatment with Methotrexate may not be indicated for some patients.
Bleeding time, clotting time and blood group determination should be done before a transfusion or surgery.
Methotrexate must be administered under the personal and close supervision of the physician, who should not prescribe to the patient, in a single time, quantities greater than the dosage needed for 6-7 days of therapy. A complete blood count should be performed weekly. Dosing should be discontinued or the dosage reduced immediately after the first signs of ulceration, haemorrhage, diarrhea or significant depression appear.
Patients with rheumatoid arthritis are at risk of developing rheumatoid arthritis lung disease often associated with interstitial lung disease.
Methotrexate, like most of the anticancer and immunosuppressive drugs, has shown carcinogenic properties in animals under particular experimental conditions. Methotrexate should only be used by physicians who have experience in the field of antimetabolites.
Patients should be advised of the potential risks and benefits of methotrexate use (including initial symptoms and signs of toxicity), the need to consult their physician quickly if necessary, and the need for close follow-up, including medical tests. laboratory to monitor toxicity The risks of effects on reproductive capacity should be discussed with patients, both female and male, who are being treated with methotrexate.
States of folate deficiency can increase the toxicity of methotrexate
Tolerability
Gastrointestinal system
Should vomiting, diarrhea, stomatitis resulting in dehydration occur, supportive therapy should be instituted and methotrexate should be discontinued until symptoms resolve.
Blood system
Methotrexate may suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia and / or thrombocytopenia. Methotrexate should be used with caution in patients with pre-existing haematopoietic deficiency (see section 4.5). The nadir of leukocytes, neutrophils and of circulating platelets is typically reached 5-13 days after administration of an IV bolus dose (with recovery in 14-28 days). Leukocytes and neutrophils may sometimes show two reductions: the first in 4-7 days and the second nadir after 12-21 days, with subsequent recovery. Clinical sequelae such as fever, infection and haemorrhage from various sites may occur. In the treatment of malignancies, methotrexate should only be continued if the potential benefits outweigh the risk of severe myelosuppression In psoriasis and rheumatoid arthritis, methotrexate should be stopped immediately in the event of a significant drop in the blood count. of blood cells.
Hepatic system
Methotrexate causes acute hepatitis and chronic hepatotoxicity (fibrosis and cirrhosis). Chronic toxicity is life-threatening and generally occurred after prolonged use (usually 2 years or more) and after an overall cumulative dose of at least 1.5 grams. In studies in patients with psoriasis, hepatotoxicity appears to be function of the total cumulative dose and appears to be increased by alcoholism, obesity, diabetes and old age. Transient abnormalities of hepatic parameters are frequently observed after methotrexate administration and usually do not represent a reason to modify treatment. Persistent liver abnormalities and / or decreases in serum albumin may indicate severe liver toxicity.
In case of psoriasis, liver function and liver damage tests, including serum albumin measurement and prothrombin time, should be performed repeatedly prior to administration. Liver function test values are often normal during the development of fibrosis. or cirrhosis.
These lesions can only be detected with biopsy. Liver biopsy is recommended:
- before starting treatment or immediately after starting therapy (2-4 months);
- upon reaching a cumulative total dose of 1.5 g;
- after each additional dose of 1.0 to 1.5 g.
In case of moderate fibrosis or any type of cirrhosis, discontinue treatment. For mild fibrosis it is usually suggested to repeat the biopsy in 6 months. Milder histological changes such as fatty liver and low-grade portal inflammation are relatively common before starting therapy. Although these minor changes do not usually represent a reason for discontinuing or not prescribing methotrexate treatment, the drug should be used with caution.
In rheumatoid arthritis, the patient's age at the time of first methotrexate administration and the duration of therapy have been reported as risk factors for hepatotoxicity. Persistent abnormalities in liver function tests may precede the onset of fibrosis or cirrhosis in the rheumatoid arthritis population. In patients with rheumatoid arthritis being treated with methotrexate, liver function tests should be performed at baseline and at 4-8 week intervals.
A liver biopsy should be performed prior to treatment in patients with a history of excessive alcohol consumption; Baseline values of persistently abnormal liver function tests or chronic hepatitis type B or C. A liver biopsy should be performed during therapy in case of persistent liver function test abnormalities or if serum albumin levels drop below below normal values (in the "context of a" well-controlled rheumatoid arthritis).
If liver biopsy results show slight changes (Roenigk scale I, II, IIIa), Methotrexate therapy can be continued by monitoring the patient according to the above recommendations. Methotrexate therapy should be discontinued in all patients who show persistent liver function test abnormalities and refuse to undergo a liver biopsy, and in all patients in whom liver biopsy shows moderate to severe changes (Roenigk IIIb scale or IV).
Immunological states
Methotrexate should be used with extreme caution in the presence of active infections and is generally contraindicated in patients with manifest or laboratory-evidenced immunodeficiency syndromes.
Immunization
Vaccinations may be less immunogenic during Methotrexate therapy. Immunization with live virus vaccines is generally not recommended. There have been reports of disseminated vaccine infection following smallpox virus immunization in patients receiving Methotrexate.
Infections
Pneumonia can occur (which in some cases can lead to respiratory failure). Life-threatening opportunistic infections, especially Pneumocystis carinii pneumonia, can occur with treatment with Methotrexate. When a patient presents with pulmonary symptoms, the possibility of Penumocystis carinii pneumonia should always be considered.
Nervous system
Cases of leukoencephalopathy have been reported following intravenous administration of Methotrexate in patients undergoing craniospinal irradiation. Severe neurotoxicity, frequently manifesting as focal or generalized seizures, has been reported with an unexpectedly increased frequency in pediatric patients with acute lymphoblastic leukemia treated with intermediate doses of methotrexate administered intravenously (1 g / m2). In symptomatic patients, microangiopathic leukoencephalopathy and / or calcifications have commonly been observed in studies using diagnostic imaging methods. Chronic leukoencephalopathy has also been reported in patients who have repeatedly received high doses of methotrexate with calcium folinate rescue, even without irradiation of the skull. There have also been cases of leukoencephalopathy in patients receiving oral methotrexate. Withdrawal of Methotrexate does not always lead to complete recovery.
A transient acute neurological syndrome has been observed in patients treated with high-dose regimens. Manifestations of this neurological syndrome can include behavioral abnormalities, focal sensory-motor signs, including transient blindness, and abnormal reflexes. The exact cause is unknown. After intrathecal use of Methotrexate, the toxicity that can occur in the central nervous system can be classified as follows: acute chemical arachnoiditis manifesting with symptoms such as eg headache, back pain, neck stiffness and fever; subacute myelopathy characterized e.g. by paraparesis / paraplegia associated with involvement of one or more spinal nerve roots; chronic leukoencephalopathy manifesting e.g. with confusion, irritability, somnolence, ataxia, dementia, seizures and coma. central nervous system can be progressive and even fatal. Cranial irradiation combined with intrathecal administration of Methotrexate has been shown to increase the incidence of leukoencephalopathy. Signs of neurotoxicity (meningeal irritation, permanent or transient paresis, encephalopathy) should be monitored following of intrathecal administration of methotrexate.
Intrathecal and intravenous administration of Methotrexate can cause acute encephalitis and acute encephalopathy with a fatal outcome.
There have been reports of patients with periventricular central nervous system lymphoma who developed brain herniation with intrathecal Methotrexate administration.
Cases of severe neurological adverse reactions ranging from headache to paralysis, coma and stroke-like episodes have been reported mainly in young people and adolescents who received Methotrexate in combination with cytarabine.
Respiratory system
Pulmonary signs and symptoms, such as dry non-productive cough, fever, cough, chest pain, dyspnoea, hypoxemia, and chest x-ray infiltrate, or nonspecific pneumonia occurring during treatment with methotrexate may indicate potentially harmful injury and require discontinuation of treatment and careful monitoring. Lung lesions can occur at any dosage. Infection (including pneumonia) should be ruled out.
Pulmonary function tests may be useful if lung disease is suspected especially if baseline data are available.
Urinary system
Methotrexate can cause kidney damage which can lead to acute kidney failure. It is recommended that extreme attention be paid to renal function including adequate hydration, alkalinization of the urine, methotrexata dosage and evaluation of renal function.
If possible the concomitant use of proton pump inhibitors (PPIs) and high dose methotrexate should be avoided and caution should be exercised in patients with renal impairment.
Skin
Serious, occasionally fatal skin reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome) and erythema multiforme, have been reported following single or multiple doses of Methotrexate.
Reactions occurred within a period of days of oral, intramuscular, intravenous, or intrathecal administration of Methotrexate. Healing was reported with discontinuation of treatment
Laboratory tests
General
Patients on methotrexate therapy should be carefully monitored in order to detect any toxic effects promptly.
For proper clinical evaluation of patients to undergo or undergo therapy with Methotrexate the following laboratory tests should be performed: complete blood count with platelet count, hematocrit, urinalysis, kidney function test and liver function test, "Hepatitis B and hepatitis C infection. A chest X-ray must also be performed. The purpose of these tests is to establish the presence of any dysfunctions and it is necessary to perform them before, during and at the end of therapy. More frequent monitoring it may also be indicated at the start of therapy or when the dosage is changed, or during periods of increased risk of high blood levels of Methotrexate (eg dehydration). Complete blood counts should be performed daily for the first month of therapy and 3 times per week thereafter. A liver biopsy or bone marrow biopsy may be useful or important during long-term or high dose therapy. .
Pulmonary function test
Pulmonary function tests may be useful if lung disease is suspected especially if baseline data are available.
Serum levels of Methotrexate
Monitoring of serum levels of Methotrexate can significantly reduce its toxicity and mortality. Patients with the following conditions are predisposed to develop high or prolonged Methotrexate levels and benefit from periodic level monitoring: pleural effusion, ascites, gastrointestinal tract occlusion, previous cisplatin therapy, dehydration, aciduria, impaired renal function.
Some patients may have prolonged clearance of Methotrexate in the absence of these characteristics. It is important that patients are identified within 48 hours as the toxicity of Methotrexate may not be reversible if calcium folinate rescue is delayed for more than 42-48 hours.
The method of monitoring Methotrexate concentrations varies from center to center.
Monitoring of Methotrexate concentrations should include determination of Methotrexate levels at 24, 48 or 72 hours, and assessment of the rate of reduction in Methotrexate concentrations (or determining how long to continue the rescue with calcium folinate).
Interactions Which drugs or foods can modify the effect of Methotrexate
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Salicylates, some sulfonamides, para-amino-benzoic acid (PABA), phenylbutazone, diphenylhydantoin, tetracyclines and chloramphenicol can displace Methotrexate from binding to plasma proteins. Methotrexate partially binds to serum albumin and toxicity may be increased by displacement caused by other strongly binding drugs to plasma proteins, such as salicylates, phenylbutazone, phenytoin and sulphonamides and some antibiotics such as penicillins, tetracycline, pristinamycin, probenecid and chloramphenicol
Since Methotrexate is eliminated unchanged by renal excretion after glomerular filtration, active tubular secretion, as well as passive tubular reabsorption, any nephrotoxic drug can reduce the renal excretion of Methotrexate. Therefore, it is good practice not to administer these drugs during treatment with Methotrexate. Renal tubular transport of methotrexate is reduced by probenecid, the use of methotrexate with this drug should be carefully monitored. Phenylbutazone in combination with Methotrexate has in some cases caused toxicity with fever and skin ulceration, bone marrow depression and death in septicemia. The mechanism of this action is threefold: displacement of Methotrexate from binding to plasma proteins, inhibition of renal tubular secretion and bone marrow depression. Furthermore, phenylbutazone also appears to cause kidney damage which can lead to a buildup of Methotrexate.
Non-steroidal anti-inflammatory drugs (NSAIDs) should not be given before or in combination with high-dose regimens of Methotrexate, such as those used in the treatment of osteosarcoma. It has been reported that co-administration of NSAIDs with high-dose therapy of Methotrexate increases and prolongs serum levels of Methotrexate over time causing death due to severe haematological and gastrointestinal toxicity (see "SPECIAL WARNINGS"). NSAIDs and salicylates have been reported to reduce tubular secretion of methotrexate in an animal model and may potentiate it. toxicity by increasing methotrexatemia Therefore, caution should be used in case of concomitant administration of NSAIDs or salicylates with lower doses of Methotrexate (see "SPECIAL WARNINGS").
An increase in nephrotoxicity induced by high dose methotrexate has been observed when administered in combination with potentially nephrotoxic chemotherapeutic agents (e.g. cisplatin). Methotrexate in combination with leflunomide may increase the risk of pancytopenia.
When treating patients with osteosarcoma, caution should be used when administering high doses of Methotrexate in combination with a potentially nephrotoxic chemotherapeutic agent (eg cisplatin).
When high-dose methotrexate is administered in combination with potentially nephrotoxic chemotherapeutic agents (e.g. cisplatin), increased nephrotoxicity may be observed. Clearance of Methotrexate is decreased by cisplatin. Oral antibiotics such as tetracyclines, chloramphenicol and broad spectrum gastrointestinal (non-absorbable) antibiotics may decrease intestinal absorption of Methotrexate or interfere with enterohepatic circulation by inhibiting the intestinal flora and suppressing the metabolism of the drug by bacteria.
Penicillins and sulphonamides can reduce the renal clearance of Methotrexate; Increased serum concentrations of Methotrexate with concomitant haematological and gastrointestinal toxicity have been observed at both low and high doses. Therefore, the use of Methotrexate with penicillins should be closely monitored. The potential for increased hepatotoxicity related to co-administration of methotrexate with other hepatotoxic agents has not been evaluated. In such cases, however, hepatotoxicity has been reported.
Therefore, patients on Methotrexate taking other potentially hepatotoxic drugs (eg leflunomide, azathioprine, retinoids, sulfasalazine) should be monitored closely for a possible increased risk of hepatotoxicity.
It has been reported that trimethoprim / sulfamethoxazole has, in rare cases, resulted in increased bone marrow suppression in patients treated with methotrexate, possibly due to decreased tubular secretion and / or an additive antipholic effect.
Concomitant use of the antiprotozoal pyrimethamine may increase the toxic effects of methotrexate due to a cumulative antifolic effect.
Methotrexate increases the plasma levels of mercaptopurines. The combination of Methotrexate and mercaptopurine may therefore require dosage adjustment.
Vitamin preparations that contain folic acid or derivatives can reduce the response to systemically administered methotrexate, however, folate deficiency states can increase the toxicity of Methotrexate. High doses of leucovorin may reduce the efficacy of methotrexate administered intrathecally.
Methotrexate, given at the same time as radiotherapy, may increase the risk of soft tissue necrosis and osteonecrosis.
Methotrexate administered intrathecally with intravenous cytarabine may increase the risk of serious neurological adverse reactions including headache, paralysis, coma and stroke-like episodes (see "PRECAUTIONS FOR USE").
Concentrated erythrocytes (Packed Red Blood Cells)
Caution should be exercised whenever concentrated red blood cells and methotrexate are administered concomitantly. Patients receiving 24-hour methotrexate infusion and subsequent transfusions experienced increased toxicity, possibly resulting from prolonged and elevated serum methotrexate concentrations.
Psoralen and UVA radiation therapy (PUVA)
Skin cancer has been reported in some patients with psoriasis or mycosis fungoides (cutaneous T-cell lymphoma) receiving combination treatment with methotrexate plus PUVA therapy (xanthotoxin and ultraviolet radiation).
Proton pump inhibitors
Concomitant administration of proton pump inhibitors (PPIs) and methotrexate may reduce the clearance of methotrexate resulting in elevated plasma levels of methotrexate with clinical signs and symptoms of methotrexate toxicity. If possible, concomitant use of PPI and high dose methotrexate should be avoided and caution should be exercised in patients with renal impairment.
Nitrous oxide anesthesia
Nitrous oxide used as an anesthetic potentiates the effect of methotrexate on folate metabolism, resulting in severe and unpredictable stomatitis and myelosuppression. This effect can be reduced by using folic acid as a rescue. Methotrexate may decrease theophylline clearance; theophylline levels should be monitored when co-administered with Methotrexate.
Diuretics
Myelosuppression and decreased folate levels have been reported with concomitant administration of triamterene and methotrexate.
Amiodarone
Administration of amiodarone to patients on methotrexate treatment for psoriasis induced ulcerative skin lesions.
L-asparaginase
Administration of L-asparaginase has been reported to antagonize the effect of methotrexate.
Ciprofloxacin
Transport into the renal tubules is decreased by ciprofloxacin; the use of methotrexate with this drug should be closely monitored.
Warnings It is important to know that:
Fatal toxicities have been reported due to errors in intravenous and intrathecal dose calculations. Special attention should be paid to the calculation of the dose.
Due to the possibility of severe toxic reactions (which can be fatal), methotrexate should only be used for life-threatening neoplastic diseases. Cases of death have been reported with the use of methotrexate in the treatment of neoplasms. Due to the possibility of severe toxic reactions, the patient should be informed by the physician of the risks and must remain under continuous medical supervision.
There have been reports of deaths with the use of Methotrexate in the treatment of malignancies. The use of the high dosages of Methotrexate recommended in the treatment of osteosarcoma requires special attention. High dose regimens for other malignancies are considered experimental and are not Therapeutic advantage has been established Methotrexate formulations and diluents containing preservatives should not be used for intrathecal administration or for high dose therapy of Methotrexate.
Methotrexate causes hepatotoxicity, liver fibrosis and cirrhosis, but generally only after prolonged use. Acute onset increases in liver enzymes have frequently been observed; these are generally transient and asymptomatic and furthermore do not appear predictive of a subsequent liver disease. Liver biopsy after prolonged use often shows histological changes and fibrosis and cirrhosis have been reported.
Methotrexate caused the hepatitis B infection to become reactivated or the hepatitis C infection to worsen, in some cases resulting in death. Some cases of hepatitis B reactivation have occurred after discontinuation of Methotrexate. Clinical and laboratory evaluation should be performed to evaluate pre-existing liver disease in patients with previous hepatitis B and C infections. Based on these evaluations, treatment with Methotrexate may not be indicated for some patients.
Methotrexate is partially bound, after absorption, to serum albumin and its toxicity could be increased following the displacement induced by certain drugs, such as salicylates, sulfonamides, diphenylhydantoin and various antibacterial agents, such as tetracyclines, chloramphenicol and para acid. -amino-benzoic. These drugs, especially salicylates and sulfonamides, whether antibacterial, hypoglycemic or diuretic, should not be administered concomitantly with Methotrexate until the importance and significance of these clinical data is established. Vitamin preparations containing folic acid or its derivatives can alter the response to Methotrexate until its complete neutralization.
Elimination of Methotrexate from the third space (eg pleural effusion or ascites) occurs slowly. This results in a prolongation of the terminal plasma half-life and unexpected toxicity.In patients with significant fluid accumulation in the third space, it is advisable to aspirate the effusion prior to treatment with Methotrexate and monitor plasma levels.
Methotrexate should be used with extreme caution in the presence of infections, peptic ulcer, ulcerative colitis, debilitation and in very young or very old patients. Diarrhea and ulcerative stomatitis require discontinuation of treatment, otherwise hemorrhagic enteritis and death following intestinal perforation may occur.
Methotrexate should be used with extreme caution in the presence of existing infections, and is usually contraindicated in patients with manifest or laboratory-evidenced immunodeficiency syndrome.
If severe leukopenia occurs during therapy, a bacterial infection may occur; in this case, it is advisable to discontinue use of the drug and to initiate adequate antibiotic therapy. In severe depression of bone marrow activity, blood or platelet transfusions are required.
Malignant lymphomas may occur in patients receiving low dose Methotrexate, which may regress after discontinuation of Methotrexate treatment, and therefore may not require cytotoxic treatment. Discontinue Methotrexate first and if lymphoma does not regress, institute appropriate treatment.
Like other cytotoxic drugs, Methotrexate can induce a "tumor lysis syndrome" in patients with rapidly growing tumors. Appropriate supportive and pharmacological measures can prevent or alleviate this complication.
Unexpectedly severe (sometimes fatal) suppression of bone marrow activity, aplastic anemia and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high doses) and NSAIDs.
Methotrexate-induced lung disease, including acute or chronic interstitial pneumonia and pleural effusion, can arise at any time during therapy; it has been reported at low doses. It is not always fully reversible and fatal outcomes have been reported.
Pulmonary symptoms (especially dry, non-productive cough) may require discontinuation of treatment and careful examination.
Methotrexate has been found to exert an immunosuppressive action; this effect should be considered when evaluating the use of the drug when the immunological response in a patient may be important or essential.
Life-threatening opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with treatment with Methotrexate. When a patient presents with pulmonary symptoms, the possibility of Penumocystis carinii pneumonia should always be considered. It should be borne in mind that during a high-dose Methotrexate therapy it is essential to ensure a diuresis of at least 2 liters in 24 hours and a urinary pH of not less than 6.5.
Methotrexate can cause severe hematopoietic tissue depression and should be used with caution in patients with bone marrow impairment and previous or concomitant broad field radiotherapy. All patients undergoing Methotrexate therapy should be carefully monitored and it should be noted that the following symptoms are manifestations of its toxicity: gastrointestinal ulceration and haemorrhage, including stomatitis, bone marrow depression, mainly affecting the elements of the white series, and alopecia. Generally in each individual, toxicity is directly related to dose.
Methotrexate, given at the same time as radiotherapy, may increase the risk of soft tissue necrosis and osteonecrosis.
Methotrexate should not be administered with other drugs in the same infusion.
Medicinal product containing sodium therefore not suitable for subjects who must follow a low sodium diet.
Pregnancy, breastfeeding and fertility
Ask your doctor or pharmacist for advice before taking any medicine.
Fertility
Methotrexate has been reported to cause impaired fertility, oligospermia and menstrual dysfunction in humans, during and for a short time after discontinuation of therapy.
Pregnancy
The risks of reproductive effects should be discussed with patients of both sexes receiving methotrexate.
Methotrexate is contraindicated during pregnancy. Its use can cause teratogenic effects, fetal death, embryotoxicity and abortion when administered to pregnant women. In the treatment of neoplastic diseases it should only be used if the potential benefits outweigh the risk to the fetus
Women of childbearing age should not initiate Methotrexate therapy until pregnancy has been ruled out; they must be fully informed of the serious risks to the fetus if pregnancy occurs during treatment with Methotrexate. If either partner is being treated with Methotrexate, pregnancy should be avoided. The optimal time interval between either partner ending treatment with Methotrexate and becoming pregnant has not yet been clearly established (see "Contraindications"). The recommendations regarding the time intervals, taken from the published literature, range from 3 months to a year.
Feeding time
Methotrexate is found in human breast milk. Methotrexate is contraindicated in breastfeeding women due to its potential to produce serious adverse reactions in the infant.
The highest ratio of Methotrexate concentrations in breast milk to plasma was 0.08: 1.
If it is necessary to administer the drug while breastfeeding, it should be stopped before starting treatment.
Effects on ability to drive and use machines
Some effects mentioned in the "Undesirable effects" section, such as dizziness and fatigue may affect the ability to drive or use machines.
Use in elderly patients
Fatal toxicities have been reported due to erroneous daily rather than weekly intake especially in elderly patients. Patients should be stressed that the recommended dose should be taken weekly for rheumatoid arthritis and psoriasis (see "Precautions for use").
Due to impaired hepatic and renal function and reduced folate reserves in elderly patients, reduced doses should be considered and these patients should be closely monitored for the earliest signs of toxicity.
Use in pediatric patients
Safety and efficacy in pediatric patients have only been established for anticancer chemotherapy and polyarticular juvenile idiopathic arthritis.
Published clinical studies evaluating the use of methotrexate in children and adolescents (ie patients aged 2 to 16 years) with juvenile idiopathic arthritis have demonstrated a safety comparable to that observed in adults with rheumatoid arthritis.
Fatal toxicities have been reported due to errors in intravenous and intrathecal dose calculations. Overdose has occurred due to errors in intravenous and intrathecal dose calculations (particularly in young people). Particular attention should be paid to calculating the dose (see "Precautions for use").
Medicinal product containing sodium therefore not suitable for subjects who must follow a low sodium diet.
The benzyl alcohol preservative has been associated with serious adverse events, including "gasping syndrome" and death in pediatric patients. Symptoms include violent onset of agonal breathing, hypotension, bradycardia, and cardiovascular collapse. Although the normal therapeutic doses of this product generally release substantially lower quantities of benzyl alcohol than those reported in association with the "gasping syndrome", the minimum quantity of benzyl alcohol at which toxicity can occur is not known. The risk of benzyl alcohol toxicity depends on the amount administered and the liver's ability to eliminate chemicals. Premature and low-weight infants may be more prone to developing toxicity.
Severe neurotoxicity, often manifesting in the form of generalized or focal seizures, has been reported among pediatric patients with acute lymphoblastic leukemia treated with intravenous methotrexate (1 g / m2).
Dosage and method of use How to use Methotrexate: Dosage
The dosage regimens used vary considerably from one researcher to another and according to the nature and severity of the disease. The most recent literature and the doctor's experience represent some of the factors that can influence the choice of dosage and the duration of therapy.
For some years and for some neoplastic forms, high-dose Methotrexate combined with calcium folinate "rescue" has been used with good results. However, it must be kept in mind that the use of high-dose regimens in the treatment of neoplastic diseases other than osteosarcoma is to be considered in an experimental phase, and a therapeutic advantage of this approach has not been established. High doses should only be used by qualified doctors and in a hospital setting (preferably in cancer wards).
"Rescue" with calcium folinate in high dose Methotrexate therapy.
According to the most recent acquisitions, to improve the therapeutic index of Methotrexate, calcium folinate is used in a sequential antidotic treatment ("rescue" with calcium folinate). "rescue" with calcium folinate, it is in fact possible to better control tumor forms without recording, at the same time, significant increases in toxicity. "Rescue" provides for the use of calcium folinate by parenteral route in the first phase corresponding to antidotism for competition; orally in the second phase in which mainly the biochemical-metabolic component comes into play. "Rescue" doses and schedules vary according to the approach adopted. Below are some guidelines concerning the tolerability profile of therapy with high doses of Methotrexate associated with "rescue" with calcium folinate and a table with lines general guidelines for calcium folinate dosing based on methotrexate serum levels It is also advisable to consult the most recent literature.
GUIDELINES FOR HIGH-DOSAGE THERAPY OF METHOTREXATE ASSOCIATED WITH RESCUE WITH CALCIUM FOLINATE
1. The administration of Methotrexate should be delayed (until the normal ranges of the parameters indicated below are restored) if:
- the number of white blood cells is less than 1500 / microliter
- the number of neutrophils is less than 200 / microliter
- the number of platelets is less than 75,000 / microliter
- the serum bilirubin level is greater than 1.2 mg / dl
- the level of SGPT is above 450U
- mucositis is present (and until the healing process is evident)
- there is a persistent pleural effusion; this effusion must be aspirated before the infusion
2. Adequate renal function must be documented:
- Serum creatinine should be normal and creatinine clearance should be greater than 60ml / min. before starting therapy.
- Serum creatinine should be measured prior to each subsequent course of therapy. If serum creatinine has increased by 50% or more from the previous value, the creatinine clearance should be assessed and made sure it is still above 60ml / min (even if serum creatinine is still within the normal range).
3. Patients must be well hydrated and treated with sodium bicarbonate to alkalize the urine.
- Administer 1000 ml / m2 of liquid intravenously within 6 hours before the start of the infusion of Methotrexate. Continue to hydrate the patient with 125ml / m2 / h (3 liters / m2 / day) during the Methotrexate infusion and for two days following the infusion.
- Alkalize urine to maintain pH above 7.0 during Methotrexate infusion and calcium folinate therapy. This can be achieved by administering sodium bicarbonate orally or by administering it intravenously in a separate solution.
4. Measure serum creatinine and serum concentration of Methotrexate 24 hours after the start of the Methotrexate infusion and at least once daily until the Methotrexate level has dropped below 0.05 micromol.
5. The following table provides general guidelines for the dosage of calcium folinate based on the serum levels of Methotrexate (see table below).
Patients who show a delay in the early elimination phase of Methotrexate are more likely to develop irreversible oliguric renal failure. In addition to appropriate calcium folinate therapy, these patients require continued hydration and alkalinization of the urine, and close monitoring of fluid and electrolyte status, until serum Methotrexate levels have dropped below 0.05 micromol. and renal failure has not resolved. If necessary, intermittent hemodialysis with a high-flow dialyzer may be helpful in these patients.
6. Some patients will have abnormalities in elimination of Methotrexate, or abnormalities in renal function after administration of Methotrexate, which are significant but less severe than the abnormalities described in the table below. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity occurs, calcium folinate rescue should be continued for an additional 24 hours (for a total of 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other drugs that interact with Methotrexate (eg drugs that may interfere with the binding of Methotrexate to serum albumin or its elimination) should always be considered when abnormal laboratory tests or clinical toxicity are observed.
WARNING: DO NOT GIVE CALCIUM FOLINATE INTRATHECAL.
GUIDELINES FOR THE DOSAGE OF CALCIUM FOLINATE AS RESCUE THERAPY FOLLOWING THE "USE OF HIGHER DOSES" OF METHOTREXATE
Instructions for Use:
People who have contact with cancer drugs or work in areas where these drugs are used, may be exposed to these agents either by air contact or by direct contact with contaminated objects. Potential health effects can be reduced by adhering to institutional procedures, published guidelines, and local regulations regarding the preparation, administration, transport and disposal of hazardous drugs. There is no general agreement that all procedures recommended in the guidelines are necessary and appropriate.
Methotrexate powder for solution for injection:
Methotrexate 500 mg and Methotrexate 1g powder for solution for injection must be reconstituted immediately before use, respectively, with 10 ml and 20 ml of water for injections or physiological saline or 5% dextrose solution, containing no preservatives. solution with a concentration of 50 mg / ml, reconstitute the bottle containing 1 g of methotrexate with 19.4 ml of liquid.
Methotrexate 50 mg powder for solution for injection must be reconstituted immediately before use with water for injections using 20 ml of water.
When high doses of Methotrexate are administered by intravenous infusion, dilute the total dose in 5% dextrose solution.
For intrathecal administration, reconstitute to a concentration of 1 mg / ml using a suitable sterile solution, free of preservatives, such as saline.
Methotrexate solution
If necessary, the solution can be further diluted, immediately before use, with physiological saline or 5% dextrose solution, containing no preservatives.
The bottles are for single use only.
If a precipitate forms, the solution must be discarded.
Do not administer Methotrexate with other drugs in the same infusion.
Overdose What to do if you have taken too much Methotrexate
In post-marketing experience, cases of methotrexate overdose have occurred generally with oral and intrathecal administration, although cases of overdose with intravenous and intramuscular administration have been reported.
There are cases of overdose in the literature in which intravenous and intrathecal treatment of carboxypeptidase G2 was used to accelerate the clearance of Methotrexate.
Withhold or reduce the dose at the first sign of ulceration or bleeding, diarrhea or marked depression of the haematopoietic system.
Symptoms of intrathecal methotrexate overdose are usually neurological including headache, nausea and vomiting, convulsions or seizures, and acute toxic encephalopathy. In some cases, no symptoms were reported.
There have been reports of deaths following intrathecally administered overdoses. Cerebellar herniation associated with increased intracranial pressure and acute toxic encephalopathy have also been reported in these cases.
Calcium folinate is indicated to reduce toxicity and counter the effects of an overdose of methotrexate administered inadvertently. Administration of calcium folinate should be started as quickly as possible. As the interval between the administration of methotrexate and the start of treatment with calcium folinate increases, its activity in counteracting toxicity decreases.
Calcium folinate, a specific antidote of Methotrexate, allows to neutralize the toxic effects exerted by the antimetabolite on the hematopoietic system and on the mucous membranes of the digestive system. In its role as an antidote, calcium folinate is used at different dosages depending on the effect to be obtained. In cases of accidental overdose, calcium folinate for intravenous infusion (up to 100 mg within 12 hours) is recommended to obtain a competitive effect. ; to obtain a metabolic biochemical effect calcium folinate is recommended intramuscularly (10-12 mg every 6 hours for 4 doses) or orally (15 mg every 6 hours for 4 doses).
In case of accidental administration, calcium folinate should be administered in doses equal to or greater than those of Methotrexate within the first hour; the administration of calcium folinate in subsequent times is less effective. Monitoring of the serum concentration of Methotrexate is essential to determine the optimal dose and duration of treatment with calcium folinate.
In the event of a massive overdose, hydration and alkalization of the urine may be required to prevent precipitation of Methotrexate and / or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis have been shown to improve the elimination of methotrexate. However, effective clearance of Methotrexate has been reported with the use of intermittent hemodialysis with a high-flux dialyzer.
Accidental intrathecal overdose may require intensive systemic support, high doses of calcium folinate, alkaline diuresis and rapid CSF drainage, and ventriculolumbar perfusion.
In case of accidental ingestion / intake of an excessive dose of methotrexate, notify your doctor immediately or go to the nearest hospital.
If you have any further questions on the use of Methotrexate, ask your doctor or pharmacist.
Side Effects What are the side effects of Methotrexate
Like all medicines, Methotrexate can cause side effects, although not everybody gets them.
For information on adverse reactions associated with methotrexate, see the relevant sections.
The most common side effects include: ulcerative stomatitis, leukopenia, nausea and abdominal discomfort. Other frequently reported side effects are: feelings of malaise and excessive fatigue, chills and fever, dizziness, less resistance to infections.
The very first signs of toxicity are usually represented by ulcerations of the oral mucosa.
Severity and incidence of acute side effects are generally related to the dosage and frequency of administration.
Other possible adverse reactions that have been reported with methotrexate by system organ and by frequency are listed below. In the oncological setting, concomitant treatments and pre-existing diseases make it difficult to attribute a specific reaction to methotrexate. See section 4.4 for specific references to long-term and medically important events, including those following treatment. long-term or at high cumulative doses (e.g. liver toxicity).
Frequency categories are defined as: very common (≥ 1/10), common (≥ 1/100,
* exclusively for injecting
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly through the national reporting system at "https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse". By reporting side effects you can help provide more information on the safety of this medicine
Expiry and Retention
Methotrexate powder for solution for injection: store at a temperature not exceeding 25 ° C. Protect from light and humidity.
Methotrexate solution for injection: store at temperatures between 15 ° C-22 ° C. Protect from light.
Expiry: See the expiry date printed on the package.
Warning: do not use the medicine after the expiry date indicated on the package.
The expiry date indicated refers to the product in intact packaging, correctly stored. The expiry date refers to the last day of the month.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
KEEP THE MEDICINAL PRODUCT OUT OF THE SIGHT AND REACH OF CHILDREN.
DO NOT HANDPIECE METHOTREXATE IF YOU ARE PREGNANT OR INTEND TO GET PREGNANT.
COMPOSITION
Methotrexate 50 mg powder for solution for injection:
One bottle of lyophilized powder contains:
Active ingredient: Methotrexate sodium salt 54.84 mg equivalent to methotrexate 50 mg.
Excipients: sodium chloride, sodium hydroxide. Contains no preservatives.
Methotrexate 500 mg powder for solution for injection:
One bottle of lyophilized powder contains:
Active ingredient: Methotrexate sodium salt 548.4 mg equivalent to methotrexate 500 mg.
Excipients: sodium hydroxide. Contains no preservatives.
Methotrexate 1 g powder for solution for injection:
One bottle of lyophilized powder contains:
Active ingredient: Methotrexate sodium salt 1.097 g equivalent to methotrexate 1 g.
Excipients: sodium hydroxide. Contains no preservatives.
Methotrexate 50 mg / 2 ml solution for injection:
A bottle of 50 mg in 2 ml contains:
Active ingredient: Methotrexate sodium salt 54.84 mg equivalent to methotrexate 50 mg.
Excipients: sodium hydroxide, sodium chloride, water for injections. Contains no preservatives.
Methotrexate 500 mg / 20 ml solution for injection:
A bottle of 500 mg in 20 ml contains:
Active ingredient: Methotrexate sodium salt 548.4 mg equivalent to methotrexate 500 mg.
Excipients: sodium hydroxide, sodium chloride, water for injections. Contains no preservatives.
Methotrexate 1 g / 10 ml solution for injection:
A bottle of 1 g in 10 ml contains:
Active ingredient: Methotrexate sodium salt 1.097 g equivalent to methotrexate 1 g.
Excipients: sodium hydroxide, water for injections. Contains no preservatives.
Methotrexate 5 g / 50 ml solution for injection:
A bottle of 5 g in 50 ml contains:
Active ingredient: Methotrexate sodium salt 5.484 g equivalent to methotrexate 5 g.
Excipients: sodium hydroxide, water for injections. Contains no preservatives.
PHARMACEUTICAL FORM AND CONTENT
Methotrexate 50 mg powder for solution for injection:
1 Bottle of 50 mg lyophilized powder
Methotrexate 500 mg powder for solution for injection:
1 Bottle of 500 mg lyophilized powder
Methotrexate 1 g powder for solution for injection:
1 Bottle of 1g lyophilized powder
Methotrexate 50 mg / 2 ml solution for injection:
1 Bottle of 50 mg in 2 ml
Methotrexate 500 mg / 20 ml solution for injection:
1 bottle of 500 mg in 20 ml
Methotrexate 1 g / 10 ml solution for injection:
1 Bottle of 1 g in 10 ml
Methotrexate 5 g / 50 ml solution for injection:
1 Bottle of 5 g in 50 ml.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
HIGH DOSAGE METHOTREXATE
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Methotrexate 50 mg powder for solution for injection:
One bottle of lyophilized powder contains:
Active ingredient: Methotrexate sodium salt 54.84 mg equivalent to methotrexate 50 mg.
Methotrexate 500 mg powder for solution for injection:
One bottle of lyophilized powder contains:
Active ingredient: Methotrexate sodium salt 548.4 mg equivalent to methotrexate 500 mg.
Methotrexate 1 g powder for solution for injection:
One bottle of lyophilized powder contains:
Active ingredient: Methotrexate sodium salt 1.097 g equivalent to methotrexate 1 g.
Methotrexate 50 mg / 2 ml solution for injection:
A bottle of 50 mg in 2 ml contains:
Active ingredient: Methotrexate sodium salt 54.84 mg equivalent to methotrexate 50 mg.
Methotrexate 500 mg / 20 ml solution for injection:
A bottle of 500 mg in 20 ml contains:
Active ingredient: Methotrexate sodium salt mg 548.4 (equivalent to methotrexate 500 mg).
Methotrexate 1 g / 10 ml solution for injection:
A bottle of 1 g in 10 ml contains:
Active ingredient: Methotrexate sodium salt 1.097 g equivalent to methotrexate 1 g.
Methotrexate 5 g / 50 ml solution for injection:
A bottle of 5 g in 50 ml contains:
Active ingredient: Methotrexate sodium salt 5.484 g equivalent to methotrexate 5.0 g.
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
- Powder for solution for injection
- Injectable solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Methotrexate is indicated for the antineoplastic chemotherapy treatment of the following forms: breast carcinoma, choriocarcinoma and similar trophoblastic diseases, acute and subacute lymphatic and meningeal leukemia, lymphosarcoma, mycosis fungoides.
Clinical research has shown that it is considerably more effective in childhood leukemia than in adult leukemia. In some cases of acute leukemia it has produced clinical improvement and prolonged survival time for a period ranging from a few weeks to 2 years. The haematological picture, obtained from the blood test and from the smears of the bone marrow after administration of Methotrexate, can become almost indistinguishable from the normal one for variable periods of time. The best effects were observed in acute leukemias characterized by the presence of highly immature forms in the bone marrow and blood. Favorable results obtained with Methotrexate in choriocarcinoma have been reported.
Methotrexate is particularly indicated in mono or polychemotherapy, for the treatment of: osteogenic sarcoma, acute leukemia, bronchogenic carcinoma, epidermoid carcinoma of the head and neck.
04.2 Posology and method of administration
The dosage regimens used vary considerably from one researcher to another and according to the nature and severity of the disease. The most recent literature and the doctor's experience represent some of the factors that can influence the choice of dosage and the duration of therapy.
For some years and for some neoplastic forms, high-dose Methotrexate combined with calcium folinate "rescue" has been used with good results. However, it must be kept in mind that the use of high-dose regimens in the treatment of neoplastic diseases other than osteosarcoma is to be considered in an experimental phase, and a therapeutic advantage of this approach has not been established. High doses should only be used by qualified doctors and in a hospital setting (preferably in cancer wards).
'Rescue "with calcium folinate in high dose Methotrexate therapy.
According to the most recent acquisitions, to improve the therapeutic index of Methotrexate, calcium folinate is used in a sequential antidotic treatment ("rescue" with calcium folinate). "rescue" with calcium folinate, it is in fact possible to better control tumor forms without recording, at the same time, significant increases in toxicity. The "rescue" involves the use of calcium folinate by parenteral route in the first phase corresponding to antidotism for competition; orally in the second phase in which mainly the biochemical-metabolic component comes into play. "Rescue" doses and schedules vary according to the approach adopted. Below are some guidelines concerning the tolerability profile of therapy with high doses of Methotrexate associated with "rescue" with calcium folinate and a table with lines general guidelines for calcium folinate dosing based on methotrexate serum levels It is also advisable to consult the most recent literature.
GUIDELINES FOR HIGH-DOSAGE THERAPY OF METHOTREXATE ASSOCIATED WITH RESCUE WITH CALCIUM FOLINATE
The administration of Methotrexate should be delayed (until the normal ranges of the parameters indicated below are restored) if:
• the number of white blood cells is less than 1500 / microliter
• the number of neutrophils is less than 200 / microliter
• the number of platelets is less than 75,000 / microliter
• the level of serum bilirubin is higher than 1.2 mg / dl
• the SGPT level is higher than 450 U
• mucositis is present (and until the healing process is evident)
• there is a persistent pleural effusion; this effusion must be aspirated before the infusion
Adequate renal function must be documented:
Serum creatinine should be normal and creatinine clearance should be above 60ml / min. before starting therapy.
Serum creatinine should be measured prior to each subsequent course of therapy. If serum creatinine is increased by 50% or more from the previous value, creatinine clearance should be evaluated and ascertained that it is still above 60ml / min (even if serum creatinine is still within the normal range).
Patients must be well hydrated and treated with sodium bicarbonate to alkalize the urine.
Administer 1000 ml / m2 of liquid intravenously within 6 hours before the start of the infusion of Methotrexate. Continue to hydrate the patient with 125ml / m2 / h (3 liters / m2 / day) during the Methotrexate infusion and for two days following the infusion.
Alkalize urine to maintain pH above 7.0 during Methotrexate infusion and calcium folinate therapy. This can be achieved by administering sodium bicarbonate orally or by administering it intravenously in a separate solution.
Measure the serum creatinine and the serum concentration of Methotrexate 24 hours after the start of the Methotrexate infusion and at least once a day until the Methotrexate level has dropped below 0.05 micromol.
The following table provides general guidelines for the dosage of calcium folinate based on the serum levels of Methotrexate (see table below).
Patients who show a delay in the early elimination phase of Methotrexate are more likely to develop irreversible oliguric renal failure. In addition to appropriate calcium folinate therapy, these patients require continued hydration and alkalinization of the urine, and close monitoring of fluid and electrolyte status, until serum Methotrexate levels have dropped below 0.05 micromol. and renal failure has not resolved. If necessary, intermittent hemodialysis with a high-flow dialyzer may be helpful in these patients.
Some patients will have abnormalities in elimination of Methotrexate, or abnormalities in renal function after administration of Methotrexate, which are significant, but less severe than the abnormalities described in the table below. These abnormalities may or may not be associated with significant clinical toxicity. manifests significant clinical toxicity, calcium folinate rescue should be continued for an additional 24 hours (for a total of 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other drugs that interact with Methotrexate (p . eg. drugs that may interfere with the binding of Methotrexate to serum albumin or its elimination) should always be considered when abnormal laboratory tests or clinical toxicity are observed.
WARNING: DO NOT GIVE CALCIUM FOLINATE INTRATHECAL.
GUIDELINES FOR THE DOSAGE OF CALCIUM FOLINATE AS RESCUE THERAPY FOLLOWING THE "USE OF HIGHER DOSES" OF METHOTREXATE
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Methotrexate is contraindicated during pregnancy. Its use can cause teratogenic effects, fetal death, embryotoxicity and abortion when administered to pregnant women. In the treatment of neoplastic diseases it should only be used if the potential benefits outweigh the risk to the fetus.
Women of childbearing age should not initiate Methotrexate therapy until pregnancy has been ruled out; they must be fully informed of the serious risks to the fetus if pregnancy occurs during treatment with Methotrexate. If either partner is being treated with Methotrexate, pregnancy should be avoided. The optimal time interval between either partner ending treatment with Methotrexate and becoming pregnant has not yet been clearly established (see 4.4). The recommendations regarding the time intervals, taken from the published literature, range from 3 months to a year.
Methotrexate is found in human breast milk. Methotrexate is contraindicated in breastfeeding women due to its potential to produce serious adverse reactions in the infant.
The highest ratio of Methotrexate concentrations in breast milk to plasma was 0.08: 1.
Methotrexate formulations and diluents that contain preservatives should not be used for intrathecal administration or for high dose therapy of Methotrexate.
04.4 Special warnings and appropriate precautions for use
General
Methotrexate has the potential to induce severe toxic reactions, usually related to dosage.
Fatal toxicities have been reported due to errors in intravenous and intrathecal dose calculations. Special attention should be paid to the calculation of the dose.
Due to the possibility of severe toxic reactions (which can be fatal) Methotrexate should only be used in cases of cancer with risk of death.
There have been reports of deaths with the use of Methotrexate in the treatment of malignant neoplasms. Due to the possibility of severe toxic reactions the patient should be informed by the physician of the risks and should remain under continuous medical supervision.
Methotrexate is contraindicated during pregnancy. Its use can cause teratogenic effects, fetal death, embryotoxicity and abortion when administered to pregnant women. In the treatment of neoplastic diseases it should only be used if the potential benefits outweigh the risk to the fetus. Women of childbearing age should not initiate therapy with Methotrexate until pregnancy has been ruled out; they must be fully informed of the serious risks to the fetus if pregnancy occurs during treatment with Methotrexate. If either partner is being treated with Methotrexate, pregnancy should be avoided. The optimal time interval between either partner ending treatment with Methotrexate and becoming pregnant has not yet been clearly established (see 4.3). The recommendations regarding the time intervals, taken from the published literature, range from 3 months to a year. The use of the high dosages of Methotrexate recommended in the treatment of osteosarcoma requires special attention. Methotrexate can cause kidney damage which can lead to acute kidney failure. It is recommended that extreme attention be paid to renal function including adequate hydration, alkalinization of urine, methotrexatemia dosage and evaluation of renal function.
High-dose regimens for other malignancies are considered experimental and a therapeutic advantage has not been established. Formulations of Methotrexate and diluents that contain preservatives should not be used for intrathecal administration or for high dose therapy of Methotrexate.
The physician must be well informed about the various characteristics of the drug and its clinical use.
Patients undergoing Methotrexate therapy should be closely monitored in order to identify and evaluate the signs and symptoms of possible toxic or side effects as soon as possible. Pre-treatment monitoring and periodic haematological checks are necessary for the use of Methotrexate in chemotherapy, due to the possible suppressive effect on hematopoietic function attributable to the drug. It can occur suddenly at any time and even at low doses.
Any sharp drop in blood cell counts indicates that drug administration should be discontinued immediately and appropriate therapy instituted. In patients with cancer and pre-existing bone marrow aplasia, leukopenia, thrombocytopenia or anemia, the product should be used with caution. and only if strictly necessary. Methotrexate is excreted primarily via the kidneys. Methotrexate therapy in patients with renal insufficiency should be undertaken with extreme caution and at reduced dosage regimens, as impaired renal function decreases the elimination of Methotrexate. Its use, in the presence of impaired renal function, can cause a dangerous increase in the serum levels of the drug and, consequently, a further aggravation of pre-existing renal damage. The renal status of the patient should be determined before and during therapy with Methotrexate proceeding with great caution if severe renal insufficiency is found. In this case, the dosage should be reduced or the drug suspended until the kidney function improves.
Methotrexate causes hepatotoxicity, liver fibrosis and cirrhosis but generally after prolonged use.
Acute onset increases in liver enzymes have frequently been observed; these are generally transient and asymptomatic and furthermore do not appear predictive of a subsequent liver disease. Liver biopsy after prolonged use often shows histological changes and fibrosis and cirrhosis have been reported.
Bleeding time, clotting time and blood group determination should be done before a transfusion or surgery.
Methotrexate is partially bound, after absorption, to serum albumin and its toxicity could be increased following the displacement induced by certain drugs, such as salicylates, sulfonamides, diphenylhydantoin and various antibacterial agents, such as tetracyclines, chloramphenicol and para acid. -amino-benzoic. These drugs, especially salicylates and sulfonamides, whether antibacterial, hypoglycemic or diuretic, should not be administered concomitantly with Methotrexate, until the importance and significance of these clinical data is established. Vitamin preparations containing folic acid or its derivatives can alter the response to Methotrexate until its complete neutralization.
Elimination of Methotrexate from the "third space" (eg pleural effusion or ascites) occurs slowly. This results in a prolongation of the terminal plasma half-life and unexpected toxicity. In patients with significant fluid accumulation in the third space, it is advisable to aspirate the effusion prior to treatment with Methotrexate and monitor plasma levels.
Methotrexate should be used with extreme caution in the presence of infections, peptic ulcer, ulcerative colitis, debilitation and in very young or very old patients. Diarrhea and ulcerative stomatitis require discontinuation of treatment, otherwise hemorrhagic enteritis and death following intestinal perforation may occur.
If severe leukopenia occurs during therapy, a bacterial infection may occur; in this case, it is advisable to discontinue use of the drug and to initiate adequate antibiotic therapy. In severe depression of bone marrow activity, blood or platelet transfusions are required.
Like other cytotoxic drugs, Methotrexate can induce a "tumor lysis syndrome" in patients with rapidly growing tumors. Appropriate general and pharmacological supportive measures can prevent or alleviate this complication.
Unexpectedly severe (sometimes fatal) suppression of bone marrow activity, aplastic anemia and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high doses) and NSAIDs.
Methotrexate-induced lung disease, including acute or chronic interstitial pneumonia, can arise at any time during therapy; it has been reported at low doses. It is not always fully reversible and fatal outcomes have been reported. Pulmonary symptoms (especially a dry, non-productive cough) may require discontinuation of treatment and careful examination.
It has been found that Methotrexate can exert an immunosuppressive action; this effect should be considered when evaluating the use of the drug when the immunological response in a patient may be important or essential.
Patients on methotrexate should be monitored closely. Methotrexate can cause severe toxicity. In any case, when Methotrexate is used in chemotherapy, the physician must evaluate the necessity and usefulness of the preparation against the risk of toxic effects or side effects. The toxic effects can be related, in frequency and severity, to the dose or to the frequency of administration, but toxicity has been observed at all doses and can occur at any time during treatment. Most adverse reactions are reversible if diagnosed early. When such reactions occur, the dose should be reduced or the administration discontinued. medication and take appropriate treatment (see Overdose). If necessary, such treatments may include the use of calcium folinate and / or intermittent hemodialysis with a high-flux dialyzer. If Methotrexate therapy is resumed, this should be done with much caution with adequate consideration of the further necessity of the drug and with increased attention to the possibility bile recurrence of toxicity.
It should be borne in mind that during a high-dose Methotrexate therapy it is essential to ensure a diuresis of at least 2 liters in 24 hours and a urinary pH of not less than 6.5.
Methotrexate can cause severe hematopoietic tissue depression and should be used with caution in patients with bone marrow impairment and previous or concomitant broad field radiotherapy. All patients undergoing Methotrexate therapy should be carefully monitored and it should be noted that the following symptoms are manifestations of its toxicity: gastrointestinal ulceration and haemorrhage, including stomatitis, bone marrow depression, mainly affecting the elements of the white series, and alopecia. Generally in each individual, toxicity is directly related to dose.
Malignant lymphomas may occur in patients receiving low dose Methotrexate, which may regress after discontinuation of Methotrexate treatment, and therefore may not require cytotoxic treatment. Discontinue Methotrexate first and if lymphoma does not regress, institute appropriate treatment.
Methotrexate, given at the same time as radiotherapy, may increase the risk of soft tissue necrosis and osteonecrosis.
Methotrexate must be administered under the personal and close supervision of the physician, who should not prescribe to the patient, in a single time, quantities greater than the dosage needed for 6-7 days of therapy. A complete blood count should be performed weekly. Dosing should be discontinued or the dosage reduced immediately after the first signs of ulceration, haemorrhage, diarrhea or significant depression appear.
Methotrexate, like most of the anticancer and immunosuppressive drugs, has shown carcinogenic properties in animals under particular experimental conditions. Methotrexate should only be used by physicians who have experience in the field of antimetabolites.
Patients should be advised of the potential risks and benefits of using Methotrexate (including initial symptoms and signs of toxicity), the need to consult their physician quickly if necessary, and the need for close follow-up, including medical tests. laboratory to monitor for toxicity The risks of effects on reproductive performance should be discussed with patients, both female and male, who are being treated with Methotrexate.
States of folate deficiency can increase the toxicity of Methotrexate.
Tolerability
Gastrointestinal system
Should vomiting, diarrhea, stomatitis resulting in dehydration occur, methotrexate should be discontinued until symptoms resolve.
Hematopoietic system
Methotrexate can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia and / or thrombocytopenia. Methotrexate should be used with caution, especially in patients with malignant diseases and pre-existing haematopoietic deficiency. methotrexate should only be continued if the potential benefits outweigh the risk of severe myelosuppression.
Hepatic system
Methotrexate causes acute hepatitis and chronic hepatotoxicity (fibrosis and cerrosis). Chronic toxicity is potentially fatal and usually occurs after prolonged use (usually 2 years or more) and after an overall cumulative dose of at least 1.5 grams. In studies conducted on patients with psoriasis, hepatotoxicity appears to be a function of the total cumulative dose and appears to be increased by alcoholism, obesity, diabetes and old age. Transient abnormalities of hepatic parameters are frequently observed following methotrexate administration and usually do not represent a reason to modify treatment. Persistent liver abnormalities and / or decreases in serum albumin may indicate severe liver toxicity.
If liver biopsy results show slight changes (Roenigk scale I, II, IIIa), Methotrexate therapy can be continued by monitoring the patient according to the above recommendations. Methotrexate therapy should be discontinued in all patients who show persistent liver function test abnormalities and refuse to undergo a liver biopsy, and in all patients in whom liver biopsy shows moderate to severe changes (Roenigk IIIb scale or IV).
Immunological states
Methotrexate should be used with extreme caution in the presence of active infections and is generally contraindicated in patients with manifest or laboratory-evidenced immunodeficiency syndromes.
Immunization
Immunization may be ineffective during Methotrexate therapy. Immunization with live virus vaccines is generally not recommended. Cases of disseminated vaccine infection after immunization with smallpox virus have been reported in patients receiving Methotrexate.
Infections
Pneumonia can occur, (which in some cases can lead to respiratory failure). Life-threatening opportunistic infections, especially pneumonia, can occur with Methotrexate treatment Pneumocystis carinii. When a patient presents with pulmonary symptoms, the possibility of Penumocystis carinii pneumonia should always be considered.
Nervous system
Cases of leukoencephalopathy have been reported following intravenous administration of Methotrexate in patients undergoing craniospinal irradiation. Severe neurotoxicity, frequently manifesting as focal or generalized seizures, has been reported with an unexpectedly increased frequency in pediatric patients with acute lymphoblastic leukemia treated with intermediate doses of methotrexate administered intravenously (1 g / m2). In symptomatic patients, microangiopathic leukoencephalopathy and / or calcifications have commonly been observed in studies using diagnostic imaging methods. Chronic leukoencephalopathy has also been reported in patients who have repeatedly received high doses of methotrexate with calcium folinate rescue, even without irradiation of the skull. There have also been cases of leukoencephalopathy in patients receiving oral methotrexate. Withdrawal of Methotrexate does not always lead to complete recovery.
A transient acute neurological syndrome has been observed in patients treated with high-dose regimens. Manifestations of this neurological syndrome can include behavioral abnormalities, focal sensory-motor signs, including transient blindness, and abnormal reflexes. The exact cause is unknown.
After intrathecal use of Methotrexate, the toxicity that can occur in the central nervous system can be classified as follows: acute chemical arachnoiditis manifesting with symptoms such as eg headache, back pain, neck stiffness and fever; subacute myelopathy characterized e.g. by paraparesis / paraplegia associated with involvement of one or more spinal nerve roots; chronic leukoencephalopathy manifesting e.g. with confusion, irritability, somnolence, ataxia, dementia, seizures and coma. central nervous system can be progressive and even fatal. Cranial irradiation combined with intrathecal administration of Methotrexate has been shown to increase the incidence of leukoencephalopathy. Signs of neurotoxicity (meningeal irritation, permanent or transient paresis, encephalopathy) should be monitored following of intrathecal administration of methotrexate.
Intrathecal and intravenous administration of Methotrexate can cause acute encephalitis and acute encephalopathy with a fatal outcome.
There have been reports of patients with periventricular central nervous system lymphoma who developed brain herniation with intrathecal Methotrexate administration.
Respiratory system
Pulmonary signs and symptoms, for example dry nonproductive cough, fever, cough, chest pain, dyspnoea, hypoxemia, and chest x-ray infiltrate, or nonspecific pneumonia occurring during treatment with methotrexate may indicate potentially harmful injury and require discontinuation of treatment and careful monitoring. Lung lesions can occur at any dosage. Infection (including pneumonia) should be ruled out.
Pulmonary function tests may be useful if lung disease is suspected especially if baseline data are available.
Urinary system
Methotrexate can cause kidney damage which can lead to acute kidney failure. It is recommended that extreme attention be paid to renal function including adequate hydration, alkalinization of urine, methotrexatemia dosage and evaluation of renal function.
Skin
Serious, occasionally fatal skin reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome) and erythema multiforme, have been reported following single or multiple doses of Methotrexate.
Reactions occurred within a period of days of oral, intramuscular, intravenous, or intrathecal administration of Methotrexate. Healing was reported with discontinuation of treatment.
Laboratory tests
General
The following laboratory tests should be performed for proper clinical evaluation of patients to undergo or undergo therapy with Methotrexate: complete blood count with platelet count, hematocrit, urinalysis, renal function test and liver function test. In addition, a chest X-ray should be taken. The purpose of these tests is to establish the presence of any dysfunctions and it is necessary to carry them out before, during and at the end of the therapy. More frequent monitoring may also be indicated at the start of therapy or when the dosage is changed, or during periods of increased risk of high blood levels of Methotrexate (eg dehydration). A complete blood count should be performed every day for the first month of therapy and 3 times a week thereafter. It may be useful or important to perform a liver biopsy or bone marrow biopsy during long-term therapy or at high doses.
Pulmonary function test
Pulmonary function tests may be useful if lung disease is suspected especially if baseline data are available
Serum levels of Methotrexate
Monitoring of serum levels of Methotrexate can significantly reduce its toxicity and mortality. Patients with the following conditions are predisposed to develop high or prolonged Methotrexate levels and benefit from periodic level monitoring: pleural effusion, ascites, gastrointestinal tract occlusion, previous cisplatin therapy, dehydration, aciduria, impaired renal function.
Some patients may have prolonged clearance of Methotrexate in the absence of these characteristics. It is important that patients are identified within 48 hours as the toxicity of Methotrexate may not be reversible if calcium folinate rescue is delayed for more than 42-48 hours.
The method of monitoring Methotrexate concentrations varies from center to center.
Monitoring of Methotrexate concentrations should include determination of Methotrexate levels at 24, 48 or 72 hours, and assessment of the rate of reduction in Methotrexate concentrations (or determining how long to continue the rescue with calcium folinate).
Use in elderly patients:
Due to impaired hepatic and renal function and reduced folate reserves in elderly patients, reduced doses should be considered and these patients should be closely monitored for the earliest signs of toxicity.
Safety and efficacy in pediatric patients have only been established for anticancer chemotherapy. Fatal toxicities have been reported due to errors in intravenous and intrathecal dose calculations. Special attention should be given to dose calculations.
Medicinal product containing sodium therefore not suitable for subjects who must follow a low sodium diet.
04.5 Interactions with other medicinal products and other forms of interaction
Salicylics, some sulfonamides, para-amino-benzoic acid (PABA), phenylbutazone, diphenylhydantoin, tetracyclines and chloramphenicol can displace Methotrexate from binding to plasma proteins.
Methotrexate partially binds to serum albumin and toxicity may be increased by displacement caused by other strongly binding drugs to plasma proteins, such as salicylates, phenylbutazone, phenytoin and sulphonamides.
Since Methotrexate is eliminated unchanged by renal excretion after glomerular filtration, active tubular secretion, as well as passive tubular reabsorption, any nephrotoxic drug can reduce the renal excretion of Methotrexate. Therefore, during treatment with Methotrexate it is good practice not to administer these. drugs. Renal tubular transport of methotrexate is reduced by probenecid, the use of methotrexate with this drug should be carefully monitored. Phenylbutazone in combination with Methotrexate has in some cases caused toxicity with fever and skin ulceration, bone marrow depression and death in septicemia. The mechanism of this action is threefold: displacement of Methotrexate from binding to plasma proteins, inhibition of renal tubular secretion and bone marrow depression. Furthermore, phenylbutazone also appears to cause kidney damage which can lead to a buildup of Methotrexate.
Non-steroidal anti-inflammatory drugs (NSAIDs) should not be given before or in conjunction with high-dose regimens of Methotrexate, such as those used in the treatment of osteosarcoma. It has been reported that concomitant administration of NSAIDs with high-dose therapy Methotrexate increases and prolongs serum levels of Methotrexate over time, resulting in deaths due to severe haematological and gastrointestinal toxicity (see 4.4).
Methotrexate in combination with leflunomide may increase the risk of pancytopenia
NSAIDs and salicylates have been reported to reduce tubular secretion of methotrexate in an animal model and may potentiate its toxicity by increasing methotrexatemia. Therefore caution should be used in case of concomitant administration of NSAIDs or salicylates with lower doses of Methotrexate (see 4.4).
When treating patients with osteosarcoma, caution should be used when administering high doses of Methotrexate in combination with a potentially nephrotoxic chemotherapeutic agent (eg cisplatin). Clearance of Methotrexate is decreased by cisplatin.
Oral antibiotics such as tetracyclines, chloramphenicol and broad spectrum gastrointestinal (non-absorbable) antibiotics may decrease intestinal absorption of Methotrexate or interfere with enterohepatic circulation by inhibiting the intestinal flora and suppressing the metabolism of the drug by bacteria.
Penicillins and sulfonamides can reduce the renal clearance of Methotrexate; Increased serum concentrations of Methotrexate with concomitant haematological and gastrointestinal toxicity have been observed at both low and high doses. Therefore, the use of Methotrexate with penicillins should be closely monitored.
The potential increase in hepatotoxicity related to the co-administration of methotrexate with other hepatotoxic agents has not been evaluated. In such cases, however, hepatotoxicity has been reported. Therefore, patients on Methotrexate taking other potentially hepatotoxic drugs (eg leflunomide, azathioprine, retinoids, sulfasalazine) should be monitored closely for a possible increased risk of hepatotoxicity.
Methotrexate may decrease the theophylline clearance; theophylline levels should be monitored when administered concomitantly with Methotrexate.
It has been reported that trimethoprim / sulfamethoxazole has, in rare cases, resulted in increased bone marrow suppression in patients treated with methotrexate, possibly due to decreased tubular secretion and / or an additive antipholic effect.
Methotrexate increases the plasma levels of mercaptopurines. The combination of Methotrexate and mercaptopurine may therefore require dosage adjustment.
Vitamin preparations that contain folic acid or derivatives can reduce the response to systemically administered methotrexate, however, folate deficiency states can increase the toxicity of methotrexate. High doses of leucovorin may reduce the efficacy of methotrexate administered intrathecally.
Methotrexate, given at the same time as radiotherapy, may increase the risk of soft tissue necrosis and osteonecrosis.
04.6 Pregnancy and lactation
See sections 4.3 and 4.4.
04.7 Effects on ability to drive and use machines
Some effects mentioned in section 4.8 such as dizziness and fatigue may affect the ability to drive or use machines.
04.8 Undesirable effects
The most common side effects include: ulcerative stomatitis, leukopenia, nausea and abdominal discomfort. Other frequently reported side effects are: feelings of malaise and excessive fatigue, chills and fever, dizziness, less resistance to infections. Severity and incidence of acute side effects are generally related to the dosage and frequency of administration.
Other possible side effects are listed below. In an oncological picture, concomitant treatment and a pre-existing disorder make it difficult to attribute a specific reaction to Methotrexate.
Skin: rash erythematous, erythema multiforme, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, skin necrosis, exfoliative dermatitis, skin ulceration, pruritus, urticaria, photosensitivity, pigmentation changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis , appearance of nodules.
Disorders of the lymphatic system and blood: depression of bone marrow activity, suppression of haematopoiesis, leukopenia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, eosinophilia, anemia, hypogammaglobulinaemia, haemorrhages at various locations, septicemia, aplastic anemia, reversible lymphadenopathy and lymphoproliferative disorders (including lymphoproliferative disorders).
Metabolism and nutrition disorders: diabetes.
Digestive system: pancreatitis, enteritis, gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, haematemesis, melaena, gastrointestinal ulcer and haemorrhage, liver toxicity resulting in acute liver atrophy, necrosis, fatty degeneration, chronic fibrosis or cirrhosis acute hepatitis, reduction serum albumin levels, increases in liver enzymes, liver failure.
Urogenital system: severe nephropathy / renal insufficiency, azotemia, cystitis, haematuria, changes in ovogenesis or spermatogenesis, transient oligospermia, menstrual disturbances, leukorrhea, vaginal discharge, dysuria, sterility, abortion, fetal malformations, loss of libido, impotence, infertility.
Disorders of the nervous system: headache, somnolence, blurred vision, speech disturbances including dysarthria and aphasia, leukoencephalopathy (after oral administration), hemiparesis, paresis and convulsions (after parenteral administration only). Transient cognitive dysfunction, mood changes, unusual head sensations, episodes of leukoencephalopathy / encephalopathy (after parenteral administration only) have been reported with low dose regimens. Aphasia, hemiparesis, paresis and convulsions, if found, are usually related to haemorrhage or complications from intra-arterial catheterization Convulsions, paresis, increased cerebrospinal fluid pressure, have been found after intrathecal administration.
Disorders of the immune system: anaphylactoid reactions, hypogammaglobulinemia.
Cardio-circulatory system: pericarditis, pericardial effusion, hypotension and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis and pulmonary embolism), vasculitis.
Infections and infestations: Cases of opportunistic infections, including fatal ones, have been reported in patients receiving Methotrexate therapy for neoplastic and non-neoplastic diseases. The most common infection was pneumonia, including Pneumocystis carinii pneumonia. Other reported infections include nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, Herpes simplex hepatitis and disseminated herpes simplex; fatal sepsis, cytomegalovirus infections including cytomegaloviral pneumonia .
Psychiatric disorders: mood changes, transient cognitive dysfunction.
Ocular apparatus: conjunctivitis, severe changes in vision of unknown etiology,
temporary blindness / loss of vision, blurred vision.
Benign and malignant neoplasms (including cystic forms and polyps): lymphomas, including reversible lymphoma, tumor lysis syndrome (only after parenteral administration).
Pregnancy, perinatal period and puerperium: fetal abnormalities, fetal death, abortion.
Respiratory system: pulmonary fibrosis; interstitial pneumonia including deaths and occasionally chronic obstructive pulmonary disease, alveolitis, interstitial, pharyngitis occurred.
Other side effects: arthralgia / myalgia, metabolic alterations, diabetes, osteoporosis, proteinuria, tumor lysis syndrome, soft tissue necrosis and osteonecrosis, cell atypia of various tissues, painful erosions of psoriatic plaques, stress fractures. Anaphylactoid reactions and sudden deaths have also been reported.
04.9 Overdose
In post-marketing experience, cases of methotrexate overdose have occurred generally with oral and intrathecal administration, although cases of overdose with intravenous and intramuscular administration have been reported.
Symptoms of intrathecal methotrexate overdose are usually neurological including headache, nausea and vomiting, convulsions or seizures, and acute toxic encephalopathy. In some cases, no symptoms were reported. There have been reports of deaths following intrathecally administered overdoses. Cerebellar herniation associated with increased intracranial pressure and acute toxic encephalopathy have also been reported in these cases.
There are cases of overdose in the literature in which intravenous and intrathecal treatment of carboxypethidase G2 was used to accelerate the clearance of Methotrexate.
Withhold or reduce the dose at the first sign of ulceration or bleeding, diarrhea or marked depression of the haematopoietic system.
Calcium folinate is indicated to reduce toxicity and counter the effects of inadvertently administered methotrexate overdose. Administration of calcium folinate should be started as quickly as possible. As the interval between the administration of methotrexate and the start of treatment with calcium folinate increases, its activity in counteracting toxicity decreases.
Calcium folinate, a specific antidote of Methotrexate, allows to neutralize the toxic effects exerted by the antimetabolite on the hematopoietic system and on the mucous membranes of the digestive system. In its role as an antidote, calcium folinate is used in different dosages depending on the clinical effect to be obtained. In cases of accidental overdose, calcium folinate for intravenous infusion is recommended to obtain a competitive effect (up to 100 mg within 12 hours. ); to obtain a metabolic biochemical effect calcium folinate is recommended intramuscularly (10-12 mg every 6 hours for 4 doses) or orally (15 mg every 6 hours for 4 doses).
In case of accidental administration, calcium folinate should be administered in doses equal to or greater than those of Methotrexate within the first hour; the administration of calcium folinate in subsequent times is less effective. Monitoring of the serum concentration of Methotrexate is essential to determine the optimal dose and duration of treatment with calcium folinate.
In the event of a massive overdose, hydration and alkalization of the urine may be required to prevent precipitation of Methotrexate and / or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis have been shown to improve the elimination of methotrexate. However, effective clearance of Methotrexate has been reported with the use of intermittent hemodialysis with a high-flux dialyzer.
Accidental intrathecal overdose may require intensive systemic support, high doses of calcium folinate, alkaline diuresis and rapid CSF drainage, and ventriculo-lumbar perfusion.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic
ATC code: L01BA01
Methotrexate is a competitive folic acid antagonist. The mechanism of action of Methotrexate at the molecular level is threefold: depletion of intracellular folate by inactivation of dihydrofolicoreductase; direct inhibition of thymidylatosynthetase; inhibition of folate-dependent enzymes involved in purine neosynthesis. It binds strongly but reversibly to dihydrofolicoreductase, thus inhibiting the enzymatic conversion of folic acid to tetrahydrofolic. This enzymatic arrest leads to a depletion of the reduced folates necessary for the transfer of mono-carbon units in many biochemical reactions involving the biosynthesis of thymidyl acid (nucleotide specific for DNA) and inosinic acid precursor of the purines necessary for the synthesis of both DNA and RNA. However, inhibition of thymidyl acid synthesis is the most important mechanism of cytotoxicity of Methotrexate. Therefore Methotrexate interferes with DNA synthesis and repair and cell replication.
The mechanism of action of Methotrexate is closely linked to the cell cycle, acting above all during the synthesis of DNA in the S phase; in fact, those rapidly multiplying cellular tissues with high growth fraction (cells in cycle) are the most sensitive to the cytotoxic effects of Methotrexate.
Actively proliferating tissues such as cancer cells, bone marrow cells, embryonic cells, oral and intestinal mucosa and bladder cells are generally more sensitive to this effect than Methotrexate. When cell proliferation in tumor tissues is greater than that in most normal tissues, Methotrexate can impair tumor growth without causing irreversible damage to normal tissues.
High-dose methotrexate, followed by calcium folinate rescue, is used as part of the treatment of patients with non-metastatic osteosarcoma. The initial rationale for high-dose methotrexate therapy was based on selective rescue. of calcium folinate, of normal tissues. More recent evidence suggests that high doses of methotrexate may also overcome resistance to methotrexate caused by impaired active transport mechanisms, decreased affinity of dihydrofolate reductase for methotrexate, increased levels of dihydrofolate reductase due to " gene amplification, or decreased polyglutamation of Methotrexate. The current mechanism of action is unknown.
Low doses of Methotrexate are able to arrest S-phase leukemic myeloblasts for approximately 20 hours while they are not active on G1, G2 or M-phase cells. Higher doses of Methotrexate (> 30 mg / m2) arrest S-phase myeloblasts for more than 48 hours and slow down the passage of cells from the G2 phase to the S phase.
Methotrexate also inhibits protein synthesis as the reduced folates act as cofactors for the interconversion of the amino acids glycine to serine and homocysteine to methionine. This may be the mechanism that explains the action of high-dose Methotrexate in arresting G1-phase cells. Folicoreductase is a secondary target when the concentration of intracellular Methotrexate is high; in these particular conditions, thymidylatosynthetase and purine neosynthesis become primary targets and it is this chemical lesion responsible for immediate cytolysis.
In fact, folicoreductase represents a "high affinity receptor" for Methotrexate while the enzymes involved in purine biosynthesis and thymidylatosynthetase behave as "low affinity receptors".
05.2 Pharmacokinetic properties
After administration of high doses of Methotrexate from 50 to 200 mg / kg, mean plasma peaks ranging between 0.14 mM and 1 mM are reached during the 6-hour infusion, according to a dose-dependent trend. plasma, superimposable to that found with the "use of conventional dosages, has a three-phase trend with a half-life in the first phase of about 45", corresponding to the distribution phase; the "half-life of the second phase is variable between 2 and 3 hours and corresponds to the renal clearance; the half-life of the final phase is 8-12 hours; the prolongation of this phase represents a combined effect of release from cell compartments, from the entero-hepatic circulation and reabsorption from the renal tubules. After intrathecal, intramuscular or intraperitoneal administration, the blood peak occurs in 15-30 ". When the drug is administered intrathecally, it leaves the cerebrospinal fluid rather slowly and plasma levels are maintained 2 to 3 times longer than after IV administration.Therefore, intrathecal administration may result in greater toxicity than administration parenteral.
At doses of 30 mg / m2 or lower, Methotrexate is generally well absorbed with a mean bioavailability of approximately 60%. The absorption of doses above 80 mg / m2 is significantly less, probably due to a saturation effect.
Plasma protein binding:
From 50% to 70% of the administered Methotrexate binds reversibly to plasma proteins, mainly albumin. In interstitial liquids, on the other hand, the binding to proteins is low, ranging from 0 to 17%. The alterations of the serum-protein picture affect the quantity of free (extra-cellular) Methotrexate and consequently on intra-cellular penetration as well as on renal clearance Many drugs such as salicylates, sulfonamides, PABA, phenylbutazone, etc., compete for this link.
Volumes of apparent distribution, tissue diffusion:
After intravenous administration, Methotrexate is rapidly distributed in a volume equal to 18% of the body weight, corresponding to the extracellular space and therefore in a volume equal to 76% of the body weight, corresponding to the total water of the organism. liver level with a liver / plasma ratio of 4 after 3 hours and 8 after 24 hours of iv administration of 80 mg / m2. The drug is concentrated in the gallbladder up to> 1000 times the plasma level, secreted with the bile, and finally reabsorbed, in part, by the intestinal mucosa. The diffusion of Methotrexate in the subarachnoid spaces, in the pleural and peritoneal cavity occurs slowly and with characteristics similar to passive transport. If these "third spaces" are pathologically dilated, such as in the case of an ascitic or pleural effusion, they can act as a reserve and prolong the persistence of Methotrexate in the plasma compartment. The concentration ratios of Methotrexate in plasma with respect to: milk, tears, liquor and saliva are respectively 20/1, 33/1, 300/1. The tissues where Methotrexate is preferentially localized are: the proximal tubule of the nephron, the intestinal epithelium and hepatocytes. The mechanism of penetration of Methotrexate into normal and neoplastic cells is active, mediated by membrane carrier and therefore with energy expenditure. Methotrexate competes with reduced folate for active transport across the cell membrane by a process mediated by a single active transporter. At serum concentrations greater than 100 micromolar, passive diffusion becomes the primary route through which they can be effective intracellular concentrations reached. The uptake of the drug by myeloblasts in healthy subjects and in leukemics occurs with some slowness and takes from 1 to 4 hours before an equilibrium is established. Higher concentrations of Methotrexate are reached in tumor tissues than in healthy tissues.
Kinetics of passage of the blood brain barrier:
The blood brain barrier obstructs the entry into the CNS of systemically administered Methotrexate. Therapeutically dosed Methotrexate does not penetrate the blood brain barrier when administered orally or parenterally. High concentrations of Methotrexate in the cerebrospinal fluid can be obtained through intrathecal administration. The ratio of CSF to plasma concentrations is 0.02 - 0.05. At high doses, 50 mg / kg of Methotrexate, the CSF concentration reaches 7 x 10-6M / L (after 6 hours of infusion), while for doses equal to 100 mg / kg it is 3 x 10-6M / l. After intrathecal administration of Methotrexate, the drug slowly leaves this compartment to pass into circulation according to a bimodal kinetics : the two half-lives a and b are respectively 1.7 and 6.6 hours. The second half-life b is prolonged to 7.3 hours when acetazolamide is administered simultaneously, to 7.7 hours when probenec is administered id (2,500 mg) or at 7.9 hours in the presence of intracranial hypertension.
Pathway and kinetics of elimination:
Methotrexate is eliminated in the urine, faeces and bile; clearance of Methotrexate from plasma is approximately 110 mg / min / m2, of which more than 90% is due to renal emunctory (when renal function is intact). Approximately 43% of the administered dose appears in the urine in the first hour . Almost half of an IV administered dose is excreted unchanged in the urine within 6 hours of administration; this percentage rises to 90% within 24 hours and to 95% within 30 hours. Renal elimination of the drug as well as by filtration glomerularity occurs mainly by active tubular secretion. Less than 2% of a dose given per i.v. it is excreted in the faeces. Delayed clearance of the drug may occur in the presence of "third space reserves" such as in the case of large pleural or peritoneal effusions.
Renal excretion is the major route of elimination and is dose and route of administration dependent. With IV administration, 80-90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion which amounts to approximately 10% or less of the administered dose. An enterohepatic circulation of Methotrexate has been hypothesized.
Renal excretion takes place through glomerular filtration and active tubular secretion. Impaired renal function, as well as concomitant use of drugs such as weak organic acids which also undergo tubular secretion, can markedly increase the serum levels of Methotrexate. An excellent correlation has been reported between Methotrexate clearance and endogenous creatinine clearance. Methotrexate clearance rates vary widely and generally decrease at high doses. Delayed drug clearance has been identified as one of the major factors responsible for the toxicity of Methotrexate. It has been hypothesized that the toxicity of Methotrexate to normal tissues depends more on the duration of exposure to the drug rather than on the maximum levels reached. When a patient exhibits delayed elimination of the drug due to impaired renal function, a spread into the third space, or other causes, the serum concentrations of Methotrexate may remain elevated for prolonged periods of time.
The potential toxicity of high dose regimens or delayed excretion is reduced by the administration of calcium folinate during the final phase of elimination of Methotrexate from plasma.
Metabolism:
After absorption, Methotrexate is converted by intracellular and hepatic metabolism into polyglutamate forms which can then be converted back into Methotrexate by hydrolase. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of polyglutamate Methotrexate can remain in the tissues for an extended period. The retention and prolonged pharmacological action of these active metabolites vary for different cell types, tissues and tumors. A small amount of conversion to 7-hydroxymethotrexate may occur at commonly prescribed doses. Accumulation of this metabolite can become significant at the high doses used for osteogenic sarcoma. The water solubility of 7-hydroxymethotrexate is 3-5 times lower than Methotrexate.
Approximately 6% of an administered dose i.v. and 35% of a dose administered orally are metabolized to 7-hydroxy-methotrexate in the enterohepatic circulation, by the action of an aldehyde oxidase, and to 2,4 diamino-N10-methylpteroic acid (DAMPA) by the action of intestinal bacterial flora. These metabolites were isolated and identified in the plasma and urine of patients, while polyglutamate derivatives of Methotrexate were found in the liver. 7-hydroxy-methotrexate would be responsible for the nephrotoxicity of the drug used at high doses due to its poor water solubility.
Half-life: The reported terminal half-life for Methotrexate is approximately 3-10 hours for patients receiving rheumatoid arthritis treatment or low dose cancer therapy (less than 30 mg / m2). For patients receiving high doses of Methotrexate, the terminal half-life is 8 - 15 hours.
05.3 Preclinical safety data
The LD50 in mice was 94 ± 9 mg / kg for i.p. administration; it resulted instead equal to 180 ± 45 mg / kg when administered orally. In rats, the LD50 was variable between 6 and 25 mg / kg for i.p.
When Methotrexate is administered to rats from day 14 to day 18 of pregnancy, it can induce: weight loss of the mother, resorption, abortion or hypotrophy of the fetus. The drug can induce pregnancy termination in various animal species such as: mice, rats, rabbits. Anorexia, watery diarrhea and vaginal bleeding have sometimes been observed in animals receiving the drug at repeated doses above 0.5 mg / kg. , while with single doses of 1.6 mg / kg no such effects were found. Methotrexate, like most anticancer and immunosuppressive drugs, has shown carcinogenic properties in animals under particular experimental conditions.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
METHOTREXATE 50 mg powder for solution for injection:
Sodium chloride, Sodium hydroxide. Contains no preservatives.
METHOTREXATE 500 mg powder for solution for injection:
Sodium hydroxide. Contains no preservatives.
METHOTREXATE 1 g powder for solution for injection:
Sodium hydroxide. Contains no preservatives.
METHOTREXATE 50 mg / 2ml solution for injection:
Sodium hydroxide, sodium chloride, water for injections.
Contains no preservatives.
METHOTREXATE 500 mg / 20 ml solution for injection:
Sodium hydroxide, sodium chloride, water for injections.
Contains no preservatives.
METHOTREXATE 1g / 10ml solution for injection:
Sodium hydroxide, water for injections.
Contains no preservatives.
METHOTREXATE 5g / 50 m1 solution for injection:
Sodium hydroxide, water for injections.
Contains no preservatives.
06.2 Incompatibility
Methotrexate is compatible with: dextrose in Ringer's lactate, dextrose in Ringer's, dextrose in sodium chloride, dextrose in water, Ringer's lactate, sodium chloride.
Methotrexate should not be administered with other drugs in the same infusion.
06.3 Period of validity
Powder for solution for injection: 3 years.
Solution for injection: 2 years.
The expiry date refers to the product in intact packaging, correctly stored.
06.4 Special precautions for storage
Methotrexate powder for solution for injection: store at a temperature not exceeding 25 ° C.
Protect from light and humidity.
The product should be used immediately after reconstitution; any unused solution must be discarded.
Methotrexate solution for injection: store at temperatures between 15 ° C-22 ° C. Protect from light.
The product cannot be reused after the first withdrawal; any unused solution must be discarded.
06.5 Nature of the immediate packaging and contents of the package
Methotrexate powder for solution for injection:
Type I or III glass bottle - Rubber stopper for lyophilisate with aluminum seal.
- bottle of 50 mg
- bottle of 500 mg
- 1 g bottle
Methotrexate solution for injection:
Type I glass bottle
Rubber cap with aluminum seal.
- bottle of 50 mg / 2 ml
- bottle of 500 mg / 20 ml
- 1 g / 10 ml bottle
- bottle of 5 g / 50 ml
06.6 Instructions for use and handling
Use each bottle only once.
If a precipitate forms, the solution must be discarded.
Do not administer Methotrexate with other drugs in the same infusion.
People who have contact with cancer drugs or work in areas where these drugs are used, may be exposed to these agents either by air contact or by direct contact with contaminated objects. Potential health effects can be reduced by adhering to institutional procedures, published guidelines, and local regulations regarding the preparation, administration, transport and disposal of hazardous drugs. There is no general agreement that all procedures recommended in the guidelines are necessary and appropriate
Methotrexate powder for solution for injection:
Methotrexate 500 mg and Methotrexate 1 g powder for solution for injection should be reconstituted immediately prior to use, respectively, with 10 ml and 20 ml of water for injections or physiological saline or 5% dextrose solution, containing no preservatives. obtain a solution with a concentration equal to 50 mg / ml, reconstitute the bottle containing 1 g of methotrexate with 19.4 ml of liquid.
Methotrexate 50 mg powder for solution for injection must be reconstituted immediately before use with water for injections using 20 ml of water.
When high doses of Methotrexate are administered by intravenous infusion, dilute the total dose in 5% dextrose solution.
For intrathecal administration, reconstitute to a concentration of 1 mg / ml using a suitable sterile solution, free of preservatives, such as saline.
Methotrexate solution for injection
If necessary, the solution can be further diluted, immediately before use, with physiological saline or 5% dextrose solution, containing no preservatives.
07.0 MARKETING AUTHORIZATION HOLDER
WYETH LEDERLES.p.A.
Via Nettunense, 90
04011 Aprilia (LT)
08.0 MARKETING AUTHORIZATION NUMBER
Methotrexate 50 mg powder for solution for injection - A.I.C. No. 019888041
Methotrexate 500 mg powder for solution for injection - A.I.C. No. 019888054
Methotrexate 1 g powder for solution for injection - A.I.C. No. 019888104
Methotrexate 50 mg / 2 ml solution for injection - A.I.C. No. 019888080
Methotrexate 500 mg / 20 ml solution for injection - A.I.C. No. 019888092
Methotrexate 1 g / 10 ml solution for injection - A.I.C. No. 019888066
Methotrexate 5 g / 50 ml solution for injection - A.I.C. No. 019888078
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Methotrexate 50 mg powder for solution for injection - September 1963 / June 2005
Methotrexate 500 mg powder for solut. injectable: September 1984 / June 2005
Methotrexate 1 g powder for solution for injection: April 2000 / June 2005
Methotrexate 50 mg / 2 ml solution for injection: April 2000 / June 2005
Methotrexate 500 mg / 20 ml solution for injection: April 2000 / June 2005
Methotrexate 1 g / 10 ml solution for injection: April 2000 / June 2005
Methotrexate 5 g / 50 ml solution for injection: April 2000 / June 2005
10.0 DATE OF REVISION OF THE TEXT
March 2009
