Active ingredients: Methotrexate
Methotrexate Teva 25 mg / ml solution for injection
Methotrexate Teva 100 mg / ml solution for injection
Why is Methotrexate used - Generic drug? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Antineoplastic, antimetabolite.
THERAPEUTIC INDICATIONS
Methotrexate Teva is indicated in the treatment of choriocarcinoma, destructive chorionadenoma and vesicular or hydatiform mola. The use of Methotrexate Teva both alone and in polychemotherapy induces remissions on the main solid tumors (sarcomas, lymphomas, cervico-facial carcinomas, carcinoma of the breast, lung and cervix of the uterus) managing to maintain these remissions even for long periods . Methotrexate Teva is also indicated for acute leukemia. Recent studies have highlighted the excellent therapeutic response induced by methotrexate in lymphoblastic leukemia of the child. Methotrexate has also shown therapeutic validity also in the lymphosarcoma of the child in stage III and IV.
Contraindications When Methotrexate should not be used - Generic drug
- Hypersensitivity to the active substance or to any of the excipients listed in the Composition section
- Severe hepatic insufficiency (see "Dose, method and time of administration")
- Severe renal insufficiency (creatinine clearance
- Severe blood disorder (in patients with pre-existing blood dyscrasias, such as: bone marrow hypoplasia, thrombocytopenia, severe anemia.)
- Alcoholism
- Infectious disease in progress
- Evidence of immunodeficiency syndrome
- Pregnancy and breastfeeding (see "Special warnings")
- Ulceration of the oral cavity and ascertained gastrointestinal ulcer in the active phase
- Simultaneous vaccination with live vaccines
Precautions for use What you need to know before taking Methotrexate - Generic drug
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 condition.
Serious, sometimes fatal, skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome) and erythema multiforme have been reported within days of single or multiple dose administration of methotrexate.
Life-threatening opportunistic infections, including Pneumocystis carinii pneumonia, can occur with methotrexate therapy. If a patient experiences pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered.
Pulmonary signs and symptoms, eg. dry non-productive cough, fever, cough, chest pain, dyspnoea, hypoxemia, and a chest x-ray infiltrate or non-specific pneumonia may indicate a potentially dangerous injury and require discontinuation of treatment and careful investigation. Lung injury can occur at any dosage. Pulmonary disease induced by methotrexate can occur at any time during therapy and has been reported at doses of 7.5 mg / week. It is not always completely reversible. An infection (including pneumonia) should be ruled out.
Methotrexate should only be used by physicians who are familiar with the various characteristics of the drug and its mode of action. Chest X-ray, kidney and liver function evaluation are recommended prior to initiation of methotrexate therapy. and blood tests.
Patients undergoing therapy should be subjected to appropriate monitoring so that signs and symptoms of possible toxic effects or adverse reactions can be detected and evaluated promptly.
Due to the frequent onset of hematopoietic depression, which can be early and occur even with apparently safe dosages, pre-treatment and periodic haematological checks are indispensable in the use of Methotrexate Teva in chemotherapy.
Any noticeable decrease in blood cell counts indicates the need for "immediate cessation of therapy and appropriate measures."
Methotrexate can cause kidney damage which can lead to acute kidney failure. It is recommended that extreme attention be paid to renal function, including alkalinization of urine, measurement of serum methotrexate levels and evaluation of renal function.
Methotrexate therapy in patients with renal insufficiency should be undertaken with extreme caution as renal insufficiency reduces the elimination of methotrexate. The patient's kidney condition should be determined before and during therapy with Methotrexate Teva.
The dose of the drug should be reduced or administration suspended until kidney functions are improved or restored. In case of administration of high doses of methotrexate it is necessary to maintain a high level of hydration and induce alkaline diuresis. This is a measure to prevent the precipitation of methotrexate or its metabolites in the renal tubules.
Alkalization of urine to pH 6.5 - 7 by oral or intravenous administration of sodium bicarbonate (5 x 625 mg tablets every 3 hours) or acetazolamide (500 mg orally 4 times a day) is recommended as a preventive measure.
It is essential to regularly include the following laboratory tests as part of the monitoring of patients receiving methotrexate: complete blood tests, urinalysis, kidney and liver function tests and, in the case of high dose administration, determination of plasma levels. of methotrexate. It may be useful and important to perform a liver biopsy or bone marrow aspirate studies when high doses are used or in case of long-term therapy.
Methotrexate should be used with extreme caution in patients with renal insufficiency, infections, peptic ulcer, ulcerative colitis, ulcerative stomatitis, diarrhea, debilitation and in very young or elderly subjects. If severe leukopenia occurs during therapy, this increases the risk of developing bacterial infections.
In these cases it is advisable to stop the administration of the drug and to undertake an appropriate antibiotic therapy. In the case of severe bone marrow depression, blood or platelet transfusions may be necessary.
The immunological response to a concomitantly administered vaccine may be diminished, as methotrexate has some immunosuppressive activity.
Live vaccines
A severe reaction could result from concomitant use of a live vaccine and therefore concomitant administration of live vaccines with methotrexate is contraindicated (see "Contraindications"). There have been reports of disseminated vaccine infection after immunization with smallpox virus in patients with methotrexate therapy.
In all cases where Methotrexate Teva is used in chemotherapy, the physician should weigh the need or utility of the drug against the risks of toxic effects and secondary reactions. Often these reactions are reversible if detected early. When toxic effects are observed. or secondary reactions, the dosage should be reduced or the administration suspended and appropriate corrective measures should be undertaken according to the clinical opinion of the physician. The resumption of therapy with Methotrexate Teva must be carried out with caution, adequately considering the new need for the drug and monitoring, as far as possible, the reappearance of toxicity phenomena.
Interactions Which drugs or foods can modify the effect of Methotrexate - Generic drug
Medicinal products with high plasma protein binding
Medicinal products with high plasma protein binding (such as: salicylates, sulphonamides, diphenylhydantoins, tetracycline, chloramphenicol and p-aminobenzoic acid), can displace methotrexate which binds extensively to proteins, increasing its potential for toxicity when administered simultaneously.
Non-steroidal anti-inflammatory drugs (NSAIDs)
If methotrexate is administered before or concurrently with NSAIDs, including salicylates, extreme caution should be exercised, as cases of severe methotrexate toxicity and even deaths due to reduced methotrexate excretion have been reported. These medicinal products have been reported to reduce the tubular secretion of methotrexate in an animal model and therefore may increase the toxicity of methotrexate. It is recommended that methotrexate dosage be closely monitored during NSAID treatment.
Similarly, the possibility should be considered that weak organic acids, including salicylates, may delay renal excretion of methotrexate and increase accumulation.
Drugs with similar pharmacological activity
Drugs with similar pharmacological activity, such as pyrimethamine, should not be given to patients taking methotrexate.
Folic acid
Vitamin preparations containing folic acid or its derivatives, taken concomitantly with methotrexate, can alter the response to methotrexate. High doses of calcium folinate may reduce the efficacy of intrathecally administered methotrexate.
Other potential hepatotoxic agents
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 receiving methotrexate with other potentially hepatotoxic drugs (eg leflunomide, azathioprine, retinoids, sulfasalazine) should be monitored closely for possible risk of hepatotoxicity. For the same reason concomitant use of alcohol should be avoided.
Probenecid, penicillins, proton pump inhibitors
Renal tubular transport is reduced by probenecid, penicillins and proton pump inhibitors, which can lead to potentially toxic methotrexate levels. The use of methotrexate with these medicinal products should be closely monitored. Haematological and gastrointestinal toxicities have been observed in association with high and low doses of methotrexate.
Potentially nephrotoxic chemotherapeutic agents
An increase in nephrotoxicity may be observed when a high dose of methotrexate is administered in combination with a potentially nephrotoxic chemotherapeutic agent (eg cisplatin).
Folate antagonists
In rare cases it has been reported that concomitant administration of methotrexate and folate antagonists, eg. trimethoprim and co-trimoxazole can cause bone marrow suppression.
Oral antibiotics and non-absorbable broad-spectrum antibiotics
Oral antibiotics, such as tetracyclines, and non-absorbable broad-spectrum antibiotics can reduce intestinal absorption of methotrexate or interfere with enterohepatic circulation by inhibiting intestinal flora and suppressing bacterial metabolism of methotrexate.
Theophylline
Methotrexate may reduce the theophylline clearance, so theophylline levels should be monitored in case of concomitant treatment.
Warnings It is important to know that:
Methotrexate Teva should only be used by doctors experienced in antimetabolic chemotherapy. Careful monitoring of patients on methotrexate therapy is required. Methotrexate can cause severe toxicity.
Pathological changes (see "Undesirable Effects") can also occur without first noticing signs of gastrointestinal or haematological toxicity. It is therefore essential that liver function is checked before starting treatment and monitored regularly throughout therapy. Particular attention should be paid in the presence of pre-existing liver damage or impaired liver function.
If necessary, drainage of pleural effusions or ascites should be performed prior to treatment. This is because methotrexate slowly escapes from the "reserves from third spaces" (eg pleural effusions, ascites). This causes a "prolonged terminal half-life and unexpected toxicity.
Symptoms of gastrointestinal toxicity, which initially manifests itself with diarrhea and ulcerative stomatitis, require discontinuation of therapy otherwise they can result in hemorrhagic enteritis and death by intestinal perforation. Methotrexate is therefore contraindicated in the presence of ulcerations of the oral cavity and gastrointestinal ulcer in active phase (see "Contraindications"). Dehydration can potentiate the toxicity of methotrexate. It is recommended to alkalize the urine and to favor a high diuresis, especially in the treatment with high doses.
Methotrexate, given at the same time as radiotherapy, may increase the risk of soft tissue necrosis and osteonecrosis.
Acute onset elevations in liver enzymes are frequently found, usually transient and asymptomatic, which do not appear to be predictive of subsequent liver disease. Persistent liver abnormalities and / or decreased serum albumin may indicate severe liver toxicity. Liver biopsy after prolonged use often shows histological changes and fibrosis and cirrhosis have been reported.
Treatment should not be started or should be discontinued if liver function test abnormalities are found or developed during therapy (see "Dose, method and time of administration" and "Contraindications").
Malignant lymphomas can occur in patients treated with low doses of methotrexate, in which case therapy should be discontinued. If the lymphoma shows no signs of spontaneous regression, another cytotoxic therapy should be instituted.
States of folate deficiency can increase the toxicity of methotrexate.
Fertility, pregnancy and breastfeeding
Pregnancy
Teratogenicity of methotrexate has been demonstrated; congenital anomalies and fetal death caused by methotrexate have been reported. Therefore, the drug should not be administered to pregnant women (see "Contraindications"). In addition, methotrexate is not recommended in women of childbearing potential unless the expected benefits outweigh the risks considered. Women of childbearing potential should not initiate methotrexate therapy until pregnancy is ruled out. If the patient becomes pregnant while taking the drug , the patient should be informed of the potential risk to the fetus.
Feeding time
The presence of methotrexate has been found in human breast milk, therefore the drug is contraindicated during breastfeeding.
Fertility
Methotrexate affects spermatogenesis and therefore patients on methotrexate treatment and their partners should be adequately informed. Conception should be avoided for at least three months after cessation of methotrexate treatment.
Driving and using machines
In relation to the possibility of neurological disorders occurring, the use of machines is not recommended during therapy.
Important information about some of the excipients
Methotrexate Teva 25 mg / ml solution for injection:
- 2 ml bottle: This medicine contains less than 1 mmol (23 mg) sodium per 2 ml, ie it is essentially "sodium free".
- 20 ml bottle: This medicine contains approximately 4 mmol (92 mg) sodium per 20 ml. To be taken into consideration in people with reduced kidney function or who follow a low sodium diet.
Methotrexate Teva 100 mg / ml solution for injection:
- 10 ml bottle: This medicine contains approximately 4.4 mmol (101.2 mg) sodium per 10 ml. To be taken into consideration in people with reduced kidney function or who follow a low sodium diet.
- 50 ml bottle: This medicine contains approximately 22 mmol (506 mg) sodium per 50 ml. To be taken into consideration in people with reduced kidney function or who follow a low sodium diet.
Dosage and method of use How to use Methotrexate - Generic drug: Posology
"If methotrexate is used to treat cancer, the dose should be adjusted with caution according to the" body surface area ".
"After administration of incorrectly calculated doses, fatal cases of intoxication have been reported."
Methotrexate Teva can be administered intramuscularly, intravenously (bolus injections or infusion), intrathecal, intra-arterial and intraventricular. Dosing is based on the patient's body weight or body surface area except for intrathecal or intraventricular administration in which cases a maximum dose of 15 mg is recommended. Doses should be reduced in cases of blood deficiency or liver and kidney dysfunction.
When methotrexate Teva is given by infusion it must only be diluted with normal saline. Large doses (more than 100 mg) are usually given as intravenous infusions for periods not exceeding 24 hours. Part of the dose may initially be given by intravenous injection. Methotrexate Teva has been used with positive effects in a wide variety of neoplastic diseases, alone or in combination with other cytotoxic agents, hormones, immunotherapy, radiotherapy or surgery. Therapeutic regimens therefore vary considerably in relation to clinical uses, particularly when a regimen of intermittent strong doses is followed by administration of calcium folinate in order to preserve normal cells from toxic effects. Dosage regimens for calcium folinate are discussed at the end of this section. Examples of doses of Methotrexate Teva that have been used for particular indications are rip ortati below.
CHORIOCARCINOMA AND OTHER TROPHOBLASTIC TUMORS
Intramuscularly in doses of 15-30 mg per day for 5-day cycles. These cycles are generally repeated 3-5 times as appropriate, with rest periods of one or more weeks between cycles, until any symptoms of toxicity have subsided. The efficacy of the therapy is neatly evaluated in the 24 hours through quantitative analyzes of the chorionic gonadotropins (HCG) which should return to normal values or below 50 IU / 24 hours generally after the III or the IV treatment cycle, and should also follow in usually a complete resolution of the detectable lesions in 4 or 6 weeks. One or two courses of Methotrexate Teva are generally recommended after normalization of the HCG. A careful clinical evaluation is essential before each cycle of the drug. Doses greater than 60 mg intramuscular every 48 hours can be administered 4 times, followed by calcium folinate therapy.
This cycle is repeated at intervals of at least 7 days until the urinary HCG level returns to normal. No less than 4 courses of treatment are generally required.
Patients with complications, such as extensive metastases, can be treated with methotrexate Teva in cyclical combinations with other cytotoxic drugs.
DESTRUCTIVE CHORIONADENOMA AND IDATID MOLLE
Since the hydatid mola can be followed by choriocarcinoma, prophylactic therapy with Methotrexate Teva is recommended. Destructive chorionadenoma is considered an invasive form of the hydatid mola. Methotrexate Teva is given in such cases in doses similar to those recommended for choriocarcinoma.
ACUTE LYMPHATIC (LYMPHOBLASTIC) LEUKEMIA IN CHILDREN AND YOUNG ADOLESCENTS
Methotrexate Teva in doses of 3.3 mg / m2 in combination with Prednisone 60 mg / m2, administered generally, is used as inductive therapy. Methotrexate Teva alone or in combination with other agents appears to be a drug of choice to ensure the maintenance of drug-induced remission. When remission has occurred and supportive care has produced general clinical improvements, maintenance therapy is initiated as follows: Intramuscular methotrexate Teva 30 mg / m2 twice weekly.
A dosage of 2.5 mg / kg in a vein every 14 days was also employed. If a recurrence of the disease is observed, re-induction or remission can be achieved by repeating the initial inductive therapy.
MENINGEAL LEUKEMIA
Cerebrospinal fluid (CSF) should be examined in all leukemic patients in order to diagnose possible leukemic invasion of the central nervous system.
Since the transition of methotrexate from plasma to CSF is minimal in adequate therapy, Methotrexate Teva is administered in intrathecal doses of 12 mg / m2 or in maximum doses of 15 mg at intervals of 2-5 days, this therapy is usually repeated until at which CSF cell counts return to normal (usually 2-3 weeks). At this point, a further dose is recommended. A second common course of administration is Methotrexate Teva 12 mg / m2 once a week for two weeks and then once a month.
It is now common practice, due to the frequent cases of meningeal leukemia, to administer methotrexate Teva intrathecally in equal doses, as a prophylaxis in all cases of lymphocytic leukemia. Although intravenous doses of an additional 50 mg of methotrexate should not significantly penetrate the CSF, higher doses, of the order of 500 mg / m2, produce cytotoxic levels of methotrexate in the CSF. This type of therapy was used for a short time, then followed by administration of calcium folinate as initial maintenance therapy to prevent leukemic invasion of the central nervous system in children with a poor prognosis of lymphocytic leukemia.
LYMPHOMA
Non-Hodgkin's lymphomas, for example infantile lymphosarcoma, have recently been treated with 3-30 mg / kg (approximately 9-900 mg / m2) of Methotrexate Teva by intravenous injection and infusion, followed by calcium folinate at the highest doses.
Some cases of Burkitt's lymphoma, if treated in the first stage with courses of 15 mg / m2 per day for 5 days, have shown prolonged remissions. A combination chemotherapy is also used in all stages of the disease and a course of 15 mg / day of methotrexate Teva intrathecally for 4 days has been shown to be useful in controlling episodes of invasion of the central nervous system.
BREAST CANCER
Methotrexate Teva in intravenous doses of 10-60 mg / m2, is commonly included in regimens of cyclical combinations with other cytotoxic drugs in the treatment of advanced breast cancer.
A similar regimen has also been used as adjuvant therapy in primary cases followed by mastectomy and / or radiotherapy.
OSTEGENIC SARCOMA
The use of methotrexate alone or in cyclic combination regimens has been introduced as adjuvant therapy to the primary treatment of ostegenic sarcoma. This has involved the use of intravenous infusions of 20-300 mg / kg (approximately. 600-9000 mg / m2. ) of Methotrexate Teva followed by calcium folinate for support. Methotrexate Teva can also be used as the sole treatment in cases of ostegenic sarcoma metastases.
BRONCHOGENIC CARCINOMA
Intravenous infusions of 20-100 mg / m2 of Methotrexate Teva have been included in cyclic combination regimens in the treatment of advanced cancers. High doses of Methotrexate Teva together with calcium folinate as supportive therapy can also be used as a single treatment.
TUMOR OF THE HEAD AND NECK
Intravenous infusions of 240-1080 mg / m2 of Methotrexate Teva with calcium folinate can be used as adjuvant pre-operative therapy in the treatment of advanced cancers. Intra-arterial infusions of Methotrexate Teva are indicated for certain head and neck cancers, although this form of administration is now used less frequently.
BLADDER CARCINOMA
Intravenous injections or infusions of Methotrexate Teva in doses above 100 mg every 1 to 2 weeks can be used in the treatment of bladder cancer. Diuretics and moisturizers are used in addition to reduce the excessive toxicity of the drug that can occur in cases of renal disorders.
Support therapy with calcium folinate
The dose of calcium folinate is variable and depends on the dose of methotrexate. In general, amounts greater than 120 mg are administered in divided doses over 14-24 hours by intramuscular injection, intravenous bolus or intravenous infusion in saline, followed by 12-15 mg i.m. or 15 mg orally, every 6 hours for the next 48 hours. Supportive therapy is usually started 25 hours after starting the infusion of methotrexate Teva. Dosage of 15 mg orally every 6 hours for 48 to 72 hours may be sufficient when lower methotrexate Teva dosages (less than 100 mg) are used. The clinical use of high doses of methotrexate combined with calcium folinate as supportive therapy in the treatment of many previously resistant cancers is risky and remains the subject of much research.
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 I-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 / lel "renal failure has not resolved. If necessary, "intermittent hemodialysis with a high-flux dialyzer may be helpful in these patients."
Senior citizens
Due to impaired liver and kidney function and reduced folate reserves, methotrexate should be used with extreme caution in elderly patients. Dose reduction should be considered and these patients should be closely monitored for any early signs of toxicity.
Patients with hepatic insufficiency
Methotrexate should be administered with great caution, if not avoided, in patients with previous or current significant liver disease, especially if induced by alcohol abuse. Methotrexate is contraindicated in the presence of bilirubin values> 5 mg / dl ( 85.5 µmol / l).
Patients with renal insufficiency
Methotrexate should be used with caution in patients with impaired renal function. The dose should be corrected as follows:
Overdose What to do if you have taken an overdose of Methotrexate - Generic Drug
In post-marketing experience, overdose has generally occurred with oral and intrathecal administration of methotrexate, although overdose has also been reported with intravenous and intramuscular administration.
Symptoms of an overdose with intrathecal administration are usually CNS symptoms, including headache, nausea and vomiting, seizures or convulsions, and acute toxic encephalopathy. In some cases, no symptoms were reported. Deaths have been reported as a result of intrathecal overdose. In these cases, cerebellar hernias associated with increased intracranial pressure and acute toxic encephalopathy have been reported.
Cases of overdose, sometimes fatal, have been reported due to incorrect daily rather than weekly oral methotrexate intake. In these cases the commonly reported symptoms were haematological and gastrointestinal reactions.
Calcium folinate is the antidote to neutralize the immediate toxic effects of methotrexate on the haematopoietic system. It can be administered orally, intramuscularly, intravenous bolus or infusion. The longer the time interval between the administration of methotrexate and the initiation of therapy with calcium folinate, the lower the effectiveness of calcium folinate in counteracting toxicity. Monitoring of serum methotrexate concentration is essential to determine the optimal dose and duration of treatment with calcium folinate.
Other supportive care such as blood transfusions and kidney dialysis may be needed.
In cases of 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 acute intermittent hemodialysis performed with a high-flux dialyzer.
Following intrathecal overdose it may be necessary to administer high doses of calcium folinate systemically or to induce alkaline diuresis.
If you have any questions about the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Methotrexate - Generic drug
Like all medicines, this medicine can cause side effects, although not everybody gets them.
In general, the incidence and severity of acute adverse reactions are related to dose, frequency of administration and duration of target organ exposure to significant blood levels of methotrexate.
The most relevant undesirable effects are suppression of the haematopoietic system and gastrointestinal disorders.
The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea and abdominal pain. Other frequently reported adverse events are malaise, unexplained fatigue, chills and fever, dizziness and reduced resistance to infections.
List of adverse reactions
Frequencies of adverse reactions are classified as follows: very common (≥ 1/10), common (≥ 1/100,
Infections and infestations
- Common: pneumonia, herpes zoster
- Uncommon: opportunistic infection (sometimes fatal), cystitis, vaginitis, increased susceptibility to infections
- Rare: sepsis, pharyngitis
- Very rare: pneumocystis carinii pneumonia, nocardiosis, histoplasmosis, cryptococcosis, herpes simplex hepatitis, disseminated herpes simplex and furunculosis
Neoplasms benign, malignant and unspecified (including cysts and polyps)
- Uncommon: lymphoma
- Very rare: tumor lysis syndrome, lymphoproliferative disorder
Disorders of the blood and lymphatic system
- Very common: thrombocytopenia, leukopenia
- Common: bone marrow depression, anemia, pancytopenia
- Rare: megaloblastic anemia
- Very rare: aplastic anemia, neutropenia and lymphadenopathy
Disorders of the immune system
- Uncommon: anaphylactic reaction
- Very rare: hypogammaglobulinemia
Metabolism and nutrition disorders
- Uncommon: precipitated diabetes mellitus
Psychiatric disorders
- Rare: mood alterations
- Very rare: loss of libido
Nervous system disorders
- Common: headache
- Uncommon: dizziness, hemiparesis, convulsions, leukoencephalopathy (following high dose intravenous administration, intrathecal or low dose methotrexate after craniospinal irradiation)
- Rare: (temporary) cognitive impairment, paresis, language disorders not otherwise specified including dysarthria and aphasia
- Very rare: sensory disturbances (unusual head sensations)
Eye disorders
- Rare: eye irritation, visual disturbances, blurred vision
- Very rare: conjunctivitis, transient blindness, loss of vision
Cardiac pathologies
- Very rare: pericarditis, pericardial effusion
Vascular pathologies
- Rare: thromboembolic event (including arterial thrombosis, cerebral thrombosis, thrombophlebitis, deep vein thrombosis and pulmonary embolism)
- Uncommon: vasculitis
Respiratory, thoracic and mediastinal disorders
- Common: interstitial pneumonia (sometimes fatal)
- Uncommon: pulmonary fibrosis
- Very rare: chronic interstitial lung disease
Gastrointestinal disorders
- Very common: abdominal pain, stomatitis, nausea, anorexia, vomiting
- Uncommon: intestinal ulcers, gastrointestinal bleeding, diarrhea
- Rare: gingivitis, enteritis, melaena
- Very rare: haematemesis
Hepatobiliary disorders
- Uncommon: fatty liver transformation, liver fibrosis, liver cirrhosis
- Rare: hepatotoxicity, acute hepatitis
- Very rare: hepatic atrophy, hepatic necrosis
Skin and subcutaneous tissue disorders
- Common: erythematous rash, pruritus
- Uncommon: Stevens-Johnson syndrome; toxic epidermal necrolysis (Lyell's syndrome), urticaria, photosensitivity, pigmentation abnormalities, alopecia
- Rare: nodulosis, ecchymosis, acne, erythema multiforme, skin ulcers, psoriasis exacerbation *
- Very rare: telangiectasia
* Psoriasis lesions can be aggravated by concomitant exposure to ultraviolet rays. The recall phenomenon has been reported both in patients undergoing radiotherapy and in those with skin damaged by the sun's rays.
Musculoskeletal and connective tissue disorders
- Uncommon: arthralgia, myalgia, osteoporosis
Renal and urinary disorders
- Uncommon: renal failure, dysuria, nephropathy
- Very rare: azotemia, haematuria
Pregnancy, puerperium and perinatal conditions
- Rare: miscarriage
Diseases of the reproductive system and breast
- Uncommon: vaginal ulcers
- Very rare: impotence, infertility, oligospermia, menstrual disorders, vaginal discharge
Congenital, familial and genetic disorders
- Uncommon: fetal malformation
General disorders and administration site conditions
- Very common: mucositis
- Common: malaise, asthenia
- Uncommon: fever
- Very rare: death
Diagnostic tests
- Very common: increased liver enzymes
- Uncommon: decreased serum albumin
Injury, poisoning and procedural complications
- Rare: stress fracture
Description of selected adverse reactions following intrathecal administration of methotrexate
The acute form is a "chemical arachnoiditis which manifests itself with headache, back or shoulder pain, neck stiffness and fever.
The subacute form may include paresis, usually transient, paraparesis / paraplegia with involvement of one or more spinal nerve roots, paralysis, and cerebellar dysfunction.
The chronic form is a leukoencephalopathy manifested by irritability, confusion, ataxia, spasticity, occasional seizures, dementia, somnolence, coma, and rarely death.
This central nervous system toxicity can be progressive. The combined use of craniospinal irradiation and intrathecally administered methotrexate has been shown to increase the incidence of leukoencephalopathy. Any signs of neurotoxicity (meningeal irritation, transient or permanent paresis, encephalopathy) should be monitored following intrathecal administration of methotrexate.
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 the "address www.agenziafarmaco.it/it/responsabili". By reporting side effects you can help provide more information on the safety of this medicine. "
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the package after "EXP". The expiry date refers to the last day of that month. Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
SPECIAL STORAGE PRECAUTIONS
The product should be stored below 25 ° C away from direct sunlight. Methotrexate Teva should only be diluted with normal saline for infusion, so diluted it is stable for at least 24 hours.
Other information
COMPOSITION
Methotrexate Teva 25 mg / ml solution for injection
Each ml of solution contains:
- Active ingredient 25.0 mg methotrexate (50 mg / 2 ml and 500 mg / 20 ml).
- Excipients Sodium chloride, sodium hydroxide, hydrochloric acid, water for injections.
Methotrexate Teva 100 mg / ml solution for injection
Each ml of solution contains:
- Active ingredient Methotrexate 100.0 mg (1 g / 10 ml and 5 g / 50 ml).
- Excipients Sodium hydroxide, 1 N hydrochloric acid, 1 N sodium hydroxide, water for injections.
PHARMACEUTICAL FORM AND CONTENT
Solution for injection for intravenous, intrathecal, intramuscular and intra-arterial use.
Methotrexate Teva 25 mg / ml solution for injection 2 ml and 20 ml bottles.
Methotrexate Teva 100 mg / ml solution for injection 10 ml and 50 ml bottles.
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
METOTRESSATE TEVA INJECTABLE SOLUTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Methotrexate Teva 25 mg / ml solution for injection.
Each ml of solution contains:
Methotrexate 25 mg.
Methotrexate Teva 100 mg / ml solution for injection.
Each ml of solution contains:
Methotrexate 100 mg.
03.0 PHARMACEUTICAL FORM
Solution for injection for intravenous, intrathecal, intramuscular and intra-arterial use.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Methotrexate Teva is indicated in the treatment of choriocarcinoma, destructive chorionadenoma and vesicular or hydatiform mola. The use of Methotrexate Teva both alone and in polychemotherapy induces remissions on the main solid tumors (sarcomas, lymphomas, cervico-facial carcinomas, carcinoma of the breast, lung and cervix of the uterus) managing to maintain these remissions even for long periods . Methotrexate Teva is also indicated for acute leukemia. Recent studies have highlighted the excellent therapeutic response induced by methotrexate in lymphoblastic leukemia of the child. Methotrexate has also shown therapeutic validity also in the lymphosarcoma of the child in stage III and IV.
04.2 Posology and method of administration
"If methotrexate is used to treat cancer, the dose should be adjusted with caution according to the" body surface area ".
"Fatal cases of intoxication have been reported after administration of incorrectly calculated doses.
Methotrexate Teva can be administered intramuscularly, intravenously (bolus injections or infusion), intrathecal, intra-arterial and intraventricular.
Dosing is based on the patient's body weight or body surface area except for intrathecal or intraventricular administration in which cases a maximum dose of 15 mg is recommended.
Doses should be reduced in cases of blood deficiency or liver and kidney dysfunction.
When methotrexate Teva is given by infusion it must only be diluted with normal saline. Large doses (more than 100 mg) are usually given as intravenous infusions for periods not exceeding 24 hours. Part of the dose may initially be given by intravenous injection. Methotrexate Teva has been used with positive effects in a wide variety of neoplastic diseases, alone or in combination with other cytotoxic agents, hormones, immunotherapy, radiotherapy or surgery. Therapeutic regimens therefore vary considerably in relation to clinical uses, particularly when a regimen of intermittent strong doses is followed by the administration of calcium folinate in order to preserve normal cells from toxic effects.Dosing regimens for calcium folinate are discussed at the end of this section.
Examples of doses of Methotrexate Teva that have been used for particular indications are given below.
Choriocarcinoma and other trophoblastic tumors . Intramuscularly in doses of 15-30 mg per day for 5-day cycles. These cycles are generally repeated 3-5 times as appropriate, with rest periods of one or more weeks between cycles, until any symptoms of toxicity have subsided. The efficacy of therapy is neatly assessed over 24 hours through quantitative analyzes of chorionic gonadotropins (HCG) which should return to normal values or below 50IU / 24 hours generally after the third or fourth treatment cycle, and should also generally follow. complete resolution of detectable lesions in 4 or 6 weeks. One or two courses of Methotrexate Teva are generally recommended after normalization of the HCG. A careful clinical evaluation is essential before each cycle of the drug. Doses greater than 60 mg intramuscular every 48 hours can be administered 4 times, followed by calcium folinate therapy. This cycle is repeated at intervals of at least 7 days until the urinary HCG level returns to normal. No less than 4 courses of treatment are generally required. Patients with complications, such as extensive metastases, can be treated with methotrexate Teva in cyclical combinations with other cytotoxic drugs.
Destructive chorionadenoma and hydatid mola . Since the hydatid mole may be followed by choriocarcinoma, prophylactic therapy with METOTRESSATE TEVA is recommended. Destructive chorionadenoma is considered an invasive form of the hydatid mola. Methotrexate Teva is given in such cases in doses similar to those recommended for choriocarcinoma.
Acute lymphatic (lymphoblastic) leukemia in children and young adolescents . Methotrexate Teva in doses of 3.3 mg / m2 in combination with Prednisone 60 mg / m2, administered generally, is used as inductive therapy. Methotrexate Teva alone or in combination with other agents appears to be a drug of choice to ensure the maintenance of drug-induced remission. When remission has occurred and supportive care has produced general clinical improvements, maintenance therapy is initiated as follows: Intramuscular methotrexate Teva 30 mg / m2 twice weekly. A dosage of 2.5 mg / kg in a vein every 14 days was also employed. If a recurrence of the disease is observed, re-induction or remission can be achieved by repeating the initial inductive therapy.
Meningeal leukemia
Cerebrospinal fluid (CSF) should be examined in all leukemic patients in order to diagnose possible leukemic invasion of the central nervous system.
Since the transition of methotrexate from plasma to CSF is minimal in adequate therapy, Methotrexate Teva is administered in intrathecal doses of 12 mg / m2 or in maximum doses of 15 mg at intervals of 2-5 days, this therapy is usually repeated until at which CSF cell counts return to normal (usually 2-3 weeks). At this point, a further dose is recommended. A second common course of administration is Methotrexate Teva 12 mg / m2 once a week for two weeks and then once a month. It is now common practice, due to the frequent cases of meningeal leukemia, to administer methotrexate Teva intrathecally in equal doses, as a prophylaxis in all cases of lymphocytic leukemia. Although intravenous doses of an additional 50 mg of methotrexate should not significantly penetrate the CSF, higher doses, of the order of 500 mg / m2, produce cytotoxic levels of methotrexate in the CSF. This type of therapy was used for a short time, then followed by administration of calcium folinate as initial maintenance therapy to prevent leukemic invasion of the central nervous system in children with a poor prognosis of lymphocytic leukemia.
Lymphoma
Non-Hodgkin's lymphomas, for example infantile lymphosarcoma, have recently been treated with 3-30 mg / kg (approximately 9-900 mg / m2) of Methotrexate Teva by intravenous injection and infusion, followed by calcium folinate at the highest doses. Some cases of Burkitt's lymphoma, if treated in the first stage with courses of 15 mg / m2 per day for 5 days, have shown prolonged remissions. A combination chemotherapy is also used in all stages of the disease and a course of 15 mg / day of methotrexate Teva intrathecally for 4 days has been shown to be useful in controlling episodes of invasion of the central nervous system.
Breast cancer
Methotrexate Teva in intravenous doses of 10-60 mg / m2, is commonly included in regimens of cyclical combinations with other cytotoxic drugs in the treatment of advanced breast cancer. A similar regimen has also been used as adjuvant therapy in primary cases followed by mastectomy and / or radiotherapy.
Ostegenic sarcoma . The use of methotrexate alone or in cyclic combination regimens has been introduced as adjuvant therapy to the primary treatment of ostegenic sarcoma. This involved the use of intravenous infusions of 20-300 mg / kg (approximately 600-9000 mg / m2). of Methotrexate Teva followed by calcium folinate for support. Methotrexate Teva can also be used as the sole treatment in cases of ostegenic sarcoma metastases.
Bronchogenic carcinoma
Intravenous infusions of 20-100 mg / m2 of Methotrexate Teva have been included in cyclic combination regimens in the treatment of advanced cancers. High doses of Methotrexate Teva together with calcium folinate as supportive therapy can also be used as a single treatment.
Head and neck cancer . Intravenous infusions of 240-1080 mg / m2 of Methotrexate Teva with calcium folinate can be used as adjuvant pre-operative therapy in the treatment of advanced cancers. Intra-arterial infusions of Methotrexate Teva are indicated for certain head and neck cancers, although this form of administration is now used less frequently.
Bladder cancer
Intravenous injections or infusions of Methotrexate Teva in doses above 100 mg every 1 to 2 weeks can be used in the treatment of bladder cancer. Diuretics and moisturizers are used in addition to reduce the excessive toxicity of the drug that can occur in cases of renal disorders.
Support therapy with calcium folinate
The dose of calcium folinate is variable and depends on the dose of methotrexate. In general, amounts greater than 120 mg are administered in divided doses over 14-24 hours by intramuscular injection, intravenous bolus or intravenous infusion in saline, followed by 12-15 mg i.m. or 15 mg orally, every 6 hours for the next 48 hours. Supportive therapy is usually started 25 hours after the start of the infusion of METHOTRESSATE TEVA. Dosage of 15 mg orally every 6 hours for 48 to 72 hours may be sufficient when lower methotrexate Teva dosages (less than 100 mg) are used. The clinical use of high doses of methotrexate combined with calcium folinate as supportive therapy in the treatment of many previously resistant cancers is risky and remains the subject of much research.
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 I-folinate therapy, these patients require continued hydration and alkalization of the urine and a Close monitoring of fluid and electrolyte status until serum methotrexate levels have fallen below 0.05 micromol / l and renal failure has not resolved. If necessary, intermittent hemodialysis may be helpful in these patients with a high-flow dialyzer.
Senior citizens
Due to impaired liver and kidney function and reduced folate reserves, methotrexate should be used with extreme caution in elderly patients. Dose reduction should be considered and these patients should be closely monitored for any early signs of toxicity.
Patients with hepatic insufficiency
Methotrexate should be administered with great caution, if not avoided, in patients with previous or current significant liver disease, especially if induced by alcohol abuse. Methotrexate is contraindicated in the presence of bilirubin values> 5 mg / dl ( 85.5 mcmol / l).
Patients with renal insufficiency
Methotrexate should be used with caution in patients with impaired renal function. The dose should be corrected as follows:
04.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
- Severe hepatic insufficiency (see also section 4.2)
- Severe renal insufficiency (creatinine clearance
- Severe blood disorder (in patients with pre-existing blood dyscrasias, such as: bone marrow hypoplasia, thrombocytopenia, severe anemia.)
- Alcoholism
- Infectious disease in progress
- Evidence of immunodeficiency syndrome
- Pregnancy and lactation (see section 4.6).
- Ulceration of the oral cavity and ascertained gastrointestinal ulcer in the active phase.
- Simultaneous vaccination with live vaccines.
04.4 Special warnings and appropriate precautions for use
Methotrexate Teva should only be used by doctors experienced in antimetabolic chemotherapy. Close monitoring of patients on methotrexate therapy is necessary. Methotrexate can cause severe toxicity.
Pathological changes (see section 4.8) can also occur without first noticing signs of gastrointestinal or haematological toxicity. It is therefore essential that liver function is checked before starting treatment and monitored regularly throughout therapy.
Particular attention should be paid in the presence of pre-existing liver damage or impaired liver function.
If necessary, drainage of pleural effusions or ascites should be performed prior to treatment. This is because methotrexate slowly escapes from the "reserves from third spaces" (eg pleural effusions, ascites). This causes a "prolonged terminal half-life and unexpected toxicity.
Symptoms of gastrointestinal toxicity, which initially manifests itself with diarrhea and ulcerative stomatitis, require the interruption of therapy otherwise they can result in hemorrhagic enteritis and death by intestinal perforation. Methotrexate is therefore contraindicated in the presence of ulcerations of the oral cavity and gastrointestinal ulcer in active phase (see section 4.3).
Dehydration can potentiate the toxicity of methotrexate. It is recommended to alkalize the urine and to favor a high diuresis, especially in the treatment with high dosages.
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 condition.
Serious, sometimes fatal, skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome) and erythema multiforme have been reported within days of single or multiple dose administration of methotrexate.
Life-threatening opportunistic infections, including Pneumocystis carinii pneumonia, can occur with methotrexate therapy. If a patient experiences pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered.
Pulmonary signs and symptoms, eg. dry non-productive cough, fever, cough, chest pain, dyspnoea, hypoxemia, and a chest x-ray infiltrate or non-specific pneumonia may indicate a potentially dangerous injury and require discontinuation of treatment and careful investigation. Lung injury can occur at any dosage. Pulmonary disease induced by methotrexate can occur at any time during therapy and has been reported at doses of 7.5 mg / week. It is not always completely reversible. An infection (including pneumonia) should be ruled out.
Methotrexate should only be used by physicians who are familiar with the various characteristics of the drug and its mode of action. Chest X-ray, kidney and liver function evaluation are recommended prior to initiation of methotrexate therapy. and blood tests.
Patients undergoing therapy should be subjected to appropriate monitoring so that signs and symptoms of possible toxic effects or adverse reactions can be detected and evaluated promptly. Because of the frequent onset of hematopoietic depression, which can be early and occur even with apparently safe dosages, pre-treatment and periodic haematological checks are indispensable in the use of Methotrexate Teva in chemotherapy. Any notable decrease in blood cell counts indicates the need. an "immediate cessation of therapy and appropriate measures.
Methotrexate can cause kidney damage which can lead to acute kidney failure. It is recommended that extreme attention be paid to renal function, including alkalinization of urine, measurement of serum methotrexate levels and evaluation of renal function.
Methotrexate therapy in patients with renal insufficiency should be undertaken with extreme caution as renal insufficiency reduces the elimination of methotrexate. The patient's kidney condition should be determined before and during therapy with Methotrexate Teva.
The dose of the drug should be reduced or administration suspended until kidney functions are improved or restored. In case of administration of high doses of methotrexate it is necessary to maintain a high level of hydration and induce alkaline diuresis. This is a measure to prevent the precipitation of methotrexate or its metabolites in the renal tubules.
Alkalization of urine to pH 6.5 - 7 by oral or intravenous administration of sodium bicarbonate (5 x 625 mg tablets every 3 hours) or acetazolamide (500 mg orally 4 times a day) is recommended as a preventive measure.
It is essential to include the following laboratory tests on a regular basis as part of the monitoring of patients receiving methotrexate: complete blood tests, urinalysis, kidney and liver function tests and, in the case of high dose administration, determination of plasma levels of Methotrexate It may be useful and important to perform a liver biopsy or bone marrow aspirate studies when high doses are used or in case of long-term therapy.
Methotrexate should be used with extreme caution in patients with renal insufficiency, infections, peptic ulcer, ulcerative colitis, ulcerative stomatitis, diarrhea, debilitation and in very young or elderly subjects. If severe leukopenia occurs during therapy, this increases the risk of developing bacterial infections. In these cases it is advisable to stop the administration of the drug and to undertake an appropriate antibiotic therapy. In the case of severe bone marrow depression, blood or platelet transfusions may be necessary.
The immunological response to a concomitantly administered vaccine may be diminished, as methotrexate has some immunosuppressive activity.
Live vaccines
A severe reaction could result from concomitant use of a live vaccine and therefore concomitant administration of live vaccines with methotrexate is contraindicated (see section 4.3). Cases of disseminated vaccine infection have been reported after immunization with smallpox virus in patients treated with methotrexate.
In all cases where Methotrexate Teva is used in chemotherapy, the physician should weigh the need or utility of the drug against the risks of toxic effects and secondary reactions. Often these reactions are reversible if detected early. When toxic effects are observed. or secondary reactions, the dosage should be reduced or the administration suspended and appropriate corrective measures should be undertaken according to the clinical opinion of the physician. The resumption of therapy with Methotrexate Teva must be carried out with caution, adequately considering the new need for the drug and monitoring, as far as possible, the reappearance of toxicity phenomena.
Methotrexate, given at the same time as radiotherapy, may increase the risk of soft tissue necrosis and osteonecrosis.
Acute onset elevations in liver enzymes are frequently found, usually transient and asymptomatic, which do not appear to be predictive of subsequent liver disease. Persistent liver abnormalities and / or decreased serum albumin may indicate severe liver toxicity. Liver biopsy after prolonged use often shows histological changes and fibrosis and cirrhosis have been reported.
Treatment should not be initiated or should be discontinued if liver function test abnormalities are found or developed during therapy (see sections 4.2 and 4.3).
Malignant lymphomas can occur in patients treated with low doses of methotrexate, in which case therapy should be discontinued. If the lymphoma shows no signs of spontaneous regression, another cytotoxic therapy should be instituted.
States of folate deficiency can increase the toxicity of methotrexate.
Excipients
Methotrexate Teva 25 mg / ml solution for injection:
2 ml bottle: This medicinal product contains less than 1 mmol (23 mg) sodium per 2 ml, ie it is essentially "sodium-free".
Bottle of 20 ml: This medicine contains approximately 4 mmol (92 mg) sodium per 20 ml. To be taken into consideration in people with reduced kidney function or who follow a low sodium diet.
Methotrexate Teva 100 mg / ml solution for injection:
Bottle of 10 ml: This medicinal product contains approximately 4.4 mmol (101.2 mg) sodium per 10 ml. To be taken into consideration in people with reduced kidney function or who follow a low sodium diet.
Bottle of 50 ml: This medicinal product contains approximately 22 mmol (506 mg) sodium per 50 ml. To be taken into consideration in people with reduced kidney function or who follow a low sodium diet.
04.5 Interactions with other medicinal products and other forms of interaction
Medicinal products with high plasma protein binding
Medicinal products with high plasma protein binding (such as: salicylates, sulphonamides, diphenylhydantoins, tetracycline, chloramphenicol and p-aminobenzoic acid), can displace methotrexate, which binds extensively to proteins, increasing its potential for toxicity when administered simultaneously.
NSAIDs
If methotrexate is administered before or concurrently with NSAIDs, including salicylates, extreme caution should be exercised, as cases of severe methotrexate toxicity and even deaths due to reduced methotrexate excretion have been reported. These medicinal products have been reported to reduce the tubular secretion of methotrexate in an animal model and therefore may increase the toxicity of methotrexate. It is recommended that methotrexate dosage be closely monitored during NSAID treatment.
Similarly, the possibility should be considered that weak organic acids, including salicylates, may delay renal excretion of methotrexate and increase accumulation.
Drugs with similar pharmacological activity
Drugs with similar pharmacological activity, such as pyrimethamine, should not be given to patients taking methotrexate.
Folic acid
Vitamin preparations containing folic acid or its derivatives, taken concomitantly with methotrexate, can alter the response to methotrexate. High doses of calcium folinate may reduce the efficacy of intrathecally administered methotrexate.
Other potential hepatotoxic agents
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 receiving methotrexate with other potentially hepatotoxic drugs (eg leflunomide, azathioprine, retinoids, sulfasalazine) should be monitored closely for possible risk of hepatotoxicity. For the same reason concomitant use of alcohol should be avoided.
Probenecid, penicillins, proton pump inhibitors
Renal tubular transport is reduced by probenecid, penicillins and proton pump inhibitors, which can lead to potentially toxic methotrexate levels. The use of methotrexate with these medicinal products should be closely monitored. Haematological and gastrointestinal toxicities have been observed in association with high and low doses of methotrexate.
Potentially nephrotoxic chemotherapeutic agents
An increase in nephrotoxicity may be observed when a high dose of methotrexate is administered in combination with a potentially nephrotoxic chemotherapeutic agent (e.g. cisplatin).
Folate antagonists
In rare cases it has been reported that concomitant administration of methotrexate and folate antagonists, eg. trimethoprim and co-trimoxazole can cause bone marrow suppression.
Oral antibiotics and non-absorbable broad-spectrum antibiotics
Oral antibiotics, such as tetracyclines, and non-absorbable broad-spectrum antibiotics can reduce intestinal absorption of methotrexate or interfere with enterohepatic circulation by inhibiting intestinal flora and suppressing bacterial metabolism of methotrexate.
Theophylline
Methotrexate may reduce the theophylline clearance, so theophylline levels should be monitored in case of concomitant treatment.
04.6 Pregnancy and breastfeeding
Pregnancy
The teratogenicity of methotrexate has been demonstrated; Congenital anomalies and fetal death caused by methotrexate have been reported. Therefore, the drug should not be administered to pregnant women (see section 4.3). Furthermore, methotrexate is not recommended in women of childbearing age unless the expected benefits outweigh the risks considered. Women of childbearing potential should not initiate methotrexate therapy until pregnancy is ruled out. If the patient becomes pregnant while taking the drug, the patient should be informed of the potential risk to the fetus.
Feeding time
The presence of methotrexate has been found in human breast milk, therefore the drug is contraindicated during lactation.
Fertility
Methotrexate affects spermatogenesis and therefore patients on methotrexate treatment and their partners should be adequately informed. Conception should be avoided for at least three months after cessation of methotrexate treatment.
04.7 Effects on ability to drive and use machines
In relation to the possibility of neurological disorders occurring, the use of machines is not recommended during therapy.
04.8 Undesirable effects
In general, the incidence and severity of acute adverse reactions are related to dose, frequency of administration and duration of target organ exposure to significant blood levels of methotrexate.
The most relevant undesirable effects are suppression of the haematopoietic system and gastrointestinal disorders.
The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea and abdominal pain. Other frequently reported adverse events are malaise, unexplained fatigue, chills and fever, dizziness and reduced resistance to infections.
List of adverse reactions
Frequencies of adverse reactions are classified as follows: very common (≥ 1/10), common (≥ 1/100,
Infections and infestations
Common: pneumonia, herpes zoster
Uncommon: opportunistic infection (sometimes fatal), cystitis, vaginitis, increased susceptibility to infections
Rare: sepsis, pharyngitis
Very rare: pneumocystis carinii pneumonia, nocardiosis, histoplasmosis, cryptococcosis, herpes simplex hepatitis, disseminated herpes simplex and furunculosis
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Uncommon: lymphoma
Very rare: tumor lysis syndrome, lymphoproliferative disorder
Disorders of the blood and lymphatic system
Very common: thrombocytopenia, leukopenia
Common: bone marrow depression, anemia, pancytopenia
Rare: megaloblastic anemia
Very rare: aplastic anemia, neutropenia and lymphadenopathy
Disorders of the immune system
Uncommon: anaphylactic reaction
Very rare: hypogammaglobulinemia
Metabolism and nutrition disorders
Uncommon: precipitated diabetes mellitus
Psychiatric disorders
Rare: mood alterations
Very rare: loss of libido
Nervous system disorders
Common: headache
Uncommon: dizziness, hemiparesis, convulsions, leukoencephalopathy (following high dose intravenous administration, intrathecal or low dose methotrexate after craniospinal irradiation)
Rare: (temporary) cognitive impairment, paresis, language disorders not otherwise specified including dysarthria and aphasia
Very rare: sensory disturbances (unusual head sensations)
Eye disorders
Rare: eye irritation, visual disturbances, blurred vision
Very rare: conjunctivitis, transient blindness, loss of vision
Cardiac pathologies
Very rare: pericarditis, pericardial effusion
Vascular pathologies
Rare: thromboembolic event (including arterial thrombosis, cerebral thrombosis, thrombophlebitis, deep vein thrombosis and pulmonary embolism)
Uncommon: vasculitis
Respiratory, thoracic and mediastinal disorders
Common: interstitial pneumonia (sometimes fatal)
Uncommon: pulmonary fibrosis
Very rare: chronic interstitial lung disease
Gastrointestinal disorders
Very common: abdominal pain, stomatitis, nausea, anorexia, vomiting
Uncommon: intestinal ulcers, gastrointestinal bleeding, diarrhea
Rare: gingivitis, enteritis, melaena
Very rare: haematemesis
Hepatobiliary disorders
Uncommon: fatty liver transformation, liver fibrosis, liver cirrhosis
Rare: hepatotoxicity, acute hepatitis
Very rare: hepatic atrophy, hepatic necrosis
Skin and subcutaneous tissue disorders
Common: erythematous rash, pruritus
Uncommon: Stevens-Johnson syndrome; toxic epidermal necrolysis (Lyell's syndrome), urticaria, photosensitivity, pigmentation abnormalities, alopecia
Rare: nodulosis, ecchymosis, acne, erythema multiforme, skin ulcers, psoriasis exacerbation *
Very rare: telangiectasia
* Psoriasis lesions can be aggravated by concomitant exposure to ultraviolet rays. The phenomenon of "recall"has been reported in both patients undergoing radiation therapy and in those with sun-damaged skin.
Musculoskeletal and connective tissue disorders
Uncommon: arthralgia, myalgia, osteoporosis
Renal and urinary disorders
Uncommon: renal failure, dysuria, nephropathy
Very rare: azotemia, haematuria
Pregnancy, puerperium and perinatal conditions
Rare: miscarriage
Diseases of the reproductive system and breast
Uncommon: vaginal ulcers
Very rare: impotence, infertility, oligospermia, menstrual disorders, vaginal discharge
Congenital, familial and genetic disorders
Uncommon: fetal malformation
General disorders and administration site conditions
Very common: mucositis
Common: malaise, asthenia
Uncommon: fever
Very rare: death
Diagnostic tests
Very common: increased liver enzymes
Uncommon: decreased serum albumin
Injury, poisoning and procedural complications
Rare: stress fracture
Description of selected adverse reactions following intrathecal administration of methotrexate
The acute form is a "chemical arachnoiditis which manifests itself with headache, back or shoulder pain, neck stiffness and fever.
The subacute form may include paresis, usually transient, paraparesis / paraplegia with involvement of one or more spinal nerve roots, paralysis, and cerebellar dysfunction.
The chronic form is a leukoencephalopathy manifested by irritability, confusion, ataxia, spasticity, occasional seizures, dementia, somnolence, coma, and rarely death.
This central nervous system toxicity can be progressive. The combined use of craniospinal irradiation and intrathecally administered methotrexate has been shown to increase the incidence of leukoencephalopathy. Any signs of neurotoxicity (meningeal irritation, transient or permanent paresis, encephalopathy) should be monitored following intrathecal administration of methotrexate.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions that occur after authorization of the medicine is important, as it allows continuous monitoring of the benefit / risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via the Website: www. Agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
In post-marketing experience, overdose has generally occurred with oral and intrathecal administration of methotrexate, although overdose has also been reported with intravenous and intramuscular administration.
Symptoms of an overdose with intrathecal administration are usually CNS symptoms, including headache, nausea and vomiting, seizures or convulsions, and acute toxic encephalopathy. In some cases, no symptoms were reported. Deaths have been reported as a result of intrathecal overdose. In these cases, cerebellar hernias associated with increased intracranial pressure and acute toxic encephalopathy have been reported.
Cases of overdose, sometimes fatal, have been reported due to incorrect daily rather than weekly oral methotrexate intake. In these cases the commonly reported symptoms were haematological and gastrointestinal reactions.
Calcium folinate is the antidote to neutralize the immediate toxic effects of methotrexate. It can be administered orally, intramuscularly, intravenous bolus or infusion. The longer the time interval between the administration of methotrexate and the initiation of folinate therapy. of calcium, the lower the effectiveness of calcium folinate in counteracting toxicity. Monitoring of serum methotrexate concentration is essential to determine the optimal dose and duration of treatment with calcium folinate.
Other supportive care such as blood transfusions and kidney dialysis may be needed.
In cases of 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 acute intermittent hemodialysis performed with a high-flux dialyzer.
Following intrathecal overdose it may be necessary to administer high doses of calcium folinate systemically or to induce alkaline diuresis.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic, antimetabolite.
ATC code: L01BA01.
Methotrexate (4-amino-N10-methyl-pteroyl-glutamic acid) is a derivative of folic acid and belongs to the class of cytotoxic agents known as antimetabolites. It acts mainly during the "S" phase of cell division as a competitive inhibitor of " dihydrofolate-reductase enzyme, preventing the reduction of dihydrofolate into tetrahydrofolate, a necessary step in the process of DNA synthesis and cell multiplication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, skin epithelium, mucous membranes of the mouth and intestines and urinary bladder cells are generally more sensitive to this effect than Methotrexate Teva.
Cell proliferation in malignant tissues is greater than in normal tissues and so Methotrexate Teva can slow tumor growth without irreversible damage to normal tissues.
05.2 Pharmacokinetic properties
After parenteral injection, maximum plasma levels are reached in approximately half an hour to one hour. In approximately half an hour the absorbed drug is reversibly bound to plasma proteins but exchanges easily with body fluids and diffuses into the cells of the body tissue. The excretion of a single daily dose occurs through the kidneys in an amount ranging from 55 % to 88% or even more in 24 hours. Repeated daily doses result in higher plasma levels and a certain retention of the drug for a period of more than 24 hours which can lead to an accumulation in the tissues. The liver cells appear to retain some of the drug for prolonged periods even after a single therapeutic dose. Methotrexate Teva is withheld in cases where renal function is impaired and under such conditions can rapidly increase in serum and tissue cells. Methotrexate Teva does not cross the barrier. cerebrospinal blood when administered orally or parenterally in therapeutic doses rations of the drug, when necessary, can be achieved by direct intrathecal administration (see "Posology and method of administration").
05.3 Preclinical safety data
The LD50 in the mouse was equal to 94 mg / kg by i.p. administration; it resulted instead equal to 180 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 and 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 of the anticancer and immunosuppressive drugs, has shown carcinogenic properties in animals under particular experimental conditions.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Methotrexate Teva 25 mg / ml solution for injection
Each ml of solution contains:
Sodium chloride, sodium hydroxide, hydrochloric acid, water for injections.
Methotrexate Teva 100 mg / ml solution for injection
Each ml of solution contains:
Sodium hydroxide, sodium hydroxide 1 N q.b., hydrochloric acid 1 N q.b., water for injections 1 ml.
06.2 Incompatibility
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
06.3 Period of validity
Methotrexate Teva 25 mg / ml solution for injection
The shelf life of the product is 3 years at a temperature below 25 ° C, when the packaging is intact and correctly stored.
Methotrexate Teva 100 mg / ml solution for injection
The shelf life of the product is 2 years at a temperature below 25 ° C, when the packaging is intact and correctly stored.
06.4 Special precautions for storage
The product must be stored at a temperature below 25 ° C away from direct sunlight. Methotrexate Teva should only be diluted with normal saline for infusion, so diluted it is stable for at least 24 hours.
06.5 Nature of the immediate packaging and contents of the package
Teva methotrexate is packaged in a type I (borosilicate) neutral glass bottle closed with a butyl rubber seal and aluminum cap.
Packaging:
Methotrexate Teva 25 mg / ml solution for injection. 2 ml bottle.
Methotrexate Teva 25 mg / ml solution for injection. Bottle of 20 ml.
Methotrexate Teva 100 mg / ml solution for injection. Bottle of 10 ml.
Methotrexate Teva 100 mg / ml solution for injection. Bottle of 50 ml.
06.6 Instructions for use and handling
07.0 MARKETING AUTHORIZATION HOLDER
Teva Italia S.r.l. - Piazzale Luigi Cadorna, 4 - 20123 Milan
08.0 MARKETING AUTHORIZATION NUMBER
Methotrexate Teva 25 mg / ml solution for injection.
2 ml bottle - A.I.C. No. 026544027
Methotrexate Teva 25 mg / ml solution for injection.
20 ml bottle - A.I.C. No. 026544039
Methotrexate Teva 100 mg / ml solution for injection.
10 ml bottle - A.I.C. No. 026544041
Methotrexate Teva 100 mg / ml solution for injection.
Bottle of 50 ml - A.I.C. No. 026544054
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 30 July 1987
Date of most recent renewal: May 30, 2010
10.0 DATE OF REVISION OF THE TEXT
February 2016
