Methotrexat “Ebewe” 100 mg/ml is used in adults, adolescents and children 3 months of age and older (solely intrathecal administration, see Section 4.2 b)).

 

Methotrexat “Ebewe” in a low (single dose <100 mg/m² body surface area [BSA]) and medium dosage (single dose 100–1000 mg/m² BSA) is indicated in the following oncological diseases:

 

Malignant trophoblastic tumours (bladder moles, chorionepithelioma)

·                As mono-chemotherapy in female patients with a favourable prognosis (“low risk”)

·                In combination with other cytostatic medicinal products in female patients with an unfavourable prognosis (“high risk”)

 

Breast cancer

·                In combination with other cytostatic medicinal products as adjuvant therapy following resection of the tumour or mastectomy and as palliative therapy at an advanced disease stage

 

Tumours in the head and neck area

·                For palliative monotherapy in the metastatic stage or with relapses

 

Non-Hodgkin’s lymphoma

·                For treatment of intermediate or high-grade non-Hodgkin’s lymphoma in combination with other cytostatic medicinal products

 

Acute lymphatic leukaemia (ALL)

·                As part of complex therapy protocols in combination with other cytostatic medicinal products for remission-sustaining therapy and for prophylaxis and therapy of leukaemic meningitis

 

Methotrexat “Ebewe” in a high dosage (single dose >1000 mg/m² BSA) is indicated in the following oncological diseases:

·                Non-Hodgkin lymphoma primarily localised in the central nervous system before radiotherapy

·                Acute lymphatic leukaemia (ALL)

·                Prophylaxis and therapy of leukaemic meningitis

 

Methotrexat “Ebewe” tablets, Methotrexat “Ebewe” 20 mg/ml solution for injection in a pre-filled syringe, Methotrexat “Ebewe” 10 mg/ml – parenteral solution or Methotrexat “Ebewe” 10 mg/ml solution for injection in a pre-filled syringe are suitable for use in severe generalised, refractory psoriasis, psoriatic arthritis and rheumatoid arthritis.

Methotrexate should only be prescribed by physicians who are experienced in the use of methotrexate and who are fully aware of the risks of treatment with methotrexate.

 

WARNINGS The dose should be carefully adjusted depending on the body surface area if methotrexate is used for the therapy of tumours. Cases of fatal intoxication after administration of incorrectly calculated doses have been reported. The medical staff and patients must be comprehensively informed of the toxic effects.

 

Dosage

The dosage of methotrexate as part of polychemotherapy for malignant tumours or haemoblastoses depends on the indication and takes place individually under consideration of general condition and blood count. The doses applied for conventional, low-dose (single dose below 100 mg/m²), medium-dose (single dose 100 mg/m²–1000 mg/m²) and high-dose (single dose over 1000 mg/m²) methotrexate therapy are dependent on the respective therapy regimen.

 

The following dosage information therefore only represents reference values. Current therapy protocols are transmitted to the treating doctor upon request.

 

Conventional methotrexate therapy – no calcium folinate protection required

15–20 mg/m² (IV); twice a week

30–50 mg/m² (IV); once a week

15 mg/m²/day (IV, IM); 5 days;

Repeat in 2–3 weeks

 

Moderately-high dose of methotrexate therapy

50–150 mg/m² (IV injection); no calcium folinate protection;

Repeat in 2–3 weeks

240 mg/m² (IV infusion over 24 h); calcium folinate protection required;

Repeat in 4–7 days

0.5–1.0 g/m² (IV infusion over 36–42 h); calcium folinate protection required;

Repeat in 2–3 weeks

 

High-dose methotrexate therapy – calcium folinate protection required 

1–12 g/m² (IV 1–6 h)

Repeat in 1–3 weeks

 

a) Systemic (intravenous and intramuscular) administration of methotrexate:

Low-dose (single dose below 100 mg/m² BSA) and medium-dose (single dose between 100 mg/m² to 1000 mg/m² BSA) methotrexate therapy:

 

Malignant trophoblastic tumours (bladder moles, chorionepithelioma):

Patients with good prognosis (“low risk”): as monotherapy at a dose of 0.4 mg/kg body weight (BW) monthly on day 1 to 5; repeat after a 7-day break or 0.25–1 mg/kg BW methotrexate monthly on day 1, 3, 5 and 7; repeat after a 7-day break; calcium folinate 24 h after each methotrexate administration.

Patients with poor prognosis (“high risk”): 300 mg/m² BSA IV with combination therapy.

 

Breast cancer:

40 mg/m² BSA methotrexate IV on day 1 and 8 in combination with cyclophosphamide and fluorouracil analogous to CMF (cyclophosphamide, methotrexate, 5-fluorouracil) – protocol.

 

Tumours in the head and neck area:

40–60 mg/m² BSA methotrexate IV once weekly as monotherapy.

 

Non-Hodgkin’s lymphoma:

Single doses of 120 mg/m² BSA methotrexate as part of combination therapies.

 

Acute lymphatic leukaemia:

For the maintenance of remission as part of complex therapy protocols, single doses of 20 to 40 mg/m² BSA methotrexate.

 

High-dose methotrexate therapy (single dose >1000 mg/m² BSA):

 

Non-Hodgkin’s lymphoma located mainly in the central nervous system (CNS):

No uniform therapy and dosage schedule can be stated for the therapy of lymphomas primarily localised in the CNS. In trials, doses of at least 1500 mg/m² to 4000 mg/m² BSA methotrexate IV as a single dose over multiple cycles have been shown to be effective as monotherapy or in combination with radiotherapy and/or intrathecally administered methotrexate or with other chemotherapeutically effective medicinal products. Details can be found in the specific professional literature.

 

For the therapy of non-Hodgkin’s lymphoma located mainly in the central nervous system in patients with immunosuppression, e.g., as a result of HIV, please refer to the specific professional literature.

 

Acute lymphatic leukaemia (ALL):

ALL in adults: single doses of 1500 mg/m² BSA methotrexate as part of combination regimens.

ALL in children and adolescents: typical single doses are in the range of 1000 mg/m² BSA to 5000 mg/m² BSA (as part of combination regimens).

 

b) Intrathecal administration of methotrexate:

For prophylaxis and the therapy of leukaemic meningitis and/or the therapy of primary cerebral CNS lymphoma, the intrathecal application of methotrexate has been shown to be effective.

 

In the case of intrathecal application, methotrexate must be dosed according to age because the CSF volume correlates more closely with the – age-related – brain volume than with the body surface or the weight.

 

·                Children ≤3 months 3 mg methotrexate intrathecal

·                Children aged 4 to 11 months: 6 mg methotrexate via the intrathecal route

·                Children aged 1 year: 8 mg methotrexate via the intrathecal route

·                Children aged 2 years: 10 mg methotrexate via the intrathecal route

·                Children aged 3 to 8 years: 12 mg methotrexate via the intrathecal route

·                Patients older than 8 years: 12 mg to maximum 15 mg methotrexate via the intrathecal route

 

The time, frequency and duration of use of the intrathecal methotrexate injections is determined by the treating doctor, taking into account the specific therapy protocols and the individual therapy situation.

 

Caution: Methotrexate preparations and/or dilutions which contain preservatives may not be used intrathecally or in high doses!

 

Patients with renal impairment

Methotrexate is excreted to a significant extent via the kidneys and should therefore be used with caution in patients with renal impairment (see Sections 4.3 and 4.4). The prescribing physician may need to adjust the dose in order to prevent accumulation of the medicinal product. The following dosages are recommended in patients with impaired renal function. Additional dose adjustments may be required due to the large intersubjective pharmacokinetic variability.

 

Table 1a: Dose adjustment for methotrexate in doses of <100 mg/m² in patients with renal impairment

 

Creatinine Clearance (ml/min)	% of administered dose
≥60 30–59 <30	100 50 Methotrexate must not be administered

 

 

Table 1b: Dose adjustment for methotrexate in doses of >100 mg/m² in patients with renal impairment

 

Creatinine Clearance (ml/min)	% of administered dose
>80 ~80 ~60 <60	100 75 63 Methotrexate must not be administered

 

Patients with hepatic impairment

In patients with significant, existing or previous liver disease, especially if this is due to alcohol, methotrexate should be administered with the utmost care, if at all. If bilirubin is >5 mg/dl (85.5 μmol/l), methotrexate is contraindicated (see Section 4.3).

 

Elderly patients

Dose reduction should be considered in elderly patients due to the restricted hepatic and renal function and low folic acid reserves with advancing age (55 years and older). In addition, close monitoring of patients for possible signs of toxicity is recommended.

 

Children and adolescents

The use of methotrexate in children and adolescents must be undertaken with special caution and in line with the corresponding therapy protocols.

 

Patients with pathological fluid accumulation (pleural effusion, ascites)

Since the half-life of methotrexate may be prolonged 4-fold in patients with pathologic fluid retention, a reduction in dose, and in many cases, discontinuation of methotrexate can be required (see Sections 5.2 and 4.4).

 

Method of administration

For intravenous, intramuscular, intraarterial, intrathecal and intraventricular administration after dilution.

Methotrexat “Ebewe” 100 mg/ml – concentrate for the infusion preparation must be diluted before application with standard infusion solutions depending on the therapy regimen and infusion duration. This is possible with a glucose solution or physiological saline solution. In general, 1–2% Methotrexat “Ebewe” concentrations are administered.

 

For these methotrexate solutions, the stability at 25°C (room temperature) for 24 hours both under light influence and under light exclusion has been checked. Change infusion bottle for longer infusion times.

 

Methotrexate preparations and/or dilutions, which contain preservatives may not be used intrathecally or in high doses!

 

Estimation of serum methotrexate levels must be undertaken during treatment with methotrexate.

 

Calcium folinate

Calcium folinate (rescue) must be administered after the administration of methotrexate doses of 100 mg/m² BSA or higher as single dose.

 

Doses above 100 mg/m² are usually administered as an IV infusion. A portion of it may be injected as an initial dose intravenously (as bolus).

Methotrexat “Ebewe” can also be administered intramuscularly, intraarterially, intrathecally and intraventricularly.

Methotrexat “Ebewe” 10 mg/ml parenteral solution can be used for this or for low-dose regimens.

 

The total duration of the therapy is determined by the doctor.

• Hypersensitivity to the active substance methotrexate or to any of the other excipients listed in Section 6.1 • Severe, acute or chronic infections (such as tuberculosis and HIV) • Stomatitis, ulcers of the gastrointestinal tract • Diseases of the liver due to chronic alcohol abuse or other chronic liver disease (see Section 4.2) • Hepatic insufficiency (see Section 4.2) • Severe renal impairment (Creatinine Clearance <30 ml/min) for methotrexate in doses of <100 mg/m2 moderate and severe renal impairment (Creatinine Clearance <60 ml/min) for methotrexate in doses of >100 mg/m2 (see Sections 4.2 and 4.4) • Dysfunction of the haematopoietic system (e.g., after previous radiotherapy or chemotherapy) such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anaemia • Immunodeficiency • Excessive alcohol consumption • Pre-existing blood disease • Breastfeeding (see Section 4.6) • Pregnancy, unless there is a vital indication (see Section 4.6) • Simultaneous vaccination with live vaccines

The therapy should be carried out by a doctor experienced in tumour therapy and with sufficient experience in the therapy with methotrexate.

The incorrect use of methotrexate can lead to severe, including fatal, side effects. Healthcare professionals and patients must be clearly instructed.

 

Toxicity

During therapy with methotrexate, patients must be closely monitored due to the possibility of severe toxic reactions (which can prove fatal) so that any symptoms of poisoning can be detected quickly.

Patients should be educated on the potential benefits and risks (including the early signs and symptoms of toxicity) of methotrexate therapy. In addition, they should be informed of the need to consult a doctor as soon as they detect the occurrence of symptoms of poisoning, as well as about the necessary monitoring of symptoms of poisoning (including regular laboratory tests).

 

The discontinuation of methotrexate does not always result in the full regression of the side effects that occurred.

 

Estimation of serum methotrexate levels must be undertaken during treatment with methotrexate.

 

Methotrexate is only slowly eliminated from the pathological fluid collections such as ascites or pleural effusions in body cavities (the so-called “third space”), which results in an extended plasma elimination half-life and unexpected toxicity. These fluid collections must be removed by puncture, if possible, before therapy with methotrexate.

 

Blood and lymphatic system

Methotrexate can suppress the haematopoietic system, thereby causing anaemia, aplastic anaemia, pancytopenia, leukopenia, neutropenia and/or thrombocytopenia.

First signs of these life-threatening complications can include: fever, sore throat, ulceration of the mucous membrane of the mouth, flu-like complaints, severe exhaustion, nose bleeds and skin bleeding.

In the therapy of neoplastic conditions, the methotrexate therapy should be continued only if the potential benefit outweighs the risk of severe myelosuppression.

 

Especially during long-term therapy in elderly patients, there were reports of megaloblastic anaemia.

 

Methotrexate should not be administered if peptic ulcer or ulcerative colitis is present (see Section 4.3).

 

Special attention must be paid to the patient’s condition following therapy with medicinal products with cumulative myelotoxicity and radiation therapy involving the bone marrow, in particular for any restrictions to the bone marrow reserve. This can result in the increased sensitivity of the bone marrow to the methotrexate therapy and the increased suppression of the haematopoietic system. For longer-lasting therapy with methotrexate, bone marrow biopsies should be carried out as necessary.

 

In the case of acute lymphatic leukaemia, methotrexate may induce pain in the left epigastric region (inflammation of the splenic capsule due to the destruction of leukaemic cells).

 

Liver function

Due to the potentially hepatotoxic effects it is recommended that no additional hepatotoxic or potentially hepatotoxic medicinal products are taken during methotrexate therapy and to abstain from alcohol consumption or to significantly reduce alcohol consumption.

 

Methotrexate can cause acute hepatitis and chronic, potentially fatal hepatotoxicity (fibrosis and cirrhosis), but generally only after prolonged use. Acutely elevated levels of liver-related enzymes are commonly observed. These are generally transient and asymptomatic and do not indicate the probability of subsequent liver disease.

 

Methotrexate caused the reactivation of a hepatitis B infection or the worsening of hepatitis C infections, which in some cases resulted in death. Some cases of hepatitis B reactivation occurred after the discontinuation of methotrexate. To be able to assess a pre-existing liver disease in patients with previous hepatitis B or C infections, clinical and laboratory tests should be performed. Based on the results of this, a methotrexate therapy can then be shown to be inappropriate for some patients.

 

Also, where there are other inactive, chronic infections e.g., herpes zoster or tuberculosis, special care is advised due to the possibility of activation.

 

In the case of patients with insulin-dependent diabetes mellitus, increased caution is advised as a rule, since under a methotrexate therapy, liver cirrhosis without intermittently elevated transaminases has developed in individual cases.

 

Renal function

In patients with impaired renal function, the methotrexate therapy should only be performed with extreme caution and with a low dosage due to the delayed methotrexate elimination levels in these patients (see Section 4.2).

 

Under therapy with methotrexate, a worsening of the kidney function with an increase in specific laboratory values (creatinine, urea and uric acid in serum) can develop, resulting in acute renal failure with oliguria or anuria. This is probably caused by the precipitation of methotrexate and its metabolites in the renal tubules.

 

Conditions that lead to dehydration, such as vomiting, diarrhoea and stomatitis, can increase the toxicity of methotrexate due to the increased levels of the active substance. In these cases, a supporting therapy should be initiated and the suspension of the use of methotrexate should be considered until the symptoms abate.

 

Gastrointestinal Disorders

If ulcerative stomatitis or diarrhoea, haematemesis, black colouration of the stool or blood in the stool should occur, the therapy must be interrupted, because otherwise haemorrhagic enteritis and cases of death by intestinal perforation can occur.

 

Nervous system

Cases of leukoencephalopathy were reported after intravenous administration of methotrexate in patients who had previously received cranial irradiation.

Chronic leukoencephalopathy has also been reported in patients who were given repeated high-dose therapy with methotrexate with calcium folinate rescue without prior cranial irradiation.

There is some evidence that the combined use of cranial irradiation together with the intrathecal application of methotrexate increases the incidence of leukoencephalopathy (also see Section 4.8).

There are reports about the occurrence of leukoencephalopathy in patients who were given oral methotrexate.

 

After the intrathecal application of methotrexate, patients must be monitored for the development of signs of neurotoxicity (damage to the nervous system, such as meningeal irritation, temporary or sustained paralysis, encephalopathy).

 

Cases of serious neurological effects, which ranged from headache to paralysis, coma and stroke-like episodes, were predominantly observed in children and adolescents who had been given methotrexate intrathecal in combination with cytarabine IV.

 

A transient acute neurological syndrome has also been seen with high-dose methotrexate therapy, which may manifest as behavioural abnormalities, focal sensorimotor symptoms (including transient blindness) and abnormal reflexes. The exact cause is unknown.

 

Lung function

Special care is recommended for patients with impaired lung function.

 

Pulmonary complications, pleural effusion, alveolitis or pneumonitis with symptoms such as irritative cough, fever, general malaise, cough, chest pain, dyspnoea, hypoxemia and infiltrates in the chest X-ray or non-specific pneumonia occurring during the methotrexate therapy, can be signs of possible hazardous damage, which can potentially prove to be fatal. Lung biopsies revealed different findings (e.g., interstitial oedema, mononuclear infiltrates or non-caseating granulomas). If these complications should be suspected, the therapy with methotrexate must be discontinued immediately and a thorough investigation, including tests to exclude any possibility of infections and tumours, is required. Methotrexate induced lung disorders can occur acutely at any time during the therapy, were not always completely reversible, and were reported even at low doses of 7.5 mg/week.

 

In addition, pulmonary alveolar bleeding has been reported with the use of methotrexate in rheumatologic and similar indications. This event may also be associated with vasculitis and other comorbidities. If there is a suspicion of pulmonary alveolar bleeding, an immediate examination should be considered to confirm the diagnosis.

 

Skin and subcutaneous tissue disorders

There are reports of the occurrence of severe, sometimes fatal, skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome) after a single dose of methotrexate or continuous administration.

 

Psoriatic lesions can be aggravated by UV radiation with simultaneous methotrexate therapy. Radiation-induced dermatitis and sunburn can recur with the use of methotrexate (“recall” reactions).

 

Immune system

During methotrexate therapy, opportunistic infections, including pneumocystis jirovecii pneumonia may occur, which can prove to be fatal. If a patient presents with pulmonary symptoms, the possibility of pneumocystis jirovecii pneumonia should be considered.

 

Due to its potential effect on the immune system methotrexate can distort vaccination and test results (immunological test procedures to record immunoreactivity). During therapy with methotrexate, vaccinations that are given can prove to be ineffective. Live vaccines should not be administered during therapy with methotrexate due to the increased risk of infection.

 

Methotrexate should be used with caution in patients with active infections. Methotrexate is contraindicated in patients with obvious or laboratory-confirmed immunodeficiency syndromes. Also, caution should be exercised when administering methotrexate if patients are exposed to chickenpox or shingles.

 

Neoplasms

In patients with fast growing tumours, methotrexate, as well as other cytostatic medicinal products, can induce tumour lysis syndrome. Appropriate supportive and pharmacologic actions can prevent or mediate these complications.

 

Occasionally, the occurrence of malignant lymphoma was reported with the use of low-dosage methotrexate, which receded in some cases after the discontinuation of therapy with methotrexate. In the case of the incidence of lymphomas, the methotrexate therapy should thus be discontinued, and a suitable therapy introduced only if the lymphoma does not regress. An increased incidence of the occurrence of lymphoma under therapy with methotrexate could not be determined in a recent investigation.

 

The use of high-dose regimens for the therapy of neoplastic conditions outside of the approved indications is of an investigative nature only; a therapeutic benefit for this has not been established.

 

Musculoskeletal, connective tissue and bone disorders

The risk of the occurrence of soft tissue necrosis, or osteonecrosis, can be increased with radiotherapy during the use of methotrexate.

 

Folic acid supplement

Insufficient folic acid can increase the toxicity of methotrexate (see Section 4.5).

The use of folic or folinic acid can reduce the toxicity of methotrexate (gastrointestinal symptoms, stomatitis, alopecia and increase in liver enzymes).

Before taking folic acid supplements, the monitoring of vitamin B12 levels is recommended, since the administration of folic acid can mask a vitamin B12 insufficiency, in particular in adults aged over 50.

 

Recommended follow-up examinations and safeguards

 

Patients undergoing methotrexate therapy should be closely monitored in order to detect toxic effects immediately.

 

Before the start of therapy, the following examinations should be performed:

-          Complete blood count with differential blood count

-          Hepatic enzymes (ALAT [GPT], ASAT [GOT], AP), bilirubin

-          Serum albumin

-          Renal retention parameters (if applicable, with creatinine clearance)

-          Hepatitis serology (A, B, C)

-          Exclusion of tuberculosis, if applicable

-          Chest X-rays, if applicable

If a pulmonary disease (e.g., interstitial pneumonia) is suspected, lung function tests, particularly in the presence of corresponding reference values from the initial examination may be beneficial.

 

Depending on the dosage and/or the therapeutic protocol used, regular monitoring of methotrexate serum levels is required, especially during and after therapy with methotrexate in high doses (also see Section 4.9). By adjusting the methotrexate dose and implementing appropriate rescue measures, the toxicity and possible mortality of a methotrexate therapy can be significantly decreased.

Patients who suffer from pleural effusions, ascites, gastrointestinal tract occlusion, previous cisplatin therapy, dehydration, reduced urinary pH or impaired or damaged kidneys are particularly susceptible to developing elevated or only delayed decreasing methotrexate levels and must be strictly monitored.

Even without the aforementioned apparent reasons, some patients may also have delayed methotrexate elimination. It is important to identify these patients within 48 hours after the therapy, otherwise the methotrexate toxicity can be irreversible.

 

A calcium folinate protective (rescue) therapy must be carried out following therapy with methotrexate with a dosage of 100 mg/m² BSA. Depending on the quantity of methotrexate and the infusion time, different calcium folinate doses are necessary to protect the normal regenerative tissue from severe toxic side effects.

An adequate calcium folinate rescue must be initiated within 42 to 48 hours after methotrexate therapy. Follow-up checks of the methotrexate levels should therefore be carried out after at least 24, 48 and 72 hours and continued, if necessary, to determine how long the calcium folinate rescue must be continued.

 

During therapy with methotrexate, complete blood count monitoring should be performed with differential blood counts, including platelet and leukocyte counts (daily to once weekly).

The leukocyte and platelet counts should be assessed before the initiation of a combination therapy with methotrexate in a high dosage with regard to the specified minimum values in the respective protocol (leukocytes 1000 to 1500/μl, thrombocytes 50,000 to 100,000/μl).

 

The lowest value of circulating leukocytes, neutrophil granulocytes and thrombocytes generally occurs 5–13 days after IV use of methotrexate (with rebound after 14–28 days). Leukocytes and neutrophil granulocytes occasionally show two decreases, whereby the first occurs after 4–7 days and the second after 12–21 days, followed by a rebound.

 

Liver and kidney function tests and urine tests should be performed at regular intervals.

 

Temporary 2 to 3-fold increases in transaminases were observed in 13–20% of patients receiving methotrexate therapy. This is not generally a reason for changing the dosing regimen. However, sustained anomalies in the liver-related enzymes and/or a decrease in the serum albumin can be a sign of serious hepatotoxicity. In the case of a sustained increase in the liver-related enzymes, a reduction and/or the suspension of the therapy must be considered. In patients with a longer history of hepatic impairment, methotrexate should always be discontinued.

Enzyme determination does not allow a reliable prediction of the development of morphologically tangible liver injury, i.e., even with normal transaminases there may only be a histologically detectable liver fibrosis or, more rarely, liver cirrhosis.

 

The use of methotrexate may result in a worsening of kidney function.

Monitoring of creatinine, urea and electrolytes, especially in therapy with methotrexate in high doses, is recommended on days 2 and 3 to detect an excretion disorder caused by methotrexate early on.

Therapy with methotrexate may result in acute renal failure with oliguria/anuria and a rise in the serum creatinine, probably due to the precipitation of methotrexate and its metabolites in the renal tubules. Monitoring of renal function, including adequate hydration and alkalinisation of urine, measurement of serum methotrexate levels and monitoring of urine output is recommended.

 

If there are any indications of an impairment of renal function (e.g., pronounced side effects of prior methotrexate therapy or urinary obstruction), the creatinine clearance must be determined. Therapy with high-dose methotrexate (methotrexate doses >100 mg/m²) should only be undertaken if creatinine is normal (creatinine clearance >80 ml/min) (see Sections 4.2 and 4.3). Since methotrexate is primarily eliminated by the kidneys, higher concentrations are to be expected in patients with impaired kidney function, which may lead to serious side effects.

The dosage should be reduced in case serum creatinine levels are elevated. Methotrexate should not be administered if creatinine clearance is less than 30 ml/min. Treatment with methotrexate in doses above 100 mg/m² is contraindicated if serum creatinine is higher than 2 mg/dl and creatinine clearance is less than 60 ml/min (see Sections 4.2 and 4.3). Treatment with methotrexate over 100 mg/m² should not be initiated with a urinary pH less than 7.0. Alkalinisation of the urine must be tested at least for the first 24 hours by repeated pH monitoring (values greater than or equal to 6.8) after beginning treatment with methotrexate. Administration of adequate amounts of intravenous fluid is absolutely necessary during therapy with high-dose methotrexate.

Monitoring should be undertaken at shorter intervals in case there is a possibility of renal dysfunction or borderline renal function (e.g., elderly patients). This applies, in particular, if additional medicinal products are administered that impede the clearance of methotrexate, cause kidney damage (e.g., non-steroidal anti-inflammatory medicinal products) or can lead to haematopoietic disorders. Concomitant administration of NSAIDs is not recommended in the presence of risk factors such as renal dysfunction, including mild renal impairment. The concomitant use of proton pump inhibitors and high-dose methotrexate should be avoided, especially in patients with impaired renal function.

 

Conditions which lead to dehydration, such as vomiting, diarrhoea and stomatitis, may increase the toxicity of methotrexate due to higher levels of the active substance. In these cases, the use of methotrexate should be discontinued until the symptoms abate.

 

An inspection of the oral cavity and pharynx for mucosal changes should be done daily.

 

Particularly strict patient monitoring is necessary in the case of previous intensive radiotherapy, reduced general state of health of the patient and in young or elderly patients.

 

More frequent follow-up examinations may be required at the start of therapy, in the case of dosage changes, or during a phase in which there is an increased risk of elevated methotrexate levels (e.g., dehydration, impaired renal function, additional or increased co-administered medicinal products such as non-steroidal anti-inflammatory medicinal products).

 

Use in children and adolescents

Special caution is indicated for the use of methotrexate in the therapy of children and adolescents. The therapy should follow the therapy protocols especially developed for children.

In paediatric patients with acute lymphatic leukaemia (ALL), severe neurotoxicity may occur following therapy with medium-dose intravenous methotrexate (1 g/m² BSA), which is commonly reported as a generalised or focal epileptic seizure. Leukoencephalopathy and/or microangiopathic calcifications were often observed in diagnostic imaging for symptomatic patients.

 

Use in elderly patients

Special caution is also advised in elderly patients. Elderly patients should be examined at short time intervals to detect early signs of toxicity. The clinical pharmacology of methotrexate has not been fully investigated in the elderly. The dose of methotrexate should be adjusted to the decreased liver and renal function due to increased age. For older patients (55 years and older), partially modified therapy protocols, such as for ALL therapy, have been developed.

 

Fertility

Methotrexate has been reported to cause fertility disorders, oligospermia, menstrual disorders and amenorrhoea during treatment and for a short period after termination of therapy in humans by interfering with spermatogenesis and oogenesis during the period of administration – these effects appear to be reversible when treatment is discontinued.

 

Teratogenicity – risk for reproduction

Methotrexate causes embryotoxicity, abortion and foetal birth defects in humans. Therefore, potential reproductive, miscarriages and congenital birth defects should be discussed with patients of childbearing potential (see Section 4.6). If women of childbearing potential are treated, an effective method of contraception should be used during therapy and for a period of at least six months after discontinuation of therapy.

 

Use in men

Methotrexate can have a genotoxic effect. Therefore, men treated with methotrexate are advised not to father a child during therapy and up to 6 months thereafter. Since therapy with methotrexate can cause severe and possibly irreversible spermatogenesis disorders, men should seek advice on the possibility of sperm preservation prior to initiation of therapy (for advice on male contraception, see Section 4.6).

 

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e., it is essentially “sodium-free”.

The use of nitrous oxide (laughing gas) potentiates the effect of methotrexate on folate metabolism and leads to increased toxicity such as severe, unpredictable myelosuppression, stomatitis and neurotoxicity following intrathecal administration. The concomitant use of methotrexate and nitrous oxide should therefore be avoided, although this effect may be alleviated by the administration of calcium folinate.

 

L-asparaginase antagonises the effects of methotrexate in concomitant use with methotrexate.

 

Disease-modifying antirheumatic drugs (DMARDs) and non-steroidal anti-inflammatory drugs (NSAIDs) should not be administered before or during a high-dose methotrexate therapy. The concomitant use of NSAIDs and high-dose methotrexate resulted in increased and prolonged methotrexate serum levels, resulting in cases of death due to severe haematological (myelosuppression and aplastic anaemia) and gastrointestinal toxicity.

In animal tests, non-steroidal anti-inflammatory medicinal products (NSAIDs), including salicylic acid, led to a reduction in the tubular secretion of methotrexate and thus to an increase in its toxicity due to the elevated methotrexate level. Therefore, NSAIDs and low-dose methotrexate should only be used concomitantly with caution. In the presence of risk factors, such as impaired kidney function – even if borderline – the concomitant use with non-steroidal antiphlogistics is discouraged.

 

The concomitant use of methotrexate and DMARDs (e.g., gold compounds, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine) has not been studied and thus the intensification of the toxic effects of methotrexate cannot be excluded.

 

The co-administration of proton pump inhibitors (omeprazole, pantoprazole, lansoprazole) may cause a delay in or inhibition of the renal elimination of methotrexate and therefore cause increased methotrexate plasma levels with clinical signs and symptoms of methotrexate toxicity.

The concomitant use of proton pump inhibitors with high-dose methotrexate should therefore be avoided, especially in patients with impaired renal function.

 

The hepatotoxicity can be increased by regular alcohol consumption or the use of other hepatotoxic medicinal products such as azathioprine, leflunomide, retinoids and sulfasalazine. Patients who also take hepatotoxic medicinal products should be monitored closely. Alcohol consumption should be avoided during therapy with methotrexate.

 

Through the displacement of methotrexate from the plasma protein binding, the following medicinal products can increase the biological availability of methotrexate (indirect dosage escalation) and increase its toxicity: aminopyridine derivatives, para-amino benzoic acid, barbiturates, doxorubicin, oral contraceptives, phenylbutazone, phenytoin, probenecid, salicylates, sulphonamides, tetracyclines, tranquilizers, sulfonylureas, penicillin, pristinamycin and chloramphenicol. The concomitant use of methotrexate should therefore be monitored carefully.

 

A reduction in tubular secretion and consequently an increase in the toxicity of methotrexate, especially in the low dosage range, may be caused by the following medications: para-aminohippuric acid, non-steroidal anti-inflammatory medicinal products, probenecid, salicylates, sulphonamides and other weak organic acids. The concomitant use of methotrexate should therefore be monitored carefully.

 

Penicillin and sulphonamides can reduce the renal clearance of methotrexate in individual cases, so that increased concentrations of methotrexate with concomitant haematologic and gastrointestinal toxicity may occur.

 

The tubular secretion in the kidneys is decreased by ciprofloxacin; the use of methotrexate with this medicinal product should be monitored carefully.

 

Oral antibiotics such as tetracyclines, chloramphenicol and non-resorbable broad-spectrum antibiotics can reduce the intestinal absorption of methotrexate or influence enterohepatic circulation by inhibiting the gut flora and metabolism of methotrexate by bacteria.

 

In the case of (prior) therapy with medicinal products that can have possible side effects for the bone marrow (e.g., amidopyrine derivatives, chloramphenicol, phenytoin, pyrimethamine, sulphonamides, trimethoprim/sulfamethoxazole, cytostatics), the possibility of pronounced disorders of the haematopoiesis through the therapy with methotrexate must be taken into consideration.

 

The co-administration of medicinal products that cause a folate deficiency (e.g., sulphonamides, trimethoprim/sulfamethoxazole) can lead to increased methotrexate toxicity. Special caution is therefore also advised in the case of an existing folic acid deficiency. On the other hand, the concomitant use of medicinal products containing folic acid and vitamin preparations that contain folic acid or their derivatives can inhibit the efficacy of methotrexate.

 

Although the combination of methotrexate and sulfasalazine can cause a potentiation of methotrexate and thus more severe side effects due to the inhibition of the folic acid synthesis by sulfasalazine, in several studies such side effects were observed in patients only in rare individual cases.

 

Methotrexate can reduce theophylline clearance. Therefore, in the case of co-administration with methotrexate, the theophylline levels must be monitored.

 

Excessive consumption of beverages containing caffeine or theophylline (coffee, caffeinated drinks, black tea) should be avoided during therapy with methotrexate, as the effect of methotrexate may be reduced due to the potential interaction between methotrexate and methylxanthines on the adenosine receptors.

 

The combined use of methotrexate with leflunomide can increase the risk of pancytopenia.

 

Concomitant use of mercaptopurine and methotrexate can increase the plasma level of mercaptopurine, so that dose adjustment may be required when administered concomitantly.

 

Cases of bone marrow suppression and reduced blood folate levels have been described in connection with the concomitant use of triamterene and methotrexate.

 

The risk of the occurrence of soft tissue necrosis or osteonecrosis can be increased with radiotherapy during the use of methotrexate.

 

Cholestyramine can increase the non-renal elimination of methotrexate through an interruption of the enterohepatic cycle.

 

In the case of co-administration of erythrocyte concentrates and methotrexate, special monitoring of the patient is required. Patients who subsequently receive blood transfusions after methotrexate infusions over 24 hours may experience increased toxicity due to prolonged serum methotrexate concentrations that are persistently high.

 

In individual cases, corticosteroids led to disseminated herpes zoster in patients with herpes zoster or postherpetic neuralgia when administered concomitantly with methotrexate.

 

High-dosage calcium folinate can reduce the efficacy of methotrexate administered via the intrathecal route.

 

Anaesthetics on a nitrous oxide base potentiate the effect of methotrexate on the folic acid metabolism and cause increased toxicity such as severe, not foreseeable myelosuppression, stomatitis and neurotoxicity in the case of application via the intrathecal route. This can be reduced by the administration of calcium folinate.

 

Pyrimethamine or cotrimoxazole used in combination with methotrexate can cause pancytopenia, probably due to the additive inhibition of dihydrofolic acid caused by these substances and methotrexate (interactions between sulphonamides and methotrexate see above).

 

Regular consumption of alcohol and administration of additional hepatotoxic medicinal products increase the likelihood of hepatotoxic side effects of methotrexate.

 

The administration of additional haematotoxic medicinal products (e.g., metamizole) increases the likelihood of severe haematotoxic side effects of methotrexate.

 

The pharmacokinetic interactions between methotrexate, anticonvulsants (reduced serum methotrexate levels) and 5-fluorouracil (increased half-life of 5-fluorouracil) must be considered.

 

Especially in the case of orthopaedic interventions, where the risk of infection is high, combination therapy of methotrexate with immunomodulatory medicinal products should be used with caution.

 

Delayed clearance of methotrexate should be considered in combination with other cytostatic active substances.

 

A reduction in the phenytoin plasma level was observed in patients with acute lymphatic leukaemia during induction therapy that included high-dose methotrexate with calcium folinate rescue as well as prednisone, vincristine, and 6-mercaptopurine.

 

The use of procarbazine during a high-dose methotrexate therapy increases the risk of renal function impairment.

 

In the case of simultaneous intrathecal application of methotrexate with cytarabine IV, the risk of serious neurological side effects, such as headache, paralysis, coma and stroke-like episodes may be increased.

 

An increase in nephrotoxicity may occur in combination with high-dose methotrexate with a potentially nephrotoxic chemotherapy agent (e.g., cisplatin).

 

Considering its possible effects on the immune system, methotrexate may distort vaccination and test results (immunological processes to assess the immune response).

 

During methotrexate therapy, concomitant vaccination with live vaccines must not be carried out (see Sections 4.3 and 4.4).

 

Methotrexate may increase the effect of coumarin-like oral anticoagulants (acenocoumarol, phenprocoumon) (prolonged prothrombin time due to reduced degradation of coumarin derivatives).

 

Co-administration of levetiracetam and methotrexate reduces the methotrexate clearance and results in increased/prolonged methotrexate levels in the blood up to potentially toxic levels. Methotrexate and levetiracetam blood levels should be monitored carefully in patients receiving both medicinal products at the same time.

 

Women of childbearing potential/Contraception in women

Women must not become pregnant during methotrexate therapy. Reliable contraception is to be used during therapy and for a period of at least 6 months after discontinuation of therapy with methotrexate (see Section 4.4). Women of childbearing potential should be informed of the risk of birth defects associated with methotrexate prior to the initiation of therapy and the possibility of pregnancy should be reliably excluded by taking appropriate measures, such as a pregnancy test. During therapy, pregnancy tests should be repeated in accordance with clinical needs (e.g., after interruption of contraception). Patients of childbearing potential should be counselled about pregnancy prevention and planning. Couples should be fully informed of the serious risks to the foetus in the case of pregnancy during the therapy.

 

Contraception in men

It is not known if methotrexate accumulates in semen. In animal studies, methotrexate has been found to be genotoxic so that the risk of genotoxic effects on the sperm cannot be completely ruled out. Limited clinical evidence does not indicate that there is an increased risk of birth defects or miscarriages if the father received methotrexate in low doses (less than 30 mg/week). For higher doses, there is insufficient data to estimate the risk of birth defects or miscarriages after paternal exposure.

As a precautionary measure, sexually active male patients or their partners are recommended to use reliable contraception during therapy of the male patient and for at least 6 months after stopping methotrexate. Men should not donate semen during therapy and for a period of 6 months after discontinuation of methotrexate.

 

Pregnancy

Methotrexate is contraindicated in non-oncological indications during pregnancy (see Section 4.3). If pregnancy occurs during therapy with methotrexate and within up to six months after discontinuation of methotrexate, medical advice should be provided on the risk of harmful therapy-related effects to the child and ultrasound scans should be performed to confirm the normal development of the foetus.

In animal studies, methotrexate has been shown to cause reproductive toxicity, especially in the first trimester (see Section 5.3). It has been shown that methotrexate has a teratogenic effect in humans; it has been reported to cause death of the foetus, miscarriages and/or congenital anomalies (e.g., craniofacial, cardiovascular, central nervous system and extremity abnormalities).

Methotrexate is a potent teratogen for humans, increasing the risk of spontaneous abortion, intrauterine growth disorders and congenital birth defects in case of exposure during pregnancy.

·      Spontaneous abortions were observed in 42.5% of pregnant women receiving methotrexate therapy at low doses (less than 30 mg/week). In patients with a similar disease treated with medicinal products other than methotrexate, the reported miscarriage rate was 22.5%.

·      Serious birth defects occurred in 6.6% of live births in women who received methotrexate at low doses (less than 30 mg/week) during pregnancy. Approximately 4% of live births were affected in patients with a similar disease treated with medicinal products other than methotrexate.

 

There is insufficient data on exposure to doses of methotrexate higher than 30 mg/week during pregnancy, but higher rates of spontaneous abortion and congenital birth defects are to be expected.

Normal pregnancies were reported when methotrexate was discontinued before conception.

 

If used in oncological indications, methotrexate should not be administered during pregnancy and particularly not in the first trimester of pregnancy. The benefit of therapy must be weighed against the potential risk to the foetus in each case. If the medicinal product is used during pregnancy, or if the patient becomes pregnant during therapy with methotrexate, she should be informed about the potential risk to the foetus.

 

Breastfeeding

Since methotrexate enters the mother’s milk and can cause toxic effects in nursing children, the therapy is contraindicated during breastfeeding (see Section 4.3). If the therapy is necessary during breastfeeding, breastfeeding must be discontinued before the therapy starts.

 

Fertility

Methotrexate affects spermatogenesis and oogenesis and may reduce fertility. It has been reported that methotrexate causes oligospermia, menstrual disorders and amenorrhoea in humans. These effects appear to be reversible in most cases after discontinuation of therapy.

In oncological indications, women intending to become pregnant are advised to consult a genetic counselling office, if possible, before starting therapy, and men should seek advice regarding the possibility of sperm preservation before starting therapy since methotrexate may be genotoxic in higher doses (see Section 4.4).

 

Methotrexate has a low or moderate effect on the ability to drive and to operate machinery. Since central nervous system impairments such as fatigue and dizziness may occur during therapy. In some cases the ability to drive and/or operate machinery may be compromised. This is especially true in connection with alcohol.

The incidence and severity of side effects usually depends on the dosage and duration of the methotrexate therapy. Because serious side effects can occur even at lower doses at any time during the therapy, regular monitoring by the doctor at short time intervals is essential. Most side effects are reversible if they are detected early. Some of the severe side effects mentioned below can, however, result in sudden death in very rare cases.

 

If side effects should occur, depending on their severity and intensity, dosage should be reduced, or the therapy interrupted, and appropriate countermeasures initiated (see Section 4.9). If the therapy with methotrexate is to be resumed, this should be initiated with caution under a careful evaluation of the necessity of the therapy and with increased vigilance with regard to the possible recurrence of toxicity.

 

Myelosuppression and mucositis are generally the dosage-limiting toxic effects that occur. The severity of these effects depends on the dosage, the type and the duration of use of methotrexate. Mucositis occurred approx. 3–7 days after the administration of methotrexate, leukopenia and thrombocytopenia 5–13 days after the administration of methotrexate. Myelosuppression and mucositis are generally reversible within 14 days in patients with unimpeded elimination mechanisms.

 

The most commonly reported side effects are thrombocytopenia, leukopenia, headache, dizziness, cough, loss of appetite, diarrhoea, abdominal pain, nausea, vomiting, inflammation and ulceration of the mucous membranes of the mouth and throat (mainly within the first 24–48 hours after the use of methotrexate), elevated liver enzymes and bilirubin levels, alopecia, reduced creatinine clearance rates, fatigue and malaise.

 

The ulceration of the mucous membrane of the mouth is usually the first clinical sign of toxicity.

 

The evaluation of adverse reactions is based on the following frequencies:

Very common:     ≥1/10

Common:            ≥1/100, <1/10

Uncommon:        ≥1/1000, <1/100

Rare:                   ≥1/10,000, <1/1000

Very rare:            <1/10,000

Not known           (frequency cannot be estimated from the available data)

 

Infections and infestations

Common:          herpes zoster

Uncommon:      opportunistic infections, which may be fatal

Rare:                 sepsis (including fatal outcomes)

Very rare:          herpes simplex hepatitis, cryptococcosis, histoplasmosis, cytomegalovirus infections (including pneumonia), disseminated herpes simplex, nocardiosis, pneumocystis jirovecii pneumonia*

Not known:        pneumonia, reactivation of a hepatitis B infection, worsening of a hepatitis C infection

 

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Uncommon:      malignant lymphoma*

Very rare:          tumour lysis syndrome*

 

Blood and lymphatic system disorders*

Very common: leukopenia, thrombocytopenia

Common:          anaemia, pancytopenia, myelosuppression, agranulocytosis

Rare:                 megaloblastic anaemia

Very rare:          aplastic anaemia, eosinophilia, neutropenia, lymphadenopathy (at times reversible), lymphoproliferative disorders (partially reversible)

 

Immune system disorders

Uncommon:      allergic reactions including anaphylactic shock, immunosuppression

Very rare:          hypogammaglobulinaemia

 

Metabolism and nutritional disorders

Uncommon:      diabetes mellitus

 

Psychiatric disorders

Uncommon:      depression

Rare:                 mood swings, transient cognitive disorders

 

Nervous system disorders

Very common: headaches, dizziness

Common:          drowsiness, paraesthesia

Uncommon:      hemiparesis, confusion, seizures (in the case of parenteral administration), leukoencephalopathy/encephalopathy* (in the case of parenteral administration)

Rare:                 paresis, speech disorders including dysarthria and aphasia, myelopathy (after lumbar application)

Very rare:          muscle weakness and pain in the extremities, dysgeusia (metallic taste in the mouth), acute aseptic meningitis, meningismus (paralysis, vomiting), cranial nerve syndrome, paraesthesia/hypoaesthesia

Not known:        neurotoxicity, arachnoiditis, paraplegia, stupor, ataxia, dementia, increased pressure of the cerebrospinal fluid

The intravenous use of methotrexate may also lead to acute encephalitis and fatal acute encephalopathy.

 

Eye disorders

Common:          conjunctivitis

Rare:                 visual disturbances (at times severe), severe retinal vein thrombosis

Very rare:          periorbital oedema, blepharitis, epiphora, photophobia, transient blindness, loss of vision

 

Cardiac disorders

Very rare:          pericarditis, pericardial effusion, pericardial tamponade

 

Vascular disorders

Uncommon:      vasculitis, allergic vasculitis

Rare:                 hypotension, thromboembolic events (including arterial thrombosis, cerebral thrombosis, thrombophlebitis, deep vein thrombosis)

 

Respiratory, thoracic and mediastinal disorders*

Very common: cough

Common:          lung complications on the basis of interstitial alveolitis/pneumonitis, and resulting death (regardless of dosage and duration of therapy with methotrexate)

Uncommon:      pleural effusion, pulmonary fibrosis

Rare:                 pharyngitis, respiratory arrest, pulmonary embolism

Very rare:          chronic interstitial lung disease, bronchial asthma-like reactions such as cough, dyspnoea and pathological findings in the lung function test

Not known:        chest pain, hypoxia, pulmonary alveolar bleeding (was reported with the use of methotrexate in rheumatologic and related indications)

 

Gastrointestinal disorders*

Very common: loss of appetite, diarrhoea (mainly within the first 24–48 hours after use of methotrexate), abdominal pain, nausea, vomiting, inflammation and ulceration of the mucous membranes of the mouth and throat (mainly within the first
24–48 hours after use of methotrexate)

Uncommon:      gastrointestinal ulceration and bleeding, pancreatitis

Rare:                 enteritis, gingivitis, melena

Very rare:          haematemesis

Not known:        non-infectious peritonitis, toxic megacolon, intestinal perforation, glossitis

 

Hepatobiliary disorders*

Very common: increase in hepatic enzymes (ALT [GPT], AST [GOT]), alkaline phosphatase and bilirubin

Uncommon:      hepatotoxicity, hepatic steatosis, chronic liver fibrosis and cirrhosis, decrease in serum albumin

Rare:                 acute hepatitis

Very rare:          acute hepatic necrosis, acute liver decay, liver failure

 

Skin and subcutaneous tissue disorders*

Very common:  alopecia

Common:          exanthema, erythema, itching, photosensitivity, skin ulceration

Uncommon:      severe toxic phenomena: herpetiform skin eruptions, Stevens-Johnson syndrome*, toxic epidermal necrolysis (Lyell’s syndrome)*; urticaria, hyperpigmentation of the skin, nodulosis, painful erosions of psoriatic plaques, wound healing disorders

Rare:                 acne, petechiae, ecchymoses, erythema multiforme, erythematous skin rash, hyperpigmentation of the nails, onycholysis

Very rare:          furunculosis, telangiectasia, acute paronychia

Not known:        drug reaction with eosinophilia and systemic symptoms (DRESS), exfoliation of the skin/exfoliative dermatitis

 

Musculoskeletal, connective tissue and bone disorders

Uncommon:      arthralgia, myalgia, osteoporosis

Rare:                 stress fracture

Not known:        osteonecrosis e.g., of the jaw (secondary to lymphoproliferative diseases)

 

Renal and urinary tract disorders*

Very common: decreased creatinine clearance

Uncommon:      nephropathy, renal failure, cystitis with ulcerations (possibly with haematuria), urinary retention, dysuria, oliguria, anuria

Rare:                 hyperuricemia, increased urea and creatinine concentrations in serum, azotaemia

Very rare:          haematuria, proteinuria

 

Pregnancy, postpartum and perinatal conditions

Uncommon:      foetal malformations

Rare:                 abortion

Very rare:          foetal death

 

Reproductive system and breast disorders

Uncommon:      vaginal ulcerations and inflammation

Rare:                 transient oligospermia, transient menstrual disorders

Very rare:          impaired oogenesis/spermatogenesis*, infertility*, menstrual disorders, loss of libido, impotence, vaginal discharge, gynaecomastia

Not known:        urogenital dysfunction

 

General disorders and symptoms in the area of administration

Very common: exhaustion, malaise

Uncommon:      pyrexia, in intramuscular application of methotrexate, local side effects (burning sensation) or damage (sterile abscesses formation, destruction of fatty tissues) at the administration site may occur

Not known:        chills, necrosis at the injection site, oedema

 

* For information on serious side effects, see Section 4.4.

 

Side effects of intrathecal application of methotrexate

The CNS toxicity that may occur following intrathecal use of methotrexate may manifest differently:

-        acute chemical arachnoiditis (inflammation of the arachnoid membrane) that manifests, e.g., through headache, back pain, stiff neck and fever, for example;

-        sub-acute myelopathy, that is characterised, for example, by paraparesis/paraplegia (involving one or more roots of the spinal nerves);

-        chronic leukoencephalopathy, which is characterised, for example, by confusion, irritability, drowsiness, ataxia, dementia, seizures and coma. This CNS toxicity may progress and even lead to death.

 

There is some evidence that the combined use of cranial irradiation and intrathecal methotrexate increases the incidence of leukoencephalopathy. Following the intrathecal administration of methotrexate, close monitoring for possible signs of neurotoxicity (irritation of the meninges, temporary or permanent paralysis, encephalopathy) must be carried out.

 

The intrathecal and intravenous use of methotrexate can also cause acute encephalitis and acute encephalopathy, which can lead to death.

 

There are reports of patients with periventricular CNS lymphoma who developed a cerebral herniation following the intrathecal application of methotrexate.

 

Side effects with intramuscular use of methotrexate

Following intramuscular use of methotrexate, local side effects at the injection site (burning sensation) or damage (sterile abscess formation, necrosis of fatty tissue) can occur.

 

Symptoms of an overdose

Experience post market launch of methotrexate has demonstrated that a methotrexate overdose generally occurred after oral, but also after intravenous, intramuscular or intrathecal administration. In the reports for oral overdose, the weekly dosage was accidentally administered daily (as a full dose or divided into several separate doses).

 

Symptoms following oral and/or intravenous overdose primarily affect the haematopoietic and gastrointestinal system. For example, leukopenia, thrombocytopenia, anaemia, pancytopenia, neutropenia, myelosuppression, mucositis, stomatitis, mouth ulcers, nausea, vomiting and gastrointestinal ulceration and bleeding occurred. In some cases, there were no signs of intoxication. There are reports of overdose deaths. In these cases, sepsis, septic shock, renal failure and aplastic anaemia were reported.

 

After an intrathecal overdose, CNS symptoms generally occur associated with headache, nausea and vomiting, seizures or convulsions and acute toxic encephalopathy. In some cases, no symptoms were observed. In other cases, the intrathecal overdose had a fatal outcome, whereby cerebral herniation together with increased intracranial pressure and acute toxic encephalopathy were reported.

 

Therapeutic measures in the case of an overdose

Calcium folinate, the specific antidote, is available for the prevention and therapy of toxic side effects.

 

a)     Prevention:

In the case of a methotrexate dosage from 100 mg/m² body surface area, the use of calcium folinate must follow this therapy. For the dosage and duration of use of calcium folinate as an antidote, please refer to the specific professional literature.

 

b)     Therapy:

Treatment of intoxication symptoms following a low-dose methotrexate therapy (single dosage <100 mg/m² BSA methotrexate) that can be attributed to tetrahydrofolic acid deficiency:

Immediately 6–12 mg calcium folinate intravenously or intramuscularly. Then several administrations (at least four times) of the same dosage at 3–6 hourly intervals.

 

For intensified calcium folinate rescue in delayed methotrexate elimination under therapy with methotrexate in medium and high dosages, please refer to the specific professional literature.

 

With an increasing time interval between the administration of the methotrexate and the calcium folinate, the efficacy of the calcium folinate decreases. To determine the optimal dosage and duration of the calcium folinate administration, the methotrexate serum level must be monitored.

 

In the case of a massive overdose, hydration and alkalinisation of the urine may be necessary to avoid sedimentation of methotrexate and/or its metabolites in the renal tubules. If intoxication should be caused by a substantially delayed elimination (methotrexate serum levels), such as due to acute kidney failure, haemodialysis and/or haemoperfusion may have to be considered. An effective methotrexate clearance was achieved by haemodialysis with a high-flux dialyser. Neither standard haemodialysis nor peritoneal dialysis resulted in improved methotrexate elimination.

 

An accidental intrathecal overdose may require intensive systemic countermeasures:

High systemic – not intrathecal! – calcium folinate administration, alkaline diuresis, rapid drainage of the cerebrospinal fluid and ventriculo-lumbar perfusion.

Pharmacotherapeutic group: antineoplastic agent, antimetabolite, folic acid analogue ATC code: L01BA01

 

Mechanism of action

As a folic acid analogue, methotrexate belongs to the class of medicinal products called antimetabolites. It competitively inhibits the dihydrofolate reductase enzyme. Via this enzyme, dihydrofolic acid must be reduced to tetrahydrofolic acid before it can be used to transport a carbon group in the synthesis of purine nucleotides and thymidylates. As a result, methotrexate is actively involved in DNA synthesis and repair as well as in cell replication.

 

Clinical efficacy and safety

Highly proliferating tissue, such as malignant cells, bone marrow, foetal cells, epithelium and mucosa, is generally more sensitive to this effect of methotrexate. Cell proliferation is usually more pronounced in malignant tumours than in normal tissue, and methotrexate can therefore sustainably affect malignant growth without causing irreversible damage to normal tissue.

 

Resorption

100% with intravenous and intramuscular administration.

 

Following oral administration, methotrexate is resorbed from the gastrointestinal tract. At low dose administration (7.5 mg/m² to 80 mg/m² body surface area), the average bioavailability of methotrexate is approximately 70%, but significant inter- and intra-subject variability (25–100%) is possible. Maximum serum concentrations are reached within 1–2 hours.

 

Subcutaneous, intravenous and intramuscular administrations revealed similar bioavailability. Approximately 50% of methotrexate is bound to serum proteins. After distribution, it collects mainly in the liver, kidneys and spleen in the form of polyglutamates, which can be retained for weeks or months.

In intrathecal methotrexate application, resorption into the plasma compartment only takes place slowly and causes a potentially toxic plasma concentration to be maintained over a longer period of time.

 

Distribution

After intravenous application, the initial distribution volume is approx. 0.18 l/kg (18% of the body weight) and at steady-state conditions approx. 0.4–0.8 l/kg (40–80% of the body weight). Methotrexate competes with reduced folates for the active carrier-mediated cell membrane transport. At serum concentrations above 100 μmol/l, the intracellular concentration is achieved mainly by passive diffusion.

The plasma protein binding of methotrexate is approximately 50%.

Methotrexate achieves the highest concentrations in the kidney, gallbladder, spleen, liver, skin, and in the large and small intestines. Methotrexate passes slowly into the so-called “third space” (pleural effusions and ascites) from whence it is released in a delayed manner (whereby a possible increase in toxicity can occur!). When administered orally and parenterally at therapeutic doses, methotrexate does not penetrate the blood-CSF barrier. Therapeutically effective doses in the cerebrospinal fluid can be achieved only after intrathecal administration or maximum dose therapy.

 

In low dosages, only minimal amounts of methotrexate pass into the cerebrospinal fluid; at high dosages (300 mg/kg body weight), concentrations of between 4 and 7 μg/ml were measured in the cerebrospinal fluid. The terminal half-life is on average 6–7 hours and shows considerable fluctuations (3–17 hours). In patients with a third distribution space (pleural effusion, ascites), the half-life may be up to four times longer.

 

Biotransformation

After absorption, methotrexate is metabolised both hepatically and intracellularly to polyglutamates, which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymylate synthetase. Small amounts of methotrexate polyglutamates can remain in tissue for a long time. The retention and prolonged effect of these active metabolites vary depending on the type of cells, tissue and tumours. In conventional doses, a small amount is metabolised to 7-hydroxymethotrexate; in high-dose therapy, the accumulation of this metabolite can be significant. The water solubility of 7‑hydroxymethotrexate is three to five times lower than that of the starting compound.

The terminal half-life following administration of low-dose methotrexate (30 mg/m² BSA) is approx. 3–10 hours. In high-dose therapy, the terminal half-life is 8–15 hours.

 

Elimination

The elimination of methotrexate is mainly renal by glomerular filtration and active secretion in the proximal tubule and is dependent on the dosage and application method. When administered intravenously, 80–90% of the dose administered is excreted unchanged in the urine within
24–30 hours. Biliary excretion is limited and equals a maximum of 10% of the administered dose. Methotrexate is subject to extensive enterohepatic circulation, so that a maximum of 10% of the administered dosage is excreted via the faeces. Methotrexate undergoes a short distribution phase lasting a few minutes after intravenous injection and is eliminated during a second
12–24 hour period with a plasma half-life of 2–3 hours as well as during a third phase with a plasma half-life of 12–24 hours. In the case of impaired renal function, delayed elimination is to be expected, which can result in serious side effects. A good correlation between methotrexate clearance and endogenous creatinine clearance was determined. Limitations in excretion with impaired liver function are currently not known.

Methotrexate breaks through the placental barrier in rats and monkeys.

Chronic toxicity

In tests for chronic toxicity in mice, rats and dogs, toxic effects were identified in the form of gastrointestinal lesions, myelosuppression and hepatotoxicity.

 

Mutagenic and carcinogenic potential

Long-term studies in rats, mice and hamsters showed no evidence of a tumourigenic potential of methotrexate. Methotrexate induces in vitro and in vivo gene and chromosome mutations. There is a suspicion of a mutagenic effect in humans.

 

Reproductive toxicology

Teratogenic effects have been reported in four species (rats, mice, rabbits, cats). No malformations comparable with humans occurred in Rhesus monkeys.

Sodium hydroxide, water for injection

Known incompatibilities:

Potent oxidants and acids

Chlorpromazine HCl (cloudy and yellow precipitate)

Droperidol

Idarubicin

Metoclopramide HCl

Prednisolone sodium phosphate

Promethazine HCl

 

In addition, incompatibilities of methotrexate and cytarabine and fluorouracil have been reported, but the incompatibility with fluorouracil is questionable.

As a rule, finished infusion solutions should be used within a maximum of 24 hours after preparation; in addition, incompatibilities with other substances may occur with prolonged storage (e.g., bleomycin).

2 years The medicinal product must be used immediately after opening. For single use only. Dispose of any unused product. For Methotrexat “Ebewe”, the stability is tested under light protection at 25°C (room temperature) over 24 hours for the following solutions: 5% glucose solution 0.9% sodium chloride solution Solution for infusion after dilution The ready-to-use preparation has been shown to be chemically and physically stable for 28 days at 2°C to 8°C and at room temperature protected from light. From a microbiological point of view, the reconstituted preparation should be used immediately. If the reconstituted preparation is not used immediately, the user is responsible for the duration and conditions of storage. If the ready-to-use solution is not prepared under controlled and validated aseptic conditions, it should not be stored for longer than 24 hours at 2°C to 8°C.

Store below 25°C.

Store in the original packaging in order to protect from light.

 

For storage conditions after dilution of the medicinal product, see section 6.3.

Vials

Vials with/without transparent plastic containers (Onco-Safe)

 

Pack sizes:

Vials: 1 / 5 x 5 ml, 1 / 5 x 10 ml, 1 x 50 ml

 

Not all pack sizes may be marketed.

Before use, the solution must be visually inspected.

Only clear solutions, virtually free from particles, may be used.

 

Any contact of methotrexate with the skin or mucosa must be avoided!

If contaminated, the affected areas must be rinsed immediately with copious amounts of water.

 

Note for medical personnel:

As in general when handling cytostatics, extreme caution is also advised when handling methotrexate; gloves, face mask, protective clothing and air extraction if possible. Skin and mucosal contact must be avoided. Pregnant persons should avoid any contact with methotrexate.

 

Handling and disposal specifications specified for cytostatic agents must be observed.

 

Any unused medicinal product or waste material should be disposed of in accordance with national requirements.