This information is intended for use by health professionals

1. Name of the medicinal product

Maxtrex Tablets 10.0 mg

2. Qualitative and quantitative composition

Each tablet contains methotrexate Ph. Eur. 10.0 mg.

For excipients, see 6.1.

3. Pharmaceutical form

Tablet.

'Capsule-shaped', uncoated, convex deep yellow tablets marked with 'M10' and scored on the same side.

4. Clinical particulars
4.1 Therapeutic indications

Methotrexate is a folic acid antagonist and is classified as an antimetabolite cytotoxic agent.

Methotrexate has been used to produce regression in a wide range of neoplastic conditions including acute leukaemias, non-Hodgkin's lymphoma, soft-tissue and osteogenic sarcomas, and solid tumours particularly breast, lung, head and neck, bladder, cervical, ovarian, and testicular carcinoma.

Methotrexate has also been used in the treatment of severe, uncontrolled psoriasis which is not responsive to other therapy.

4.2 Posology and method of administration

Method of Administration: Oral.

Dosage for cancer treatment:

A test dose of 5 - 10 mg parenterally is recommended, one week prior to therapy to detect idiosyncratic adverse events. Single doses, not exceeding 30 mg/m2, on not more than 5 consecutive days. A rest period of at least two weeks is recommended between treatments, in order to allow the bone marrow to return to normal.

Doses in excess of 100 mg are usually given parenterally, when the injectable preparation should be used. Doses in excess of 70 mg/m2 should not be administered without leucovorin rescue (folinic acid rescue) or assay of serum methotrexate levels 24 - 48 hours after dosing.

If methotrexate is administered in combination chemotherapy regimens, the dosage should be reduced, taking into consideration any overlapping toxicity of the other drug components.

Important warning about the dosage of Maxtrex Tablets (methotrexate)

In the treatment of psoriasis, 10mg requiring dosing once a week e.g. dermatological diseases, Methotrexate must only be taken once a week. Dosage errors in the use of Maxtrex Tablets (methotrexate) can result in serious adverse reactions, including death. Please read this section of the summary of product characteristics very carefully.

Dosage for psoriasis:

For the treatment of severe psoriasis 10 - 25 mg orally, once a week is recommended. Dosage should be adjusted according to the patient's response and the haematological toxicity.

The prescriber should specify the day of intake on the prescription.

Use in patients with renal impairment – dose adjustments:

Methotrexate is excreted to a significant extent by the kidneys, and therefore should be used with caution in patients with impaired renal function (see sections 4.3 and 4.4). The health care provider may need to adjust the dose to prevent accumulation of drug. The table below provided recommended starting doses in renally impaired patients; dosing may need further adjustment due to wide intersubject pK variability.

Table 3 a. Dose adjustments for methotrexate doses <100 mg/m2 in patients with renal impairment

Creatinine Clearance (ml/min)

% of dose to Administer

>60

100

30-59

50

<30

Methotrexate must not be administered.

Table 3 b. Dose adjustments for methotrexate doses >100 mg/m2 in patients with renal impairment

Creatinine Clearance (ml/min)

% of dose to Administer

>80

100

= ~80

75

= ~60

63

<60

Methotrexate must not be administered.

4.3 Contraindications

Methotrexate is contra-indicated in the presence of severe/significant renal impairment (creatinine clearance less than 30 ml/min) for methotrexate doses <100 mg/m2, and moderate renal impairment (creatinine clearance less than 60 ml/min) for methotrexate doses >100 mg/m2 (see section 4.2) or significant hepatic impairment, liver disease including fibrosis, cirrhosis, recent or active hepatitis; active infectious disease; and overt or laboratory evidence of immunodeficiency syndrome(s) and serious anaemia, leucopenia or thrombocytopenia. Maxtrex should not be used concomitantly with drugs with antifolate properties (see section 4.5, Interactions with other Medicinal Products and other forms of Interaction). Methotrexate is teratogenic and should not be given during pregnancy or to mothers who are breast feeding (see Section 4.6.).

Following administration to a man or woman conception should be avoided by using an effective contraceptive method for at least 3 months after using Maxtrex Tablets 10mg (see Section 4.4 and 4.6).

Patients with a known allergic hypersensitivity to methotrexate or any of the excipients should not receive methotrexate.

4.4 Special warnings and precautions for use

It should be emphasized to the patient treated for psoriasis that the recommended dose must be taken only once a week. The prescriber should specify the day of intake on the prescription. Patients should be instructed on the importance of adhering to the once-weekly intakes, and that mistaken daily use of the recommended dose has led to fatal toxicity (see Sections 4.2 and 4.9).

Methotrexate should be used with extreme caution in patients with haematological depression, renal impairment, diarrhoea, ulcerative disorders of the GI tract and psychiatric disorders. Hepatic toxicity has been observed, usually associated with chronic hepatic disease. The administration of low doses of methotrexate for prolonged periods may give rise, in particular, to hepatic toxicity. Liver function should be closely monitored. If hepatic function abnormalities develop, methotrexate dosing should be suspended for at least two weeks. It is only appropriate to restart methotrexate provided the abnormalities return to normal and the re-exposure is deemed appropriate.

Particular care and possible cessation of treatment are indicated if stomatitis or GI toxicity occurs as haemorrhagic enteritis and intestinal perforation may result.

Reversible eosinophilic pulmonary reactions and treatment-resistant, interstitial fibrosis may occur, particularly after long-term treatment.

Methotrexate therapy in patients with impaired renal function should be undertaken with extreme caution because impairment of renal function will decrease methotrexate elimination.

Renal function should be monitored by renal function tests and urinalyses. If serum creatinine levels are increased, the dose should be reduced. If creatinine clearance is less than 30 ml/min, treatment with methotrexate should not be given. If creatinine clearance is less than 60 ml/min, methotrexate doses >100 mg/m2 not be given (see section 4.2 and 4.3).

Treatment with methotrexate doses of >100 mg/m2 should not be initiated at urinary pH values of less than 7.0. Alkalinisation of the urine must be tested by repeated pH monitoring (value greater than or equal to 6.8) for at least the first 24 hours after the administration of methotrexate is started.

Renal lesions may develop if the urinary flow is impeded and urinary pH is low, especially if large doses have been administered.

Methotrexate may cause renal damage that may lead to acute renal failure. Close attention to renal function including adequate hydration, urine alkalinization, and measurement of serum methotrexate and renal function are recommended.

As methotrexate is eliminated mainly via the kidneys, increased concentrations are to be expected in the presence of renal impairment, which may result in severe adverse reactions.

If there is the possibility of renal impairment (e.g. in elderly subjects), monitoring should take place at shorter intervals. This applies in particular when medicinal products that affect the elimination of methotrexate, or that cause kidney damage (e.g. NSAIDs) or that can potentially lead to impairment of haematopoiesis, are administered concomitantly.

If risk factors such as renal function disorders, including mild renal impairment, are present, combined administration with NSAIDs is not recommended. Dehydration may also intensify the toxicity of methotrexate.

Concomitant use of proton pump inhibitors (PPIs) and high dose methotrexate should be avoided, especially in patients with renal impairment.

Haematopoietic suppression caused by methotrexate may occur abruptly and with apparently safe dosages. Full blood counts should be closely monitored before, during and after treatment. If a clinically significant drop in white cell or platelet count develops, methotrexate therapy should be withdrawn immediately and appropriate supportive therapy given (see section 4.8, Undesirable Effects). Patients should be advised to report all symptoms or signs suggestive of infection.

Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires the initiation of cytotoxic therapy.

Methotrexate has been shown to be teratogenic – reproductive risk; it causes embryotoxicity, abortion and foetal malformations in humans. Therefore, the possible effects on reproduction, pregnancy loss and congenital malformations should be discussed with female patients of childbearing age (see section 4.6).

In non-oncologic indications, the absence of pregnancy must be confirmed before Maxtrex tablet is used. If women of a sexually mature age are treated, effective contraception must be used during treatment and for at least six months after.

For contraception advice for men see section 4.6.

If this drug is used during pregnancy for antineoplastic indications, or if the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the foetus.

Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans during and for a short period after the discontinuation of treatment, affecting spermatogenesis and oogenesis during the period of its administration - effects that appear to be reversible on discontinuing therapy.

Methotrexate has some immunosuppressive activity and therefore the immunological response to concurrent vaccination may be decreased. In addition, concomitant use of a live vaccine could cause severe antigenic reaction.

Methotrexate should only be used by clinicians that are familiar with the various characteristics of the drug and its mode of action. Before beginning methotrexate therapy or reinstituting methotrexate after a rest period, a chest x-ray, assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests. This will include a routine examination of lymph nodes and patients should report any unusual swelling to the doctor.

Patients receiving low-dose methotrexate should:

• Have a full blood count and renal and liver function tests before starting treatment. These should be repeated weekly until therapy is stabilised, thereafter patients should be monitored every 2-3 months throughout treatment.

• Patients should report all symptoms and signs suggestive of infection, especially sore throat.

If acute methotrexate toxicity occurs, patients may require treatment with folinic acid.

The disappearance of methotrexate from plasma should be monitored, if possible. This is recommended in particular when high, or very high doses are administered in order to permit calculation of an adequate dose of leucovorin (folinic acid) rescue.

Patients with pleural effusions and ascites should be drained prior to initiation of methotrexate therapy. A chest x-ray is recommended prior to initiation of methotrexate therapy or treatment should be withdrawn.

Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

Acute or chronic pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnoea, cough (especially a dry productive cough) and fever for which patients should be monitored at each follow-up visit. Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop persistent cough or dyspnoea.

In addition, pulmonary alveolar haemorrhage has been reported with MTX used in rheumatologic and related indications. This event may also be associated with vasculitis and other comorbidities. Prompt investigations should be considered when pulmonary alveolar haemorrhage is suspected to confirm the diagnosis.

Methotrexate should be withdrawn from patients with pulmonary symptoms, and a thorough investigation should be made to exclude infection. If methotrexate induced lung disease is suspected, treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted.

Lung manifestations of RA and other connective tissue disorders are recognised to occur. In patients with RA, the physician should be specifically alerted to the potential for methotrexate induced adverse effects on the pulmonary system.

4.5 Interaction with other medicinal products and other forms of interaction

Methotrexate is immunosuppressive and may therefore reduce immunological response to concurrent vaccination. Severe antigenic reactions may occur if a live vaccine is given concurrently.

Methotrexate is extensively protein bound and may displace, or be displaced by, other acidic drugs. The concurrent administration of agents such as p-aminobenzoic acid, chloramphenicol, penicillines, ciprofloxacin, diphenylhydantoins, phenytoin, acidic anti-inflammatory agents, salicylates, sulphonamides, tetracyclines, thiazide diuretics, probenicid, sulfinpyrazone or oral hypoglycaemics will decrease the methotrexate transport function of renal tubules, thereby reducing excretion and almost certainly increasing methotrexate toxicity. Methotrexate dosage should be monitored if concomitant treatment with aspirin, ibuprofen or indometacin (NSAIDs) is commenced, as concomitant use of NSAID's has been associated with fatal methotrexate toxicity.

Concomitant administration of folate antagonists such as trimethoprim, co-trimoxazole and nitrous oxide should be avoided. The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe unpredictable myelosuppression, stomatitis and neurotoxicity with intrathecal administration. While this effect can be reduced by administering calcium folinate, the concomitant use of nitrous oxide and methotrexate should be avoided (see section 4.2).

Hepatic and nephrotoxic drugs should be avoided.

Acitretin (a treatment for psoriasis) is metabolised to eretinate. Methotrexate levels may be increased by eretinate and severe hepatitis has been reported following concomitant use.

Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs.

Vitamin preparations containing folic acid or its derivatives may alter response to methotrexate.

4.6 Fertility, pregnancy and lactation

Fertility

Methotrexate affects spermatogenesis and oogenesis and may decrease fertility. In humans, Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea. These effects appear to be reversible after discontinuation of therapy in most cases.

In oncologic indications, women who are planning to become pregnant are advised to consult a genetic counselling centre, if possible, prior to therapy and men should seek advice about the possibility of sperm preservation before starting therapy as methotrexate can be genotoxic at higher doses (see section 4.4).

Women of childbearing potential/Contraception in females

Women must not get pregnant during methotrexate therapy, and effective contraception must be used during treatment with methotrexate and at least 6 months thereafter (see section 4.4). Prior to initiating therapy, women of childbearing potential must be informed of the risk of malformations associated with methotrexate and any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. a pregnancy test. During treatment pregnancy tests should be repeated as clinically required (e.g. after any gap of contraception). Female patients of reproductive potential must be counselled regarding pregnancy prevention and planning.

Contraception in males

It is not known if methotrexate is present in semen. Methotrexate has been shown to be genotoxic in animal studies, such that the risk of genotoxic effects on sperm cells cannot completely be excluded. Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to low-dose methotrexate (less than 30 mg/week). For higher doses, there is insufficient data to estimate the risks of malformations or miscarriage following paternal exposure.

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

Pregnancy

Methotrexate is contra-indicated during pregnancy in non-oncological indications (see section 4.3).

If pregnancy occurs during treatment with methotrexate and up to six months thereafter, medical advice should be given regarding the risk of harmful effects on the child associated with treatment and ultrasonography examinations should be performed to confirm normal foetal development.

In animal studies, methotrexate has shown reproductive toxicity, especially during the first trimester (see section 5.3). Methotrexate has been shown to be teratogenic to humans; it has been reported to cause foetal death, miscarriages and/or congenital abnormalities (e.g. craniofacial, cardiovascular, central nervous system and extremity-related).

Methotrexate is a powerful human teratogen, with an increased risk of spontaneous abortions, intrauterine growth restriction and congenital malformations in case of exposure during pregnancy.

Spontaneous abortions have been reported in 42.5% of pregnant women exposed to low-dose methotrexate treatment (less than 30 mg/week), compared to a reported rate of 22.5% in disease-matched patients treated with drugs other than methotrexate.

Major birth defects occurred in 6.6% of live births in women exposed to low-dose methotrexate treatment (less than 30 mg/week) during pregnancy, compared to approximately 4% of live births in in disease-matched patients treated with drugs other than methotrexate.

Insufficient data is available for methotrexate exposure during pregnancy higher than 30 mg/week, but higher rates of spontaneous abortions and congenital malformations are expected, in particular at doses commonly used in oncologic indications.

When methotrexate was discontinued prior to conception, normal pregnancies have been reported.

When used in oncological indications, methotrexate should not be administered during pregnancy in particular during the first trimester of pregnancy. In each individual case the benefit of treatment must be weighed up against the possible risk to the foetus. If the drug is used during pregnancy or if the patient becomes pregnant while taking methotrexate, the patient should be informed of the potential risk to the foetus.

Breast-feeding

Patients should not breast feed whilst taking methotrexate.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

In general, the incidence and severity of side effects are considered to be dose-related. Adverse reactions for the various systems are as follows:

Skin:

Stevens-Johnson Syndrome, epidermal necrolysis, erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration in psoriatic patients and rarely painful erosion of psoriatic plaques has been reported. The recall phenomenon has been reported in both radiation and solar damaged skin.

Haematopoietic:

Bone marrow depression is most frequently manifested by leucopenia, thrombocytopenia (which are usually reversible) and anaemia, lymphoproliferative disorders frequency very rare), or any combination may occur. Infection or hypogammaglobulinaemia has been reported.

Alimentary System:

Mucositis (most frequently stomatitis although gingivitis, pharyngitis and even enteritis, intestinal ulceration and bleeding) may occur. In rare cases the effect of Methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon. Nausea, anorexia and vomiting and/or diarrhoea may also occur.

Hepatic:

Hepatic toxicity resulting in significant elevations of liver enzymes, acute liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis or cirrhosis or death may occur, usually following chronic administration.

Urogenital System:

Renal failure and uraemia may follow methotrexate administration, particularly after high doses or prolonged administration. Vaginitis, vaginal ulcers, cystitis, haematuria and nephropathy have also been reported. Methotrexate can decrease fertility. This effect appears to be reversible after discontinuation of therapy (see section 4.6, Pregnancy and Lactation).

Pulmonary System:

Infrequently an acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Acute pulmonary oedema has also been reported after oral and intrathecal use. Pulmonary fibrosis is rare. A syndrome consisting of pleuritic pain and pleural thickening has been reported following high doses.

Epistaxis (frequency not known) has been reported. Pulmonary alveolar haemorrhage (frequency not known) has been reported for methotrexate used in rheumatologic and related indications.

In the treatment of rheumatoid arthritis, methotrexate induced lung disease is a potentially serious adverse drug reaction which may occur acutely at any time during therapy. It is not always fully reversible. Pulmonary symptoms (especially a dry, non productive cough) may require interruption of treatment and careful investigation.

Musculoskeletal, Connective tissue and Bone disorders:

Osteonecrosis of jaw (frequency not known) (secondary to lymphoproliferative disorders)

Central Nervous System:

Headaches, drowsiness, ataxia and blurred vision have occurred following low doses of methotrexate, transient subtle cognitive dysfunction, mood alteration, or unusual cranial sensations have been reported occasionally. Aphasia, paresis, hemiparesis, and convulsions have also occurred following administration of higher doses.

There have been reports of leucoencephalopathy following intravenous methotrexate in high doses, or low doses following cranial-spinal radiation.

Other reports include eye irritation, malaise, undue fatigue, vasculitis, sepsis, arthralgia/myalgia, chills and fever, dizziness, loss of libido/impotence and decreased resistance to infection. Also opportunistic infections such as herpes zoster. Osteoporosis, abnormal (usually "megaloblastic") red cell morphology, precipitation of diabetes, other metabolic changes, and sudden death in relation to or attributed to the use of methotrexate.

Although very rare, anaphylactic reactions to methotrexate have been reported.

Acute or chronic interstitial pneumonitis, often associated with blood eosinophila, may occur and deaths have been reported (see Section 4.4, Special Warnings and Special Precautions for Use).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Leucovorin is a specific antidote for methotrexate and, following accidental overdosage, should be administered within one hour at a dosage equal to, or greater than, the methotrexate dose. It may be administered by i.v. bolus or infusion. Further doses may be required. The patient should be observed carefully and blood transfusions, renal dialysis and reverse barrier nursing may be necessary.

In post-marketing experience, overdose with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose has also been reported.

Cases of overdose have been reported, sometimes fatal, due to erroneous daily intake instead of weekly intake of oral methotrexate. In these cases, symptoms that have been commonly reported are hematological and gastrointestinal reactions. For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no symptoms were reported. There have been reports of death following chronic overdose in the self-administered dosage for rheumatoid arthritis and psoriasis (see Sections 4.2 and 4.4). In these cases, events such as sepsis or septic shock, renal failure, and aplastic anaemia were also reported.

In cases of massive overdose, hydration and urinary alkalisation may be necessary to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Neither haemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser.

Cases of overdose, sometimes fatal, due to erroneous daily intake instead of weekly intake of oral methotrexate have been reported. In these cases, symptoms that have been commonly reported are haematological and gastrointestinal reactions.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Methotrexate is a folic acid antagonist and its major site of action is the enzyme dihydrofolate reductase. Its main effect is inhibition of DNA synthesis but it also acts directly both on RNA and protein synthesis. Methotrexate is a phase specific substance, the main effect being directed during the S-phase of cell division.

The inhibition of dihydrofolate reductase can be circumvented by the use of leucovorin (folinic acid; citrovorum factor) and protection of normal tissues can be carried out by properly timed administration of leucovorin calcium.

5.2 Pharmacokinetic properties

When given in low doses, methotrexate is rapidly absorbed from the GI tract giving plasma concentrations equivalent to those achieved after i.v. administration. Higher doses are less well absorbed. About 50% has been shown to be protein bound. Biphasic and triphasic plasma clearance has been shown. The majority of the dose is excreted within 24 hours in the urine mainly as unchanged drug.

5.3 Preclinical safety data

No further preclinical safety data are available.

6. Pharmaceutical particulars
6.1 List of excipients

Maize starch

Lactose

Pregelatinised starch

Polysorbate 80

Microcrystalline cellulose

Magnesium stearate

Purified water

6.2 Incompatibilities

None stated.

6.3 Shelf life

60 months.

6.4 Special precautions for storage

None stated.

6.5 Nature and contents of container

White high density polyethylene container with high density polyethylene screw closure containing 100 tablets.

6.6 Special precautions for disposal and other handling

None.

7. Marketing authorisation holder

Pfizer Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

8. Marketing authorisation number(s)

PL 00057/1009

9. Date of first authorisation/renewal of the authorisation

17 July 2002

10. Date of revision of the text

09/2018

Legal category: POM

Ref: MX 14_2