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      v: Please be aware that this electronic product information is for testing
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timestamp:
  v: 2023-09-14T00:00:00+00:00

…
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    v: Generated Narrative: Composition d86a2475-98e1-40b6-847b-7b0b1497e5fc Language: en Profile: Composition (ePI) identifier: https://medicines.org.uk/composition/22954 status: Final type: SmPC date: 2023-09-14 00:00:00+0000 author: Organisation title: Methotrexate 2.5mg Tablets
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date:
  v: 2023-09-14T00:00:00Z
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title:
  v: Methotrexate 2.5mg Tablets
section:
  title:
    v: 1. Name of the medicinal product
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      v: Methotrexate 2.5 mg Tablets
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    v: 2. Qualitative and quantitative composition
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      v: Each tablet contains methotrexate sodium equivalent to 2.5 mg of methotrexate. Excipient(s) with known effect Lactose monohydrate- 66.166 mg per tablet For the full list of excipients, see section 6.1.
section:
  title:
    v: 3. Pharmaceutical form
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      v: Tablet Round, biconvex, yellow tablets, engraved with “2.5” on one side. Scored in half on the other side and engraved with 'M' above the score line and '1' below it. The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
section:
  title:
    v: 4. Clinical particulars
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        v: 4. Clinical particulars
  section:
    title:
      v: 4.1 Therapeutic indications
    text:
      status:
        v: generated
      div:
        v: 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. The treatment of neoplastic disease. Methotrexate has also been used in the treatment of severe cases of uncontrolled psoriasis, unresponsive to conventional therapy. It is also used in the treatment of adults with severe, active, classical or definite rheumatoid arthritis who are unresponsive or intolerant to conventional therapy.
  section:
    title:
      v: 4.2 Posology and method of administration
    text:
      status:
        v: generated
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        v: Posology Methotrexate should only be prescribed by physicians with expertise in the use of methotrexate and a full understanding of the risks of methotrexate therapy. Adults and Children Methotrexate may be given by oral, intramuscular, intravenous (bolus injection or infusion), intrathecal and intra-arterial routes of administration. Dosages are based on the patient's body weight or surface area except in the case of intrathecal administration when a maximum dose of 15 mg is recommended. Doses should be reduced in cases of haematological deficiency and hepatic or renal impairment. Larger doses (greater than 100 mg) are usually given by intravenous infusion over periods not exceeding 24 hours. Part of the dose may be given in an initial rapid intravenous injection. Methotrexate has been used with beneficial effects in a wide variety of neoplastic diseases, alone and in combination with other cytotoxic agents, hormones, radiotherapy or surgery. Dosage schedules therefore vary considerably, depending on the clinical use, particularly when intermittent high-dose regimes are followed by the administration of Calcium Leucovorin (calcium folinate) to rescue normal cells from toxic effects. Examples of doses of methotrexate that have been used for particular indications are given below Choriocarcinoma and other trophoblastic tumours: Non-metastatic gestational trophoblastic neoplasms have been treated successfully with 0.25-1 mg /kg up to a maximum of 60 mg intramuscularly every 48 hours for four doses, followed by Calcium Leucovorin rescue. This course of treatment is repeated at seven day intervals until levels of urinary chorionic gonadotrophin hormone return to normal. Not less than four courses of treatment are usually necessary. Patients with complications, such as extensive metastases, may be treated with methotrexate in combination with other cytotoxic drugs. Methotrexate has also been used in similar doses for the treatment of hydatidiform mole and chorio-adenoma …
  section:
    title:
      v: 4.3 Contraindications
    text:
      status:
        v: generated
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        v: Methotrexate is contra-indicated in the presence of: • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 • Significantly impaired hepatic function • Severe/significantly impaired renal function (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) • Liver disease including fibrosis, cirrhosis, recent or active hepatitis • Active infectious disease • Pre-existing blood dyscrasias, such as bone marrow hypoplasia, significant anaemia, leucopenia, or thrombocytopenia • Alcoholism • Severe acute or chronic infections and immunodeficiency syndrome • Stomatitis, ulcers of the oral cavity and known active gastrointestinal ulcer disease • During methotrexate therapy concurrent vaccination with live vaccines must not be carried out • Methotrexate tablets should not be used concomitantly with drugs with antifolate properties (e.g. co-trimoxazole) (see section 4.5) • 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 6 months after using Methotrexate 2.5 mg tablets (see Section 4.4).
  section:
    title:
      v: 4.4 Special warnings and precautions for use
    text:
      status:
        v: generated
      div:
        v: The prescriber should specify the day of intake on the prescription. The prescriber should make sure patients understand that Methotrexate 2.5 mg Tablets (methotrexate) should only be taken once a week. Patients should be instructed on the importance of adhering to the once- weekly intakes. Methotrexate must be used only by physicians experienced in antimetabolite Chemotherapy. Because of the possibility of fatal or severe toxicity, the physician should fully inform the patient of the risks involved and provide close medical supervision. Monitoring (prior to starting treatment) – see also below Before beginning or reinstituting methotrexate after a rest period, the patient's renal, liver and bone marrow function should be assessed by history, physical examination and laboratory tests. A chest X-ray should also be taken (see Respiratory effects below). Monitoring (during and after treatment) – see also below • During treatment patients should be appropriately supervised so that toxic signs or symptoms, or adverse reactions may be detected and evaluated with minimal delay • Full blood count (including haematocrit), hepatic and renal function tests (including urinalysis) should be carried out every week until treatment is stabilized, thereafter every 2 to 3 months throughout treatment. This will include a routine examination of lymph nodes and patients should report any unusual swelling to the doctor • More frequent check-ups be necessary when - the dose is increased - there is an increased risk of raised methotrexate blood levels (e.g. dehydration, impaired renal function, additional or increased dose of medicines, such as NSAIDs, administered concomitantly (see below & section 4.5) • Haematopoietic suppression is common and may occur without warning when a patient is on an apparently “safe” dose, so full blood counts should be closely monitored during and after treatment. If any clinically significant drop in blood cell count occurs, methotrexate should be stopped im…
  section:
    title:
      v: 4.5 Interaction with other medicinal products and other forms of interaction
    text:
      status:
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        v: Methotrexate is extensively protein bound and may displace, or be displaced by, other acidic drugs. The concurrent administration of agents such as diphenylhydantoins, acidic anti-inflammatory agents, salicylates, phenylbutazone, phenytoin, barbiturates, tranquilisers, oral contraceptives, amidopyrine derivatives, p-aminobenzoic acid, thiazidediuretics, oral hypoglycaemics, doxorubicin, tetracyclines, probenicid or sulfinpyrazone or oral hypoglycaemics will decrease the methotrexate transport function of renal tubules, thereby reducing excretion and almost certainly increasing methotrexate toxicity. Concurrent use contra-indicated Methotrexate is immunosuppressive and may therefore reduce immunological response to concurrent vaccination. Severe antigenic reactions may occur if a live vaccine is given concurrently (see sections 4.3 and 4.4). On account of its possible effect on the immune system, methotrexate can falsify vaccinal and test results (immunological procedures to record the immune reaction). Avoid concomitant use General anaesthesia – The use of nitrous oxide potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe, unpredictable myelosuppression and stomatitis and in case of intrathecal administration increased severe, unpredictable neurotoxicity. Whilst this effect can be reduced by administering calcium folinate, the concomitant use of nitrous oxide and methotrexate should be avoided. Antipsychotics – increased risk of agranulocytosis with olanzapine. Retinoids – Acitretin (a treatment for psoriasis) is metabolised to eretinate. plasma concentrations of methotrexate increased by acitretin – also increased risk of hepatotoxicity. Azopropazone – excretion of methotrexate reduced. NSAIDs (see also below) should not be administered before or concurrently with high-dose methotrexate - increased and prolonged serum methotrexate concentrations with consequent increased gastrointestinal and haematological toxicity…
  section:
    title:
      v: 4.6 Fertility, pregnancy and lactation
    text:
      status:
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        v: 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 3 months after cessation of methotrexate. Men should not donate semen during therapy or for 3 months following discontinuation of methotrexate. Pregnancy Methotrexate is contraindicated 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 …
  section:
    title:
      v: 4.7 Effects on ability to drive and use machines
    text:
      status:
        v: generated
      div:
        v: Methotrexate can cause dizziness, fatigue, blurred vision and eye-irritation, which may affect the ability to drive or operate machinery.
  section:
    title:
      v: 4.8 Undesirable effects
    text:
      status:
        v: generated
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        v: Generally the frequency and severity of adverse reactions are dependent of the size of the dose, the dosing frequency, the method of administration and the duration of exposure. If adverse reactions occur, the dose should be reduced or therapy discontinued and necessary corrective therapeutic measures undertaken, such as administration of calcium folinate (see sections 4.2 and 4.4). The most common adverse reactions of methotrexate are bone marrow suppression and mucosal damage which manifest as ulcerative stomatitis, leucopenia, nausea and other gastrointestinal disorders. These adverse reactions are generally reversible and corrected in about two weeks after the single dose of methotrexate has been reduced or dose interval increased and/or calcium folinate is used. Other frequently occurring adverse reactions include e.g. malaise, abnormal fatigue, chills and fever, dizziness and reduced immunity to infections. Methotrexate causes adverse reactions most at high and frequently repeated doses, e.g. in the treatment of cancer diseases. Adverse reactions reported on methotrexate are given below according to organ systems. The frequencies of the adverse reactions are classified as follows: Very common ( 1/10); common ( 1/100 to < 1/10); uncommon ( 1/1000 to < 1/100); rare ( 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Common Uncommon Rare Very rare Not known Infections and infestations Infections (Respiratory or cutaneous bacterial) Opportunistic infections Herpes zoster infections Sepsis Neutropenic sepsis leading to fatality Sepsis resulting in death Pneumocystiscarinii/jiroveci pneumonia and other lung infection Reactivation of inactive chronic infection. Neoplasms benign, malignant and unspecified (including cysts and polyps) Lymphoma1 Blood and lymphatic system disorders Leucopenia Bone marrow depression5(especially at high-dose of methotrexate) manifested by leucopenia and thrombocytopenia (which are usu…
  section:
    title:
      v: 4.9 Overdose
    text:
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        v: Symptoms and Management 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. 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 haematological 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. The toxicity of methotrexate affects mainly the haematopoietic organs. Calcium folinate neutralises effectively the immediate haematopoietic toxic effects of methotrexate. Parenteral calcium folinate therapy should be started within one hour after the administration of methotrexate. The dose of calcium folinate should be at least as high as the dose of methotrexate received by the patient. Symptoms of an overdose are mainly the same as the undesirable effects, but stronger Massive overdose requires hydration and alkalinisation of the urine to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Haemodialysis or peritoneal dialysis has not been found to affect the elimination of methotrexate. Instead, effective clearance of methotrexate has been achieved by intermittent haemodialysi…
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  title:
    v: 5. Pharmacological properties
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        v: 5. Pharmacological properties
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      v: 5.1 Pharmacodynamic properties
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        v: Pharmacotherapeutic group: Other immunosuppressive agents, ATC code: L04AX03. Mechanism of action Methotrexate (4-amino-10-methylfolic acid) is a folic acid antagonist which inhibits the reduction of folic acid and increase of tissue cells. Its main effect is inhibition of DNA synthesis but it also acts directly both on RNA and protein synthesis. Methotrexate enters the cell through an active transport mechanism of reduced folates. As a result of polyglutamation of methotrexate caused by the folylpolyglutamylate enzyme, the duration of the cytotoxic effect of the drug substance in the cell increases. Methotrexate is a phase-specific substance the main action of which is directed to the S-phase of cell mitosis. It acts generally most effectively on actively increasing tissues, such as malignant cells, bone marrow, fetal cells, skin epithelium, oral and intestinal mucosa as well as urinary bladder cells. As the proliferation of malignant cells is higher than that of most normal cells, methotrexate can slow down the proliferation of malignant cells without causing, irreversible damage to normal tissue. Calcium folinate is a folinic acid which is used to protect normal cells from the toxic effects of methotrexate. Calcium folinate enters the cell through a specific transport mechanism, is converted in the cell into active folates and reverses the inhibition of the precursor synthesis caused by the DNA and RNA. Methotrexate is a folic acid antagonist and its major site of action is the enzyme dihydrofolate reductase. 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.
  section:
    title:
      v: 5.2 Pharmacokinetic properties
    text:
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        v: generated
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        v: Absorption The effect of orally administered methotrexate seems to be dependent on the size of the dose. When given in low doses, methotrexate is rapidly absorbed from the GI tract giving plasma concentrations equivalent to those achieved after i.v. administration. Peak concentrations in serum are reached within 1–2 hours. Generally a dose of methotrexate of 30 mg/m2 or less is absorbed rapidly and completely. The bioavailability of orally administered methotrexate is high (80–100%) at doses of 30 mg/m2 or less. Saturation of the absorption starts at doses above 30 mg/m2 and absorption at doses exceeding 80 mg/m2 is incomplete. Distribution About one half of the absorbed methotrexate binds reversibly to serum protein, but is readily distributed in tissues. Elimination: The elimination follows a triphasic pattern. Excretion takes place mainly via the kidneys. Approximately 41% of the dose is excreted unchanged in the urine within the first six hours, 90% within 24 hours. A minor part of the dose is excreted in the bile of which there is pronounced enterohepatic circulation. The half-life is approximately 3–10 hours following low dose treatment and 8–15 hours following high dose treatment. If the renal function is impaired, the concentration of methotrexate in serum and in tissues may increase rapidly. Methotrexate does not enter the cerebrospinal fluid at oral or parenteral therapeutic doses. However, cytotoxic concentrations (>10-7 M) can be achieved in the CSF with high doses (>500 mg/m2). When high drug concentrations are indicated, direct intrathecal administration should be used.

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v: 4.1 Therapeutic indications

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v: 4.5 Interaction with other medicinal products and other forms of interaction

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v: 4.6 Fertility, pregnancy and lactation

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v: 4.7 Effects on ability to drive and use machines

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v: 4.8 Undesirable effects

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v: 4.9 Overdose

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v: 5.1 Pharmacodynamic properties

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v: 5.2 Pharmacokinetic properties

title:
  v: 5.3 Preclinical safety data
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      v: 5.3 Preclinical safety data
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    v: Chronic toxicity studies in mice, rats and dogs showed toxic effects in the form of gastrointestinal lesions, myelosuppression and hepatotoxicity. Animal studies show that methotrexate impairs fertility, and is embryo- and foetotoxic. Teratogenic effects have been identified in four species (rats, mice, rabbits, cats). In rhesus monkeys no malformations occurred. Methotrexate is mutagenic in vivo and in vitro. There is evidence that methotrexate causes chromosomal aberrations in animal cells and in human bone marrow cells, but the clinical significance of these findings has not been established. Rodent carcinogenicity studies do not indicate an increased incidence of tumours.

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      l: terms
    code:
      v: 200000029836
    display:
      v: 6. Pharmaceutical particulars
section:
  title:
    v: 6.1 List of excipients
  code:
    coding:
      system:
        v: https://spor.ema.europa.eu/v1/lists/200000029659/terms/
        l: terms
      code:
        v: 200000029837
      display:
        v: 6.1 List of excipients
  text:
    status:
      v: generated
    div:
      v: Lactose monohydrate, Magnesium Stearate, Starch Pregelatinised and Sodium Hydroxide.
section:
  title:
    v: 6.2 Incompatibilities
  code:
    coding:
      system:
        v: https://spor.ema.europa.eu/v1/lists/200000029659/terms/
        l: terms
      code:
        v: 200000029838
      display:
        v: 6.2 Incompatibilities
  text:
    status:
      v: generated
    div:
      v: Not applicable
section:
  title:
    v: 6.3 Shelf life
  code:
    coding:
      system:
        v: https://spor.ema.europa.eu/v1/lists/200000029659/terms/
        l: terms
      code:
        v: 200000029839
      display:
        v: 6.3 Shelf life
  text:
    status:
      v: generated
    div:
      v: 3 years.
section:
  title:
    v: 6.4 Special precautions for storage
  code:
    coding:
      system:
        v: https://spor.ema.europa.eu/v1/lists/200000029659/terms/
        l: terms
      code:
        v: 200000029840
      display:
        v: 6.4 Special precautions for storage
  text:
    status:
      v: generated
    div:
      v: Do not store above 25°C. Store in the original container in order to protect from light.
section:
  title:
    v: 6.5 Nature and contents of container
  code:
    coding:
      system:
        v: https://spor.ema.europa.eu/v1/lists/200000029659/terms/
        l: terms
      code:
        v: 200000029841
      display:
        v: 6.5 Nature and contents of container
  text:
    status:
      v: generated
    div:
      v: Polypropylene bottles -28 or 100 tablets HDPE bottles- 28 or 100 tablets PVC/Aluminium blisters – 24, 28 or 30 tablets Not all pack sizes may be marketed
section:
  title:
    v: 6.6 Special precautions for disposal and other handling
  code:
    coding:
      system:
        v: https://spor.ema.europa.eu/v1/lists/200000029659/terms/
        l: terms
      code:
        v: 200000029842
      display:
        v: 6.6 Special precautions for disposal and other handling
  text:
    status:
      v: generated
    div:
      v: Cytotoxic drugs should only be handled by trained personnel in a designated area. The work surface should be covered with disposable plastic-backed absorbent paper. Protective gloves and goggles should be worn to avoid the drug accidentally coming into contact with the skin or eyes. Methotrexate is not vesicant and should not cause harm if it comes in contact with the skin. It should, of course, be washed off with water immediately. Any transient stinging may be treated with bland cream. If there is any danger of systemic absorption of significant quantities of methotrexate, by any route, Calcium Leucovorin cover should be given. Cytotoxic preparations should not be handled by pregnant staff. Any spillage or waste material may be disposed of by incineration. We do not make any specific recommendations with regards to the temperature of the incinerator. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

title:
  v: 7. Marketing authorisation holder
code:
  coding:
    system:
      v: https://spor.ema.europa.eu/v1/lists/200000029659/terms/
      l: terms
    code:
      v: 200000029844
    display:
      v: 7. Marketing authorisation holder
text:
  status:
    v: generated
  div:
    v: Mercury Pharmaceuticals Ltd., Dashwood House, 69 Old Broad Street, London, EC2M 1QS, United Kingdom

title:
  v: 8. Marketing authorisation number(s)
code:
  coding:
    system:
      v: https://spor.ema.europa.eu/v1/lists/200000029659/terms/
      l: terms
    code:
      v: 200000029845
    display:
      v: 8. Marketing authorisation number(s)
text:
  status:
    v: generated
  div:
    v: PL 12762/0231

title:
  v: 9. Date of first authorisation/renewal of the authorisation
code:
  coding:
    system:
      v: https://spor.ema.europa.eu/v1/lists/200000029659/terms/
      l: terms
    code:
      v: code not found
    display:
      v: 9. Date of first authorisation/renewal of the authorisation
text:
  status:
    v: generated
  div:
    v: 27th September, 1989

title:
  v: 10. Date of revision of the text
code:
  coding:
    system:
      v: https://spor.ema.europa.eu/v1/lists/200000029659/terms/
      l: terms
    code:
      v: 200000029847
    display:
      v: 10. Date of revision of the text
text:
  status:
    v: generated
  div:
    v: 14/09/2023