Methotrexate

Methotrexate is a folic acid antagonist that, as an antimetabolite, belongs to the class of cytotoxic active substances. By competitive inhibition of dihydrofolate reductase it inhibits DNA synthesis. Highly proliferating tissue (malignant cells, bone marrow, foetal cells, skin epithelium and mucosa) is generally more sensitive to this effect.

Mechanism of Action

• Folate antagonism: methotrexate competitively inhibits dihydrofolate reductase, the enzyme that keeps cells supplied with the reduced folate needed to build nucleotides, and so blocks DNA synthesis and cell division.
• Polyglutamates: inside cells methotrexate is converted by folylpolyglutamate synthase into methotrexate polyglutamates, which also inhibit other folate-dependent enzymes of nucleotide synthesis (such as thymidylate synthase and AICAR transformylase). They collect in the liver, kidneys and spleen and can be retained for weeks or months; gamma-glutamyl hydrolase converts them back to methotrexate.
• Cancer: cell proliferation is usually greater in malignant tumours than in normal tissue, so methotrexate can exert a sustained effect on malignant growth without causing irreversible damage to normal tissue.
• Psoriasis: epithelial cell proliferation is markedly increased in psoriatic skin, which is the starting point for its use in severe, treatment-resistant psoriasis and psoriatic arthritis.
• Inflammatory arthritis: it has not been clarified whether the benefit in psoriasis, psoriatic arthritis and chronic polyarthritis comes from an anti-inflammatory or immunosuppressive action, or in part from a rise in extracellular adenosine at inflamed sites. In rheumatoid arthritis the polyglutamates inhibit AICAR transformylase, so adenosine builds up outside cells and acts on adenosine receptors to dampen inflammation.

Pharmacokinetics

• Absorption: after oral doses the mean bioavailability is about 70% at low doses (7.5 to 80 mg/m² body surface area), but it varies widely between and within patients (25–100%). Peak serum levels occur within 1–2 hours. Oral absorption is saturable, so bioavailability falls at oral doses above about 25 mg. When a patient changes from oral to subcutaneous use, a dose reduction may be needed because oral bioavailability is variable. In children with juvenile idiopathic arthritis, oral bioavailability was greater when fasting.
• Distribution: about 50% is bound to serum proteins and the volume of distribution at steady state is about 1 L/kg. After distribution it collects mainly in the liver, kidneys and spleen as polyglutamates. It crosses the placental barrier in rats and monkeys.
• Metabolism: about 10% of a dose is metabolised in the liver; the main metabolite is 7-hydroxymethotrexate.
• Elimination: mostly excreted unchanged by the kidneys through glomerular filtration and active secretion in the proximal tubule. About 5–20% of methotrexate and 1–5% of 7-hydroxymethotrexate is excreted in bile, with marked enterohepatic circulation. The mean terminal half-life is 6–7 hours, with wide variation (3–17 hours).
• Special populations: elimination is markedly delayed in renal impairment. In patients with fluid collections such as pleural effusion or ascites (a third distribution compartment), the half-life can be prolonged up to four-fold. The effect of hepatic impairment on elimination is not known. In children with juvenile idiopathic arthritis, exposure rose with age and was lower than in adults.

The indications differ slightly between products. Each is listed below with the product whose SmPC states it (Jylamvo and Nordimet are centrally authorised; Metoject and Bertanel are authorised in Spain).

Rheumatological, dermatological and bowel disease (low-dose, once-weekly use)

• Rheumatoid arthritis: active rheumatoid arthritis in adults.
• Juvenile idiopathic arthritis (JIA): polyarthritic forms of active, severe JIA when the response to non-steroidal anti-inflammatory drugs (NSAIDs) has been inadequate. The Jylamvo SmPC covers adolescents and children aged 3 years and over.
• Psoriasis and psoriatic arthritis: in the Jylamvo, Metoject and Bertanel SmPCs, severe, treatment-refractory, disabling psoriasis that does not respond sufficiently to other forms of treatment such as phototherapy, PUVA (psoralen and ultraviolet A) therapy and retinoids, and severe psoriatic arthritis in adults. In the Nordimet SmPC, moderate to severe plaque psoriasis in adults who are candidates for systemic therapy, and severe psoriatic arthritis in adults.
• Crohn’s disease (injections only): Nordimet is indicated for induction of remission in moderate steroid-dependent Crohn’s disease in adults, in combination with corticosteroids, and for maintenance of remission, as monotherapy, in patients who have responded to methotrexate. The Spanish Metoject SmPC lists mild to moderate Crohn’s disease, alone or with corticosteroids, in adults who are refractory or intolerant to thiopurines.

Oncology

• Acute lymphoblastic leukaemia (ALL): maintenance treatment in adults, adolescents and children aged 3 years and over (Jylamvo).
• Other nationally authorised methotrexate medicines are also used in oncology, for example in lymphoma, osteosarcoma and breast cancer, under the indications of their own national SmPCs. Those higher-dose regimens are not covered on this page.

• Hypersensitivity to methotrexate or to any of the excipients.
• Hepatic impairment with bilirubin above 5 mg/dL (85.5 µmol/L).
• Alcohol abuse.
• Severe renal impairment (creatinine clearance below 30 mL/min). The Spanish Bertanel SmPC sets a stricter limit of below 60 mL/min.
• Pre-existing blood disorders such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anaemia.
• Immunodeficiency.
• Severe, acute or chronic infections such as tuberculosis and HIV.
• Stomatitis, ulcers of the oral cavity and known active gastrointestinal ulcers.
• Breast-feeding.
• Concurrent vaccination with live vaccines.
• Pregnancy, in all non-oncological uses (rheumatological, dermatological and bowel disease).

The incidence and severity of side effects depend on the dose and how often it is given, but serious reactions can occur even at low doses, which is why close monitoring is essential. The most frequent are gastrointestinal disorders and abnormal liver tests. The frequencies below follow the injection SmPCs (Nordimet and Metoject) and the safety summary shared by all the SmPCs; the Jylamvo oral solution SmPC arranges its table differently.

Very common (≥1/10): gastrointestinal disorders (stomatitis, dyspepsia, abdominal pain, nausea, loss of appetite) and abnormal liver function tests (raised alanine aminotransferase, aspartate aminotransferase, bilirubin and alkaline phosphatase).

Common (≥1/100 to <1/10): leukopenia, anaemia, thrombocytopenia; headache, tiredness, drowsiness; pneumonia, interstitial alveolitis or pneumonitis (often with eosinophilia); oral ulcers, diarrhoea; rash (exanthema), erythema, pruritus.

Uncommon (≥1/1,000 to <1/100): pharyngitis; pancytopenia; precipitation of diabetes mellitus; depression, confusion; dizziness.

Rare (≥1/10,000 to <1/1,000): infections (including reactivation of inactive chronic infections), sepsis, conjunctivitis; allergic reactions, anaphylactic shock, hypogammaglobulinaemia; mood alterations; visual disturbances; pericarditis, pericardial effusion, pericardial tamponade; hypotension, thromboembolic events.

Very rare (<1/10,000): lymphoma, lymphoproliferative disorders; agranulocytosis, severe bone marrow depression; pain, muscular asthenia, paraesthesia or hypoaesthesia, altered taste (metallic taste), convulsions, meningism, acute aseptic meningitis, paralysis; impaired vision, retinopathy.

Not known: eosinophilia; encephalopathy or leukoencephalopathy.

The full SmPC tables list further reactions, including skin, kidney, liver and reproductive-system effects. The most serious reactions are bone marrow suppression, lung toxicity, liver toxicity, kidney toxicity, nervous system toxicity, thromboembolic events, anaphylactic shock and Stevens-Johnson syndrome. Opportunistic infections, including Pneumocystis jirovecii pneumonia, can be fatal. In cancer treatment the main dose-limiting effects are bone marrow suppression and mucositis: mucositis generally appears about 3 to 7 days after a dose, with falls in white cells and platelets a few days later, and both usually reverse within 14 to 28 days when elimination is normal. Most reactions are reversible if found early; the dose is then reduced or treatment stopped.

Methotrexate is cleared mainly by the kidneys and is toxic to the bone marrow and liver, so medicines that reduce its clearance or add to those toxicities need particular care.

• NSAIDs and salicylates: they can raise methotrexate levels and toxicity, especially with impaired kidney function and when given within 24 hours of each other. If they are combined, blood count and renal function should be monitored. In rheumatoid arthritis, NSAIDs can be continued with low-dose methotrexate under close medical supervision, but the combination is not recommended when risk factors such as mild renal impairment are present.
• Other hepatotoxic medicines (leflunomide, azathioprine, sulfasalazine, retinoids such as acitretin and etretinate): watch closely for increased liver toxicity. With leflunomide, pancytopenia and liver toxicity may also be more frequent.
• Alcohol: avoid it. Regular alcohol use together with other hepatotoxic medicines increases the likelihood of liver reactions.
• Other medicines toxic to the blood increase the likelihood of severe blood toxicity. Metamizole can add to the haematotoxic effect of methotrexate, especially in elderly patients, and the combination should be avoided.
• Nitrous oxide: it potentiates the effect of methotrexate on folate metabolism, causing severe, unpredictable bone marrow suppression and stomatitis. Avoid the combination.
• Oral antibiotics (tetracyclines, chloramphenicol, non-absorbable broad-spectrum antibiotics): they can interfere with the enterohepatic circulation of methotrexate.
• Folic acid and folinic acid products: vitamin preparations containing them may reduce the effectiveness of methotrexate, although folic acid supplementation is part of the weekly regimen (see Administration and Dosage).
• Live vaccines: contraindicated. Methotrexate may also weaken the response to other vaccines.
• Other medicines: probenecid, penicillins, sulfonamides, sulfamethoxazole/trimethoprim (co-trimoxazole) and proton-pump inhibitors are known to reduce methotrexate clearance or add to its toxicity. The SmPC should be checked, and the prescriber told about every medicine in use, including non-prescription ones.
• Food and drink: the oral solution can be taken with or without food. DrugBank also advises avoiding alcohol, limiting caffeine (which may reduce effectiveness) and taking care with St John’s wort, and notes that milk and dairy products may reduce absorption.

Methotrexate must be prescribed and supervised by physicians with expertise in its use and a full understanding of its risks. Its two main uses are different regimens and must never be confused: low-dose, once-weekly treatment of arthritis, psoriasis and Crohn’s disease, and cancer treatment (maintenance therapy of acute lymphoblastic leukaemia) on a protocol set by an oncology specialist. This page describes the oral solution (Jylamvo) and the injections (Nordimet, Metoject, Bertanel). Methotrexate is also authorised nationally in other forms in some member states, for example tablets. Their strengths and instructions are in the national SmPC, and the once-weekly rule for rheumatological and dermatological use applies to them in the same way.

Once-Weekly Rule (Rheumatological, Dermatological and Crohn’s Disease Use)

• Once a week only, never daily. Dosage errors can result in serious adverse reactions, including death.
• The prescriber makes sure the patient or carer can follow a weekly regimen and writes the day of intake on the prescription. A fixed day of the week is chosen for each dose.
• The weekly dose should not exceed 25 mg (12.5 mL of the oral solution). Doses above 20 mg (10 mL) a week are linked to a substantial increase in toxicity, above all bone marrow depression.
• With the oral solution, folic acid 5 mg twice weekly (not on the day of methotrexate) is given in addition. With the injections, folic or folinic acid may be considered according to current guidelines.

Oral Solution (Jylamvo): Rheumatological and Dermatological Doses

The solution contains 2 mg of methotrexate per mL. The dosing syringe is marked in mL, not mg, so the prescription must state the correct volume (7.5 mg is 3.75 mL).

• Rheumatoid arthritis (adults): start with 7.5 mg (3.75 mL) once a week. Depending on disease activity and tolerability, increase by 2.5 mg (1.25 mL) per week. A response is expected after about 4–8 weeks. Once the desired effect is reached, reduce gradually to the lowest effective maintenance dose; symptoms may return after stopping.
• Polyarthritic juvenile idiopathic arthritis: 10–15 mg/m² body surface area per week (5–7.5 mL/m²); in therapy-refractory cases up to 20 mg/m² per week (10 mL/m²), with more frequent monitoring. These patients should always be referred to a rheumatology unit specialising in children and adolescents.
• Severe psoriasis and psoriatic arthritis (adults): a test dose of 2.5–5 mg (1.25–2.5 mL) is given one week before starting, and treatment begins if laboratory tests a week later are normal. The starting dose is 7.5 mg (3.75 mL) once a week, increased gradually but in general not above 25 mg a week; the usual dose is 10–25 mg (5–12.5 mL) once a week. A response is generally expected after about 4–8 weeks, after which the dose is reduced gradually to the lowest effective maintenance dose.
• These conditions need long-term treatment.

Oral Solution (Jylamvo): Oncology, Maintenance Treatment of ALL

• Low-dose methotrexate is used as maintenance treatment of ALL in children aged 3 years and over, adolescents and adults, within complex protocols together with other cytostatic medicines. Treatment follows current therapy protocols.
• Commonly accepted single doses are 20–40 mg/m² body surface area (10–20 mL/m²). When methotrexate is combined with chemotherapy regimens, the dose takes account of overlapping toxicity from the other medicines. Higher doses are given parenterally.
• Doses are usually based on body surface area, and maintenance treatment is long-term. In children, methotrexate is used with caution and follows currently published paediatric protocols.
• The weekly 25 mg ceiling above belongs to the rheumatological and dermatological regimen; oncology doses are set by the protocol, not by that limit.
• High-dose regimens used in other cancers are specialist protocols and are not described here.

Injections (Pre-Filled Pens and Syringes)

• Nordimet (subcutaneous): used once a week only. The first injection is given under direct medical supervision, and patients must be trained in the injection technique before injecting themselves. In rheumatoid arthritis, start with 7.5 mg once a week subcutaneously; the dose may be increased depending on disease activity and tolerability, in general not above 25 mg a week (doses above 20 mg a week bring significantly more toxicity, especially bone marrow suppression). A response is expected after about 4–8 weeks, and the dose is then reduced gradually to the lowest effective maintenance dose. In plaque psoriasis and psoriatic arthritis, a test dose of 5–10 mg is given subcutaneously one week before starting to detect idiosyncratic reactions, then 7.5 mg once a week, increased gradually and in general not above 25 mg a week. Dosing for juvenile idiopathic arthritis and Crohn’s disease is set out in section 4.2 of the Nordimet SmPC.
• Metoject (Spain): given subcutaneously once a week. Healthcare professionals routinely give the injection; in selected cases the doctor may leave it to the patient, who must be trained, and the first injection is given under direct medical supervision. A fixed day of the week is recommended. In rheumatoid arthritis, 7.5 mg once a week, increased by 2.5 mg a week according to disease activity and tolerability, in general not above 25 mg a week.
• Bertanel (Spain): once a week by subcutaneous, intramuscular or intravenous injection, with the day of administration written on the prescription. Healthcare professionals routinely give it; self-injection after detailed instruction is possible in some cases, with the first injection under direct medical supervision. In rheumatoid arthritis, a parenteral test dose is recommended a week before starting, then 7.5 mg once a week, increased by 2.5 mg a week. The average weekly dose is 15–20 mg, and 25 mg a week must not be exceeded.

Dose Adjustments and Special Populations

• Renal impairment (rheumatoid arthritis, juvenile arthritis, psoriasis, psoriatic arthritis; for oncology, published protocols also apply): creatinine clearance above 60 mL/min, full dose; 30–59 mL/min, 50% of the dose; below 30 mL/min, methotrexate must not be given.
• Hepatic impairment: use only with the greatest caution, if at all, in significant existing or previous liver disease, especially alcohol-related; contraindicated if bilirubin is above 5 mg/dL (85.5 µmol/L).
• Elderly (65 years and over): consider a lower dose because of reduced liver and kidney function and low folate reserves, and monitor closely for early signs of toxicity.
• Fluid collections (pleural effusion, ascites): the half-life can be prolonged four-fold, so the dose may need reducing and sometimes treatment stopping, decided case by case. Effusions and ascites should be drained before treatment starts.
• Children: doses are based on body surface area. Use below 3 years of age is not recommended because of insufficient data.
• Oral route not working: if the oral solution is ineffective, a change to intramuscular or subcutaneous methotrexate is indicated; this is also recommended when oral absorption is inadequate or the oral form is poorly tolerated.

Method of Administration

• Oral solution: for oral use only, with or without food. It is ready to use; swallow it with some water to clear any residue from the mouth. Measure the dose with the 10 mL oral dosing syringe supplied.
• Injections: subcutaneous (Bertanel also intramuscular or intravenous), as described above.

Missed Dose

The Jylamvo SmPC gives no missed-dose rule. Because the regimen is weekly, the patient should ask the prescriber or pharmacist what to do rather than taking extra doses to catch up.

Once-Weekly Dosing: Risk of Fatal Errors

Patients with rheumatological or dermatological diseases must be told unequivocally that the treatment is taken once a week and not daily. Incorrect use can cause severe and even fatal adverse reactions, so medical staff and patients must be clearly instructed, and patients must be able to follow the weekly schedule. Patients should tell their doctor immediately if any symptom of overdose occurs. EU-level safety measures in 2019 added once-weekly warnings to the packs of methotrexate medicines. With the oral solution, the syringe scale is in mL, not mg, so the prescribed volume must be checked.

Pregnancy, Contraception, Breastfeeding and Fertility

Condition for rheumatological, dermatological and bowel disease use: pregnancy must be excluded before treatment starts, and effective contraception must be used during treatment and for at least 6 months after the last dose.

• Pregnancy: contraindicated in non-oncological uses. Methotrexate causes embryotoxicity, miscarriage and foetal malformations in humans.
• Women who can become pregnant: they must be told of the malformation risk before starting, and any existing pregnancy must be excluded with certainty, for example by a pregnancy test. Tests are repeated during treatment as clinically needed (for example after any gap in contraception). Women must not become pregnant during treatment.
• Men: it is not known whether methotrexate is present in semen, and it is genotoxic in animal studies. Limited clinical evidence does not point to a higher risk of malformations or miscarriage after paternal exposure to low-dose methotrexate (below 30 mg a week); for higher doses there are insufficient data. As a precaution, sexually active men or their female partners should use reliable contraception during treatment and for at least 3 months after stopping, and men should not donate semen during treatment or for 3 months afterwards.
• Oncology use: pregnancy is not among the listed contraindications for the oncology indication; see section 4.6 of the SmPC for use in pregnancy in this indication.
• Breastfeeding: contraindicated.
• Fertility: methotrexate has been reported to impair fertility and to cause oligospermia, menstrual dysfunction and amenorrhoea during and shortly after treatment, affecting sperm and egg formation. These effects appear to be reversible after stopping.

Monitoring and Safety Tests

• Before starting, or restarting after a break: complete blood count with differential and platelets, liver enzymes, bilirubin, serum albumin, chest X-ray and kidney function tests. Tuberculosis and hepatitis B and C are excluded if clinically indicated.
• During treatment: the tests are repeated weekly for the first two weeks, then every two weeks for a month, then, depending on the white cell count and the patient’s stability, at least monthly for the next six months and at least every three months after that. Monitoring is more frequent after a dose increase, and elderly patients need short intervals.
• What is checked: the mouth and throat for mucosal changes, blood counts, liver function, kidney function with urinalysis, and lung symptoms with lung function tests if needed.
• Higher-risk patients: particularly strict monitoring is needed after earlier radiotherapy (especially of the pelvis), with impaired blood formation (for example after earlier chemotherapy or radiotherapy), in poor general condition, in advanced age and in very young children.

Bone Marrow and Infections

Methotrexate can suppress blood formation abruptly, even at apparently safe doses. A serious fall in white cell or platelet counts means treatment is stopped immediately and supportive treatment given. Patients should report any sign of infection. Opportunistic infections, including Pneumocystis jirovecii pneumonia (which can be fatal), can occur, and it should be considered in any patient with lung symptoms. Inactive chronic infections (herpes zoster, tuberculosis, hepatitis B or C) may be reactivated, so extra caution is needed.

Liver

• Treatment should not be started, or should be stopped, when liver function tests, non-invasive tests for liver fibrosis or liver biopsy show persistent or significant abnormalities.
• Transaminase rises to two or three times the upper limit of normal occur temporarily in 13–20% of patients. A persistent rise, or a fall in serum albumin, can signal severe liver toxicity, and a dose reduction or stopping should be considered.
• Fibrosis and, more rarely, cirrhosis can develop without abnormal liver tests, so non-invasive methods of assessing the liver are considered alongside the tests, and a biopsy on an individual basis. Risk factors include heavy past alcohol use, persistent enzyme elevation, liver disease, a family history of hereditary liver disorders, diabetes, obesity, earlier exposure to liver-toxic drugs or chemicals, and long treatment.
• Alcohol should be avoided, and other hepatotoxic medicines should not be added unless clearly necessary. Extra care is needed in insulin-dependent diabetes, where cirrhosis has developed in isolated cases without raised transaminases.

Kidneys and Dehydration

Because methotrexate is cleared mainly by the kidneys, renal impairment leads to higher levels and may cause severe reactions. Kidney function is checked by tests and urinalysis, the dose is reduced if serum creatinine rises, and methotrexate is not given at a creatinine clearance below 30 mL/min. Monitoring is more frequent where renal impairment is possible, for example in elderly patients or with medicines that affect elimination or damage the kidney (such as NSAIDs). Dehydration from vomiting, diarrhoea or stomatitis increases toxicity, and treatment is stopped until it has resolved. For moderately high and high doses, treatment should not be started at a urinary pH below 7.0, and urine alkalinisation (pH of 6.8 or more) is checked repeatedly for at least the first 24 hours.

Lungs

Methotrexate-induced lung disease, such as pneumonitis or interstitial pneumonia (often with blood eosinophilia), can occur acutely at any time and at any dose, including 7.5 mg a week. It is not always completely reversible and deaths have been reported. Warning signs are a dry, non-productive cough, fever, breathlessness or low blood oxygen. Patients should contact their doctor immediately about a persistent cough or breathlessness. Treatment is stopped and infection and tumour are excluded (including a chest X-ray); corticosteroids are started if methotrexate lung disease is suspected, and methotrexate is not restarted. Pulmonary alveolar haemorrhage has also been reported in rheumatological use. Particular caution is needed in patients with impaired lung function.

Digestive Tract

Diarrhoea and ulcerative stomatitis can be signs of toxicity and require stopping treatment; otherwise haemorrhagic enteritis and death from intestinal perforation may occur. Treatment must also stop after vomiting of blood, black stools or blood in the stools.

Skin and Sun

Severe, sometimes fatal skin reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome, have been reported after single or repeated doses, and epidermal necrosis can mimic them. Patients should seek medical help immediately if signs appear; methotrexate is withdrawn at once and not restarted unless these reactions have been excluded. Photosensitivity (an exaggerated sunburn reaction) can occur: intense sunlight and UV rays should be avoided unless medically indicated, and sun protection used. Radiation-induced dermatitis and sunburn can reappear (recall reactions), and psoriatic lesions can worsen with UV exposure and methotrexate.

Nervous System

Encephalopathy and leukoencephalopathy have occurred in cancer patients treated with methotrexate and cannot be ruled out in other indications. Progressive multifocal leukoencephalopathy (PML), which can be fatal, has been reported, mostly with other immunosuppressive medicines; it should be considered in immunosuppressed patients with new or worsening neurological symptoms.

Immune System, Vaccines and Lymphoma

Methotrexate may weaken the response to vaccination and affect immunological tests, and live vaccines must not be given. Malignant lymphomas may occur with low-dose methotrexate; treatment is then stopped, and cytotoxic treatment is started if the lymphoma does not regress on its own.

Folic Acid, Folinic Acid and Vitamin B12

Acute methotrexate toxicity may need treatment with folinic acid. In rheumatoid arthritis and psoriasis, folic or folinic acid supplements may reduce toxicity such as digestive symptoms, stomatitis, hair loss and raised liver enzymes. Vitamin B12 levels should be checked before folic acid is started, particularly in people over 50, because folic acid can mask a B12 deficiency. Vitamin products containing folic acid, folinic acid or their derivatives may reduce the effectiveness of methotrexate.

Excipients

Jylamvo contains sodium methyl parahydroxybenzoate (E219) and ethyl parahydroxybenzoate (E214), which may cause allergic reactions, possibly delayed.

Effect on Driving

Methotrexate has a moderate influence on the ability to drive and use machines, because tiredness, dizziness or drowsiness can occur during treatment.

Methotrexate products do not need refrigeration.

• Jylamvo oral solution: do not store above 25 °C and keep the bottle tightly closed.
• Nordimet pre-filled pens and syringes: store below 25 °C, keep in the outer carton to protect from light, and do not freeze.
• Metoject pre-filled syringes: store below 25 °C and keep in the outer packaging to protect from light.
• Bertanel pre-filled syringes: do not store above 25 °C, do not freeze, and keep in the original package to protect from light.

Keep all medicines out of the sight and reach of children.

• Jylamvo oral solution: 18 months unopened; use within 3 months after first opening.
• Nordimet: 2 years.
• Metoject: 30 months.

Do not use after the expiry date on the pack.

Prescription only (Rx). Methotrexate must be prescribed by physicians with expertise in its use and a full understanding of its risks; Jylamvo is subject to restricted medical prescription (Annex II B). The oral solution and the pre-filled pens and syringes are taken or injected by the patient, or given by a healthcare professional, so they are supplied to the patient or to the treating clinic on prescription; the first injection is given under direct medical supervision. For rheumatological and dermatological use the prescription should state the weekday of the weekly dose, and for the oral solution the prescribed volume in mL must be checked, because the dosing syringe is marked in mL and not in mg. For these non-oncological uses, pregnancy must be excluded before treatment and effective contraception used during treatment and for at least 6 months after the last dose (3 months for men). The products are stored below 25 °C and protected from light; they need no cold-chain delivery.