Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Hospira UK Limited, Horizon, Honey Lane, Hurley, Maidenhead, SL6 6RJ, UK
Methotrexate is contraindicated in:
Patients with 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).
Patients with significantly impaired hepatic function
Patients with pre-existing blood dyscrasias, such as significant marrow hypoplasia, leukopenia, thrombocytopenia or anaemia.
Patients with active infections. Patients with overt or laboratory evidence of immunodeficiency syndrome(s).
Methotrexate is contraindicated in pregnancy (see section 4.6).
Because of the potential for serious adverse reactions from methotrexate in breast fed infants, breast feeding is contraindicated in women taking methotrexate (see section 4.6).
Patients with a known allergic hypersensitivity to methotrexate or any of the other ingredients should not receive methotrexate.
Methotrexate must be used only by physicians experienced in antimetabolite chemotherapy.
Because of the possibility of fatal or severe toxic reactions, the patient should be fully informed by the physician of the risks involved and be under his constant supervision.
The prescriber should specify the day of intake on the prescription. The prescriber should make sure patients understand that methotrexate should only be taken once a week. Patients should be instructed on the importance of adhering to the once-weekly intakes.
Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnoea, cough (especially a dry non-productive cough), thoracic pain 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 methotrexate 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Methotrexate should be withdrawn from patients with pulmonary symptoms and a thorough investigation should be made to exclude infection.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.
When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered.
Methotrexate has the potential for serious, sometimes fatal toxicity. The toxic effects may be related in frequency and severity to the dose or frequency of administration but have been seen at all doses. Because the toxic reactions can occur at any time during therapy, the patients have to be observed closely and must be informed of early signs and symptoms of toxicity.
Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor (PPI) therapy. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted.
Deaths have been reported with the use of methotrexate in the treatment of psoriasis.
In the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established by biopsy and/or after dermatological consultation.
1. 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 should be withdrawn immediately. Patients should be advised to report all symptoms or signs suggestive of infection.
2. Methotrexate may be hepatotoxic, particularly at high dosage or with prolonged therapy. Liver atrophy, necrosis, cirrhosis, fatty changes, and periportal fibrosis have been reported. Since changes may occur without previous signs of gastrointestinal or haematological toxicity, it is imperative that hepatic function be determined prior to initiation of treatment and monitored regularly throughout therapy. If substantial hepatic function abnormalities develop, methotrexate dosing should be suspended for at least 2 weeks. Special caution is indicated in the presence of pre-existing liver damage or impaired hepatic function. Concomitant use of other drugs with hepatotoxic potential (including alcohol) should be avoided.
3. Methotrexate has been shown to be teratogenic; it has caused foetal death and/or congenital anomalies. Therefore it is not recommended in women of childbearing potential unless there is appropriate medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant psoriatic patients should not receive methotrexate.
4. 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.
Methotrexate may cause renal damage that may lead to acute renal failure. Close attention to renal function including adequate hydration, urine alkalinisation, 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.
5. Diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.
6. Methotrexate affects gametogenesis during the period of its administration and may result in decreased fertility which is thought to be reversible on discontinuation of therapy. Conception should be avoided during the period of methotrexate administration and for at least 6 months thereafter. Patients and their partners should be advised to this effect.
7. Methotrexate has some immunosuppressive activity and immunological responses to concurrent vaccination may be decreased. The immunosuppressive effect of methotrexate should be taken into account when immune responses of patients are important or essential. Immunisation with live virus vaccines is generally not recommended.
8. Pleural effusions and ascites should be drained prior to initiation of methotrexate therapy.
9. Deaths have been reported with the use of methotrexate. Serious adverse reactions including deaths have been reported with concomitant administration of methotrexate (usually in high doses) along with some non-steroidal anti-inflammatory drugs (NSAIDs).
10. Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.
11. Systemic toxicity may occur following intrathecal administration. Blood counts should be monitored closely.
12. A chest X-ray is recommended prior to initiation of methotrexate therapy.
13. If acute methotrexate toxicity occurs, patients may require folinic acid.
14. Severe, occasionally fatal, cutaneous or sensitivity reactions (e.g. toxic epidermic necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme, vasculitis and extensive herpetiform skin eruptions) may occur after the administration of methotrexate and recovery ensured mostly after discontinuation of the therapy.
Methotrexate has a high potential toxicity, usually dose related, and should be used only by physicians experienced in antimetabolite chemotherapy, in patients under their constant supervision. The physician should be familiar with the various characteristics of the drug and its established clinical usage.
Before beginning methotrexate therapy or reinstituting methotrexate after a rest period, assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests.
It should be noted that intrathecal doses are transported into the cardiovascular system and may give rise to systemic toxicity. Systemic toxicity of methotrexate may also be enhanced in patients with renal dysfunction, ascites, or other effusions due to prolongation of serum half-life.
In rare cases, following intrathecal administration, a tumour lysis syndrome has been observed.
Carcinogenesis, mutagenesis, and impairment of fertility: Animal carcinogenicity studies have demonstrated methotrexate to be free of carcinogenic potential. Although methotrexate has been reported to cause chromosomal damage to animal somatic cells and bone marrow cells in humans, these effects are transient and reversible. In patients treated with methotrexate, evidence is insufficient to permit conclusive evaluation of any increased risk of neoplasia.
Fertility: Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation of therapy, affecting spermatogenesis and oogenesis during the period of its administration – effects that appear to be reversible on discontinuing therapy. In addition, methotrexate causes embryotoxicity, abortion and foetal defects in humans.
Teratogenicity – Reproductive risk: Methotrexate causes embryotoxicity, abortion and foetal malformations in humans. Therefore, the possible risks of effects on reproduction, pregnancy loss and congenital malformations should be discussed with female patients of childbearing potential (see section 4.6), the absence of pregnancy must be confirmed before Methotrexate 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.
Patients undergoing therapy should be subject to appropriate supervision so that signs or symptoms of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay. Pretreatment and periodic haematological studies are essential to the use of methotrexate in chemotherapy because of its common effect of haematopoietic suppression. This may occur abruptly and on apparent safe dosage, and any profound drop in blood cell count indicates immediate stopping of the drug and appropriate therapy. In patients with malignant disease who have pre-existing bone marrow aplasia, leukopenia, thrombocytopenia or anaemia, methotrexate should be used with caution, if at all.
In general, the following laboratory tests are recommended as part of essential clinical evaluation and appropriate monitoring of patients chosen for or receiving methotrexate therapy: complete haemogram; haematocrit; urinalysis; renal function tests; liver function tests and chest X-ray.
The purpose is to determine any existing organ dysfunction or system impairment. The tests should be performed prior to therapy, at appropriate periods during therapy and after termination of therapy.
Liver biopsy may be considered after cumulative doses >1.5 g have been given, if hepatic impairment is suspected.
Methotrexate is bound in part to serum albumin after absorption, and toxicity may be increased because of displacement by certain drugs such as salicylates, sulphonamides, phenytoin, and some antibacterials such as tetracycline, chloramphenicol and para-aminobenzoic acid. These drugs, especially salicylates and sulphonamides, whether antibacterial, hypoglycaemic or diuretic, should not be given concurrently until the significance of these findings is established.
Vitamin preparations containing folic acid or its derivatives may alter response to methotrexate.
Methotrexate should be used with extreme caution in the presence of infection, peptic ulcer, ulcerative colitis, debility, and in extreme youth and old age. If profound leukopenia occurs during therapy, bacterial infection may occur or become a threat. Cessation of the drug and appropriate antibiotic therapy is usually indicated. In severe bone marrow depression, blood or platelet transfusions may be necessary.
Since it is reported that methotrexate may have an immunosuppressive action, this factor must be taken into consideration in evaluating the use of the drug where immune responses in a patient may be important or essential.
In all instances where the use of methotrexate is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse reactions. Most such adverse reactions are reversible if detected early. When such effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgement of the physician. Reinstitution of methotrexate therapy should be carried out with caution, with adequate consideration of further need for the drug and alertness as to the possible recurrence of toxicity.
Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
Methotrexate is extensively protein bound and may be displaced by certain drugs such as salicylates, hypoglycaemics, diuretics, sulphonamides, diphenylhydantoins, tetracyclines, chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents, so causing a potential for increased toxicity when used concurrently.
Concomitant use of other drugs with nephrotoxic or hepatotoxic potential (including alcohol) should be avoided.
Vitamin preparations containing folic acid or its derivatives may decrease the effectiveness of methotrexate.
Caution should be used when NSAIDs and salicylates are administered concomitantly with methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate and thereby may enhance its toxicity. Concomitant use of NSAIDs and salicylates has been associated with fatal methotrexate toxicity.
However, patients using constant dosage regimens of NSAIDs have received concurrent doses of methotrexate without problems observed.
Treatment with more than one DMARD in various regimens is being tried but there is little evidence available to assess benefit. A meta-analysis of 5 different combinations of DMARDs demonstrated that although efficacy might be greater than single DMARDs, toxicity was also increased.
Renal tubular transport is also diminished by probenecid and penicillins; use of these with methotrexate should be carefully monitored.
A potential interaction may exist between methotrexate and proton-pump inhibitors (e.g. omeprazole, pantoprazole). Omeprazole may inhibit methotrexate clearance resulting in potentially toxic methotrexate levels.
Severe bone marrow depression has been reported following the concurrent use of methotrexate and co-trimoxazole or trimethoprim. Concurrent use should probably be avoided.
The use of nitrous oxide anaesthesia potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe unpredictable myelosuppression, stomatitis and neurotoxicity. Severe neurotoxicity has particularly been reported with intrathecal administration of methotrexate following nitrous oxide anaesthesia. 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).
An increased risk of hepatitis has been reported following the use of methotrexate and the acitretin metabolite, etretinate. Consequently, the concomitant use of methotrexate and acitretin should be avoided.
Methotrexate may increase the bioavailability of mercaptopurine by interference with first-pass metabolism.
Concomitant application of methotrexate and theophylline can reduce theophylline clearance.
Methotrexate affects spermatogenesis and oogenesis and may decrease fertility. Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea in humans. 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 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.
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.
Methotrexate is contraindicated during pregnancy in non-oncological indications (see section 4.3).
Both men and women receiving methotrexate should be informed of the potential risk of adverse effects on reproduction. Women of childbearing potential should be fully informed of the potential hazard to the foetus should they become pregnant during methotrexate therapy. In cancer chemotherapy, methotrexate should not be used in pregnant women or women of childbearing potential who might become pregnant unless the potential benefits to the mother outweigh the possible risks to the foetus.
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.
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.
Methotrexate is distributed into breast milk. Because of the potential for serious adverse reactions to methotrexate in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
Not applicable.
The most common adverse reactions include ulcerative stomatitis, leukopenia, nausea and abdominal distress. Although very rare, anaphylactic reactions to methotrexate have occurred. Others reported are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. In general, the incidence and severity of side effects are considered to be dose-related. Adverse reactions as reported for the various systems are as follows:
Skin: Severe, occasionally fatal, dermatologic reactions including erythema multiforme, Stevens-Johnson syndrome, skin necrosis, exfoliative dermatitis, epidermal necrolysis. Erythematous rashes, pruritus, urticaria, dermatitis, 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 have been reported. The recall phenomenon has been reported in both radiation and solar damaged skin.
Blood: Bone marrow depression, leukopenia, thrombocytopenia, anaemia, hypogammaglobulinaemia, haemorrhage from various sites, septicaemia, lymphoproliferative disorders (frequency very rare).
Alimentary System: Gingivitis, pharyngitis, stomatitis, mucositis, anorexia, vomiting, diarrhoea, haematemesis, melaena, gastrointestinal ulceration and bleeding, pancreatitis, enteritis, hepatic toxicity resulting in active liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis, or hepatic cirrhosis. In rare cases the effect of methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon.
Hepatic: Hepatic toxicity resulting in significant elevations of liver enzymes, acute liver atrophy, necrosis, fatty metamorphosis, hepatitis, periportal fibrosis or cirrhosis or death may occur, usually following chronic administration.
Urogenital System: Renal failure, azotaemia, cystitis, haematuria, defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, abortion, foetal defects, severe nephropathy. Vaginitis, vaginal ulcers, cystitis, haematuria and nephropathy have also been reported.
Pulmonary System: Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported (see Section 4.4 Special warnings and special precautions for use). 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. Frequency Not Known: Pulmonary alveolar haemorrhage*.
* (has been reported for methotrexate used in rheumatologic and related indications)
Central Nervous System: Headaches, drowsiness, blurred vision, aphasia, cognitive disorder, hemiparesis and convulsions have occurred possibly related to haemorrhage or to complications from intraarterial catheterization. Convulsion, paresis, Guillain-Barre syndrome and increased cerebrospinal fluid pressure have followed intrathecal administration.
Other reactions related to, or attributed to the use of methotrexate such as pneumonitis, metabolic changes, precipitation of diabetes, osteoporotic effects, abnormal changes in tissue cells and even sudden death have been reported.
There have been reports of leukoencephalopathy following intravenous methotrexate in high doses, or low doses following cranial-spinal radiation.
Cardiac disorders: Pericarditis, pericardial effusion
Ear disorders: Tinnitus
Eye disorders: Conjunctivitis
Infections and infestations: Opportunistic infections (sometimes fatal e.g. fatal sepsis) have also been reported in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases, Pneumocystis carinii pneumonia being the most common. Other reported infections include, pneumonia, nocardiosis, histoplasmosis, cryptococcosis, Herpes Zoster, Herpes Simplex, hepatitis and cytomegalovirus infection, including cytomegaloviral pneumonia.
Musculoskeletal and connective tissue disorders: Arthralgia/myalgia, Osteonecrosis of jaw (secondary to lymphoproliferative disorders) - frequency unknown.
Psychiatric disorders: Mood altered
Vascular disorder: Vasculitis, hypotension, thromboembolic events (e.g. thrombophlebitis, pulmonary embolism, arterial, cerebral, deep vein or retinal vein thrombosis).
Adverse reactions following intrathecal methotrexate are generally classified into three groups, acute, subacute, and chronic. The acute form is a chemical arachnoiditis manifested by headache, back or shoulder pain, nuchal rigidity, and fever. The subacute form may include paresis, usually transient, paraplegia, nerve palsies, and cerebellar dysfunction. The chronic form is a leukoencephalopathy manifested by irritability, confusion, ataxia, spasticity, occasionally convulsions, dementia, somnolence, coma, and rarely, death. There is evidence that the combined use of cranial radiation and intrathecal methotrexate increases the incidence of leukoencephalopathy.
Additional reactions related to or attributed to the use of methotrexate such as osteoporosis, abnormal (usually ‘megaloblastic’) red cell morphology, precipitation of diabetes, other metabolic changes, and sudden death have been reported.
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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search MHRA Yellow Card in the Google Play or Apple App Store.
Immediate precipitation or turbidity results when combined with certain concentrations of droperidol, heparin sodium, metoclopramide hydrochloride, ranitidine hydrochloride in syringe.
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