Methotrexate oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Oral formulations of methotrexate.
Drugs List
Therapeutic Indications
Uses
Juvenile idiopathic arthritis
Neoplastic disease
Rheumatoid arthritis
Severe psoriasis when other regimens unsuitable/ineffective
Malignant diseases including trophoblastic neoplasm, acute leukaemias and non-Hodgkin's lymphoma.
Severe forms of psoriasis including chronic plaque psoriasis, erythrodermic psoriasis, psoriatic arthritis and pustular psoriasis, when other regimens are unsuitable or ineffective.
Active rheumatoid arthritis in adults.
Juvenile idiopathic arthritis.
Unlicensed Uses
Autoimmune disease
Crohn's disease - maintenance of remission
The maintenance of remission of Crohn's disease.
Treatment of autoimmune diseases, including juvenile dermatomyositis, vasculitis uveitis, systemic lupus erythematosus, localised scleroderma, and sarcoidosis.
Dosage
Malignant disease
Due to the complexity and specialist nature of dosage regimens for the treatment of malignant disease, specific dosing information for neoplastic disease on this agent is not included. When using this agent, specialist literature, national guidelines, cancer networks protocols and Trust chemotherapy protocols should be consulted.
Non-malignant disease
In non oncological conditions methotrexate is given ONCE WEEKLY.
Always consult disease specific protocol for exact dosing and timing instructions. Doses may vary significantly if this agent is used as monotherapy or different combinations.
Dosage schedules and regimes 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.
Doses are calculated in terms of methotrexate not methotrexate sodium.
Adults
Psoriasis
A test dose of between 2.5mg and 10mg is recommended one week prior to initiating treatment.
A typical oral methotrexate dose is 5mg to 25mg once weekly, with the dose being adjusted to the patient's response. The maximum recommended dose is 25mg a week.
To improve tolerability, the dosage of oral solutions of methotrexate may be divided into smaller doses over a longer duration.
The above dose is a ONCE WEEKLY dose. Attention should be paid to the strength of methotrexate prescribed and the frequency of dosing.
Rheumatoid arthritis
A typical oral methotrexate dose is 7.5mg to 15mg once weekly, with the dose being adjusted to the patient's response. The maximum recommended dose is 20mg a week.
To improve tolerability, the dosage of oral solutions of methotrexate may be divided into smaller doses over a longer duration.
The above dose is a ONCE WEEKLY dose. Attention should be paid to the strength of methotrexate prescribed and the frequency of dosing.
Crohn's disease (unlicensed)
A typical oral methotrexate dose is 10mg to 25mg once weekly, with the dose being adjusted to the patient's response.
The above dose is a ONCE WEEKLY dose. Attention should be paid to the strength of methotrexate prescribed and the frequency of dosing.
Children
Juvenile idiopathic arthritis
Children aged 3 to 18 years: A typical oral methotrexate dose is 10mg to 15mg per metre squared of body surface area once weekly, to a maximum of 20mg a week.
The above dose is a ONCE WEEKLY dose. Attention should be paid to the strength of methotrexate prescribed and the frequency of dosing.
Crohn's Disease (unlicensed)
Children 7 to 18 years: A typical oral methotrexate dose is 15mg per metre squared of body surface area once weekly, to a maximum of 25mg a week.
The above dose is a ONCE WEEKLY dose. Attention should be paid to the strength of methotrexate prescribed and the frequency of dosing.
Psoriasis (unlicensed)
Children 2 to 18 years: An initial recommended dose of oral methotrexate is 200micrograms per kilogram of bodyweight once weekly, to a maximum of 10mg a week. Dosage may then be increased according to patient response to 400micrograms per kilogram of bodyweight once weekly,to a maximum of 25mg a week.
The above dose is a ONCE WEEKLY dose. Attention should be paid to the strength of methotrexate prescribed and the frequency of dosing.
Juvenile dermatomyositis, localised scleroderma, sarcoidosis, systemic lupus erythematosus, sveitis, and vasculitis (unlicensed)
Children 1 month to 18 years: An initial recommended dose of oral methotrexate is 10mg to 15mg per metre squared of body surface area once weekly. Dosage may then be increased if necessary to 25mg per metre squared of body surface area once weekly.
The above dose is a ONCE WEEKLY dose. Attention should be paid to the strength of methotrexate prescribed and the frequency of dosing.
Patients with Renal Impairment
Recommendations differ on dose adjustments in patients with renal impairment. A balanced guideline to dose reductions in non-oncological indications is given below.
Creatinine clearance greater than 50millilitres per minute: No dose reduction.
Creatinine clearance between 20 and 50millilitres per minute: Reduce dose by 50%.
Creatinine clearance less than 20millilitres per minute: Contraindicated in these patients.
Additional Dosage Information
Doses exceeding 20mg per week have been associated with a substantial increase in toxicity, including bone marrow depression.
Contraindications
Infection
Alcoholism
Breastfeeding
Immunodeficiency syndromes
Pregnancy
Severe haematological disorder
Severe hepatic impairment
Severe renal impairment
Significant pleural effusion
Precautions and Warnings
Ascites
Children under 18 years
Debilitation
Diarrhoea
Elderly
Females of childbearing potential
History of high alcohol intake
History of radiotherapy
Dehydration
Diabetes mellitus
Folate deficiency
Galactosaemia
Glucose-galactose malabsorption syndrome
Haematological disorder
Hepatic impairment
History of hepatic disorder
History of hepatitis B
History of hepatitis C
History of tuberculosis
Lactose intolerance
Peptic ulcer
Pleural effusion
Psychiatric disorder
Renal impairment
Respiratory impairment
Ulcerative colitis
Ulcerative stomatitis
Administration of live vaccines is not recommended
Disease reactivation may occur in patients with latent TB
Reduce dose in patients with hepatic impairment
Reduce dose in patients with renal impairment
Advise ability to drive/operate machinery may be affected by side effects
Ascites should be drained before treatment
Concurrent radiotherapy may increase risk of serious adverse effects
Consider use of folic acid supplement to improve tolerability
Give pre-treatment counselling and consideration of oocyte cryopreservation
Give pre-treatment counselling and consideration of sperm cryopreservation
Not all available brands are licensed for all indications
Pleural effusions should be drained before treatment
Treatment to be initiated and supervised by a specialist
Some formulations contain hydroxybenzoate
Some formulations contain lactose
Consult local policy on the safe use of oral anti-cancer drugs
Staff: Not to be handled by pregnant staff
Exclude pregnancy prior to initiation of treatment
Monitor full blood count and differential WBC before and during therapy
Monitor hepatic function before treatment and regularly during treatment
Monitor renal function before treatment and regularly during treatment
Perform chest X-ray prior to and periodically during treatment
Urinalysis required pre and post treatment
Consider liver biopsy after cumulative doses exceed 1.5g
Elderly: Monitor renal function and consider dose modification
Haemopoietic suppression may occur abruptly & with apparently safe dosages
Inspect oral mucosa regularly in patients on long term treatment
Monitor for drug induced pneumonitis at each visit
Monitor for hepatotoxicity which may occur without other signs of toxicity
Take chest X-ray if fever,cough,dyspnoea or other respiratory signs occur
Advise patient to report any symptoms of infections especially sore throats
Advise patient to report breathlessness or cough immediately
Advise patients to report signs of diarrhoea and stomatitis
Discontinue if pulmonary alveolar haemorrhage occurs
Reactivation of hepatitis B may occur in chronic carriers
Reactivation of latent chronic infections may occur
Risk of developing opportunistic infections
Discontinue if evidence of interstitial lung disease
Discontinue if hepatic enzymes (AST or ALT) become persistently raised
Discontinue if malignant lymphomas develop
Discontinue if patient develops respiratory symptoms
Discontinue treatment if profound drop in platelets or WBC occur
If dehydration occurs, discontinue treatment until patient has recovered
Interrupt treatment if diarrhoea or stomatitis occur
For high doses consider urinary alkalisation and high fluid throughput
Not licensed for all indications in all age groups
Advise patient not to take echinacea products concurrently
Advise patient to consult doctor before any self medication
Advise patients to avoid aspirin and NSAID use
Advise patient to avoid alcohol during treatment
Advise patient excessive dietary caffeine may adversely effect treatment
May cause impaired fertility
Male & female: Contraception required during & for 6 months after treatment
Psoriasis: Avoid exposure to sunlight and UV rays
The following tests should be carried out regularly during therapy, at least once a month for the first 6 months and every 3 months after that:
Examination of the mouth and throat for mucosal changes.
Complete blood count with differential blood count and platelets.
Liver function tests.
Renal function tests.
Respiratory system tests.
If liver dysfunction occurs, withhold methotrexate for a minimum of two weeks before reintroduction.
The need for liver biopsy should be evaluated in patients with the following hepatic risk factors: Excessive prior alcohol consumption, persistent elevation of liver enzymes, anamnestic liver diseases, hereditary liver diseases, diabetes mellitus, obesity, history of significant exposure to hepatotoxic drugs, prolonged methotrexate treatment (cumulative dose of 1.5g or more).
High doses of methotrexate may cause the precipitation of methotrexate or its metabolites in the renal tubules. A high fluid throughput and alkalisation of the urine to pH 6.5 to 7.0 is recommended as a preventative measure.
Folate deficiency states may increase methotrexate toxicity. Folic (non-malignant conditions) or folinic acid (malignant conditions) may be required in conjunction with methotrexate use.
Alveolar haemorrhage as a result of methotrexate treatment has been shown to occur. If pulmonary alveolar haemorrhage is suspected, consider prompt investigation.
Pregnancy and Lactation
Pregnancy
Methotrexate is contraindicated in pregnancy.
Methotrexate is teratogenic in humans and is thought to cause foetal death, miscarriages and congenital abnormalities. Animal studies have shown reproductive toxicity.
When treating oncological indications, thoroughly assess the risks and benefits associated with methotrexate use in pregnancy before treatment.
Schaefer (2015) suggests a detailed scan to assess foetal development if inadvertent exposure to methotrexate occurs during pregnancy.
The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Lactation
Methotrexate is contraindicated in breastfeeding.
Methotrexate is known to be excreted in human breast milk, representing a potential risk to the nursing infant. LactMed suggests that the levels of methotrexate present in breast milk from low dose non-oncological treatments may not be harmful to nursing infants; however Schaefer (2015) states that methotrexate may accumulate in neonatal tissues. Methotrexate is contraindicated by the manufacturer.
Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Side Effects
Abdominal discomfort
Abnormal tissue cell changes
Acne
Agranulocytosis
Alopecia
Anaemia
Anaphylactic reaction
Anorexia
Aphasia
Arthralgia
Ataxia
Azotaemia
Bladder inflammation
Bone marrow depression
Chills
Cirrhosis
Confusion
Conjunctivitis
Convulsions
Cystitis
Diarrhoea
Dizziness
Drowsiness
Enteritis
Eosinophilia
Epidermal necrolysis
Exacerbation of psoriasis
Eye irritation
Fatigue
Fever
Gastro-intestinal symptoms
Gingivitis
Gynaecomastia
Haematemesis
Haematuria
Haemorrhage
Headache
Hemiparesis
Hepatic disorders
Hepatic necrosis
Hepatotoxicity
Herpes zoster
Hypogammaglobulinaemia
Hypotension
Immunosuppression
Impaired fertility
Impotence
Increased susceptibility to infection
Increases in hepatic enzymes
Interstitial pneumonitis
Leucopenia
Leukoencephalopathy
Loss of libido
Lymphoma
Malabsorption
Malaise
Melaena
Menstrual disturbances
Metabolic changes
Mood changes
Mucositis
Myalgia
Nausea
Nephropathy
Nervous system effects
Neutropenia
Oligospermia
Opportunistic infections
Osteoporosis
Pancytopenia
Paresis
Pericardial effusion
Pericarditis
Pharyngitis
Photosensitivity
Pleural thickening
Pleuritic pain
Pneumonia
Pneumonitis
Precipitation of diabetes
Psychiatric disorders
Pulmonary fibrosis
Pulmonary oedema
Renal failure
Respiratory disorders
Sepsis
Septicaemia
Skin disorder
Stevens-Johnson syndrome
Stomatitis
Telangiectasia
Thrombocytopenia
Thromboembolic disorders
Toxic megacolon
Urinary abnormalities
Vascular disorders
Vasculitis
Visual disturbances
Vulvovaginal disorders
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: March 2018
Reference Sources
Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 3rd edition (2015) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.
Summary of Product Characteristics: Maxtrex Tablets 10mg. Pfizer Limited. Revised January 2018.
Summary of Product Characteristics: Maxtrex Tablets 2.5mg. Pfizer Limited. Revised January 2018.
Summary of Product Characteristics: Methotrexate 2.5mg Tablets. Amdipharm Mercury Company Limited. Revised April 2018.
Summary of Product Characteristics: Methotrexate 10mg tablets. Orion Pharma (UK) limited. Revised June 2015.
Summary of Product Characteristics: Methotrexate 2.5mg tablets. Orion Pharma (UK) limited. Revised June 2015.
Summary of Product Characteristics: Methotrexate 10mg Tablets. Hospira UK Ltd. Revised October 2017.
Summary of Product Characteristics: Methotrexate 2.5mg Tablets. Hospira UK Ltd. Revised October 2017.
Summary of Product Characteristics: Methotrexate 2mg/ml oral solution. Rosemont. Revised April 2018.
Summary of Product Characteristics: Jylamvo 2mg/ml oral solution. Therakind limited. Revised May 2018.
The Renal Drug Handbook. Fourth Edition (2014) ed. Ashley, C and Dunleavy, A, Radcliffe Publishing Ltd, London.
US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Methotrexate. Last revised: 10 October 2017
Last accessed: 11 June 2018
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 11 June 2018
Medscape UK | Univadis prescription drug monographs & interactions are based on FDB Multilex Content
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