Drugs List

Therapeutic Indications

Uses

Neoplastic disease
Severe psoriasis when other regimens unsuitable/ineffective

Treatment of neoplastic disease including; acute lymphocytic leukaemia, prophylaxis of meningeal leukaemia, non-hodgkin's lymphoma, osteogenic sarcoma, adjuvant and in advance disease of breast cancer, metastatic or recurrent head and neck cancer, choriocarcinoma and similar trophoblastic diseases, advanced cancer of urinary bladder.

Symptomatic treatment of severe recalcitrant disabling psoriasis, when other regimens are unsuitable or ineffective.

Unlicensed Uses

Autoimmune disease
Crohn's disease - maintenance of remission
Severe Crohn's disease

Treatment of severe Crohn's disease and the maintenance of remission of Crohn's disease.

Treatment of autoimmune diseases, including severe active rheumatoid arthritis, juvenile idiopathic arthritis, juvenile dermatomyositis, vasculitis uveitis, systemic lupus erythematosus, localised scleroderma, and sarcoidosis.

Administration

For intramuscular, intravenous and intra-arterial routes of administration.

Some presentations are suitable for intrathecal use, ensure these preparations are isotonic and preservative-free.

Contraindications

Infection
Alcoholism
Breastfeeding
Immunodeficiency syndromes
Pregnancy
Severe haematological disorder
Severe hepatic impairment
Severe renal impairment

Precautions and Warnings

Ascites
Children under 18 years
Debilitation
Diarrhoea
Elderly
Females of childbearing potential
History of high alcohol intake
History of radiotherapy
Obesity
Dehydration
Diabetes mellitus
Folate deficiency
Haematological disorder
Hepatic impairment
Peptic ulcer
Renal impairment
Significant pleural effusion
Ulcerative colitis
Ulcerative stomatitis

Administration of live vaccines is not recommended
Consider screening at risk patients for hepatitis B and/or C virus
Sodium content of formulation may be significant
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 calcium leucovorin rescue if systemic absorption of therapy likely
Consider use of folic acid supplement to improve tolerability
Give pre-treatment counselling and consideration of sperm cryopreservation
Maintain adequate hydration of patient prior / during treatment
Not all available brands are licensed for all indications
Not all available brands are licensed for all routes of administration
Pleural effusions should be drained before treatment
Treatment to be initiated and supervised by a specialist
Consult local policy on the safe use of 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
Consider monitoring plasma drug levels
Elderly: Monitor renal function and consider dose modification
Examine mouth and throat for mucosal changes
Haemopoietic suppression may occur abruptly & with apparently safe dosages
If rash develops, consider possibility of Stevens-Johnson Syndrome
Monitor for drug induced pneumonitis at each visit
Monitor for hepatotoxicity which may occur without other signs of toxicity
Monitor haematocrit values
Monitor patients for signs of tumour lysis syndrome
Take chest X-ray if fever,cough,dyspnoea or other respiratory signs occur
Advise patient to report breathlessness or cough immediately
Advise patient to report symptoms of infection immediately
Advise patient to seek medical advice if severe skin reaction occurs
Advise patients to report signs of diarrhoea and stomatitis
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
Interrupt treatment if diarrhoea or stomatitis occur
Consider dose reduction in hepatic impairment
Consider dose reduction in renal impairment
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
Advise patient to avoid exposure to sunlight and UV rays during treatment

The following tests should be carried out prior to and repeated every 1 to 2 weeks until treatment has stabilised, thereafter patients should be monitored every 2 to 3 months:
Complete blood count with differential blood count and platelets
Liver tests
Renal function tests

Liver dysfunction
If liver dysfunction occurs, withhold for a minimum of 2 weeks before reintroduction.
In patients treated for psoriasis the need for liver biopsy should be considered on a case by case basis considering hepatic risk factors such as: 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).

Respiratory system
Treatment should be withdrawn from patients with respiratory symptoms and a thorough investigation including chest X-ray should be carried out to exclude infection. Pneumonitis carnii should be considered in patients with respiratory conditions. If methotrexate induced lung disease is suspected initiate corticosteroids and methotrexate treatment should not be restarted.

Additional precautions relevant for intrathecal use
Always ensure that the methotrexate chosen to prepare intrathecal dosages is of an appropriate strength and licensed for intrathecal administration.

Systemic toxicity of methotrexate may occur following intrathecal administration and be enhanced in patients with renal dysfunction, ascites or other effusions due to prolongation of serum half-life.

Additional precautions for all routes
High doses 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 or folinic acid may be required, with some manufacturers advising it should be used for all doses over 100mg.

Some sources suggest caution should be used in patients with acute porphyria. However, NAPOS classifies methotrexate as probably not porphyrinogenic.

Pregnancy and Lactation

Pregnancy

Methotrexate is contraindicated in pregnancy.

Abortion, foetal death and congenital abnormalities have occurred in pregnant women receiving methotrexate, especially during first trimester exposure.

Although methotrexate is known to persist in tissues for long periods, Briggs states that pregnancies after methotrexate is discontinued to not seem to be at an increased risk.

The effect of concurrent therapies must also be considered.

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 excreted in human breast milk in concentrations strong enough that there is a risk to the infant.

The effect of concurrent therapies must also be considered.

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
Abortion
Alopecia
Amenorrhoea during and after treatment
Anaemia
Anaphylactic reaction
Anorexia
Aphasia
Arthralgia
Ataxia
Azotaemia
Back pain
Blurred vision
Bone marrow depression
Cerebellar dysfunction
Chills
Cirrhosis
Coma
Confusion
Convulsions
Cystitis
Dementia
Diarrhoea
Dizziness
Drowsiness
Dysuria
Ecchymosis
Elevation of liver enzymes
Enteritis
Epidermal necrolysis
Erythematous rash
Exacerbation of psoriasis
Eye irritation
Fatigue
Fever
Foetal defects
Furunculosis
Gingivitis
Guillain-Barre syndrome
Haematuria
Haemorrhage
Headache
Hemiparesis
Hepatic disorders (fatty changes)
Hepatic necrosis
Hepatotoxicity
Hypogammaglobulinaemia
Impaired fertility
Increased susceptibility to infection
Interstitial pneumonitis
Irritability
Leukoencephalopathy
Liver atrophy
Loss of libido
Lymphoma
Malabsorption
Malaise
Melaena
Menstrual disturbances
Metabolic changes
Mood changes
Mucositis
Myalgia
Nephropathy
Nerve palsies
Oligospermia
Opportunistic infections
Osteoporosis
Paraplegia
Paresis
Pericardial effusion
Pericarditis
Periportal fibrosis
Pharyngitis
Photosensitivity
Pleural thickening
Pleuritic pain
Precipitation of diabetes
Pulmonary fibrosis
Pulmonary oedema
Renal failure
Sepsis
Septicaemia
Shoulder pain
Skin pigmentation changes
Spasticity
Stevens-Johnson syndrome
Stomatitis
Sudden death reported
Telangiectasia
Thrombocytopenia
Toxic megacolon
Transient cognitive dysfunction
Ulcerative stomatitis
Unusual cranial sensations
Uraemia
Vasculitis

Presentation

Vials and ampoules containing methotrexate (information for pre-filled devices is held on separate monograph).

Drugs List

Therapeutic Indications

Uses

Neoplastic disease
Severe psoriasis when other regimens unsuitable/ineffective

Treatment of neoplastic disease including; acute lymphocytic leukaemia, prophylaxis of meningeal leukaemia, non-hodgkin's lymphoma, osteogenic sarcoma, adjuvant and in advance disease of breast cancer, metastatic or recurrent head and neck cancer, choriocarcinoma and similar trophoblastic diseases, advanced cancer of urinary bladder.

Symptomatic treatment of severe recalcitrant disabling psoriasis, when other regimens are unsuitable or ineffective.

Unlicensed Uses

Autoimmune disease
Crohn's disease - maintenance of remission
Severe Crohn's disease

Treatment of severe Crohn's disease and the maintenance of remission of Crohn's disease.

Treatment of autoimmune diseases, including severe active rheumatoid arthritis, juvenile idiopathic arthritis, juvenile dermatomyositis, vasculitis uveitis, systemic lupus erythematosus, localised scleroderma, and sarcoidosis.

Dosage

Due to the complexity and specialist nature of dosage regimens for the treatment of malignant disease, specific dosing information for neoplastic disease is not included.
Doses may vary significantly if this agent is used as monotherapy or different combinations.
When using this agent, specialist literature, national guidelines, cancer network protocols and Trust chemotherapy protocols should be consulted.

Doses are calculated in terms of methotrexate not methotrexate sodium. Dosages are based on the patient's body weight or surface area except in the case of intrathecal administration when a single maximum dose is applied to all patients.

Adults

Children

Patients with Renal Impairment

Administration

For intramuscular, intravenous and intra-arterial routes of administration.

Some presentations are suitable for intrathecal use, ensure these preparations are isotonic and preservative-free.

Contraindications

Infection
Alcoholism
Breastfeeding
Immunodeficiency syndromes
Pregnancy
Severe haematological disorder
Severe hepatic impairment
Severe renal impairment

Precautions and Warnings

Ascites
Children under 18 years
Debilitation
Diarrhoea
Elderly
Females of childbearing potential
History of high alcohol intake
History of radiotherapy
Obesity
Dehydration
Diabetes mellitus
Folate deficiency
Haematological disorder
Hepatic impairment
Peptic ulcer
Renal impairment
Significant pleural effusion
Ulcerative colitis
Ulcerative stomatitis

Administration of live vaccines is not recommended
Consider screening at risk patients for hepatitis B and/or C virus
Sodium content of formulation may be significant
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 calcium leucovorin rescue if systemic absorption of therapy likely
Consider use of folic acid supplement to improve tolerability
Give pre-treatment counselling and consideration of sperm cryopreservation
Maintain adequate hydration of patient prior / during treatment
Not all available brands are licensed for all indications
Not all available brands are licensed for all routes of administration
Pleural effusions should be drained before treatment
Treatment to be initiated and supervised by a specialist
Consult local policy on the safe use of 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
Consider monitoring plasma drug levels
Elderly: Monitor renal function and consider dose modification
Examine mouth and throat for mucosal changes
Haemopoietic suppression may occur abruptly & with apparently safe dosages
If rash develops, consider possibility of Stevens-Johnson Syndrome
Monitor for drug induced pneumonitis at each visit
Monitor for hepatotoxicity which may occur without other signs of toxicity
Monitor haematocrit values
Monitor patients for signs of tumour lysis syndrome
Take chest X-ray if fever,cough,dyspnoea or other respiratory signs occur
Advise patient to report breathlessness or cough immediately
Advise patient to report symptoms of infection immediately
Advise patient to seek medical advice if severe skin reaction occurs
Advise patients to report signs of diarrhoea and stomatitis
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
Interrupt treatment if diarrhoea or stomatitis occur
Consider dose reduction in hepatic impairment
Consider dose reduction in renal impairment
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
Advise patient to avoid exposure to sunlight and UV rays during treatment

The following tests should be carried out prior to and repeated every 1 to 2 weeks until treatment has stabilised, thereafter patients should be monitored every 2 to 3 months:
Complete blood count with differential blood count and platelets
Liver tests
Renal function tests

Liver dysfunction
If liver dysfunction occurs, withhold for a minimum of 2 weeks before reintroduction.
In patients treated for psoriasis the need for liver biopsy should be considered on a case by case basis considering hepatic risk factors such as: 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).

Respiratory system
Treatment should be withdrawn from patients with respiratory symptoms and a thorough investigation including chest X-ray should be carried out to exclude infection. Pneumonitis carnii should be considered in patients with respiratory conditions. If methotrexate induced lung disease is suspected initiate corticosteroids and methotrexate treatment should not be restarted.

Additional precautions relevant for intrathecal use
Always ensure that the methotrexate chosen to prepare intrathecal dosages is of an appropriate strength and licensed for intrathecal administration.

Systemic toxicity of methotrexate may occur following intrathecal administration and be enhanced in patients with renal dysfunction, ascites or other effusions due to prolongation of serum half-life.

Additional precautions for all routes
High doses 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 or folinic acid may be required, with some manufacturers advising it should be used for all doses over 100mg.

Some sources suggest caution should be used in patients with acute porphyria. However, NAPOS classifies methotrexate as probably not porphyrinogenic.

Pregnancy and Lactation

Pregnancy

Methotrexate is contraindicated in pregnancy.

Abortion, foetal death and congenital abnormalities have occurred in pregnant women receiving methotrexate, especially during first trimester exposure.

Although methotrexate is known to persist in tissues for long periods, Briggs states that pregnancies after methotrexate is discontinued to not seem to be at an increased risk.

The effect of concurrent therapies must also be considered.

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 excreted in human breast milk in concentrations strong enough that there is a risk to the infant.

The effect of concurrent therapies must also be considered.

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
Abortion
Alopecia
Amenorrhoea during and after treatment
Anaemia
Anaphylactic reaction
Anorexia
Aphasia
Arthralgia
Ataxia
Azotaemia
Back pain
Blurred vision
Bone marrow depression
Cerebellar dysfunction
Chills
Cirrhosis
Coma
Confusion
Convulsions
Cystitis
Dementia
Diarrhoea
Dizziness
Drowsiness
Dysuria
Ecchymosis
Elevation of liver enzymes
Enteritis
Epidermal necrolysis
Erythematous rash
Exacerbation of psoriasis
Eye irritation
Fatigue
Fever
Foetal defects
Furunculosis
Gingivitis
Guillain-Barre syndrome
Haematuria
Haemorrhage
Headache
Hemiparesis
Hepatic disorders (fatty changes)
Hepatic necrosis
Hepatotoxicity
Hypogammaglobulinaemia
Impaired fertility
Increased susceptibility to infection
Interstitial pneumonitis
Irritability
Leukoencephalopathy
Liver atrophy
Loss of libido
Lymphoma
Malabsorption
Malaise
Melaena
Menstrual disturbances
Metabolic changes
Mood changes
Mucositis
Myalgia
Nephropathy
Nerve palsies
Oligospermia
Opportunistic infections
Osteoporosis
Paraplegia
Paresis
Pericardial effusion
Pericarditis
Periportal fibrosis
Pharyngitis
Photosensitivity
Pleural thickening
Pleuritic pain
Precipitation of diabetes
Pulmonary fibrosis
Pulmonary oedema
Renal failure
Sepsis
Septicaemia
Shoulder pain
Skin pigmentation changes
Spasticity
Stevens-Johnson syndrome
Stomatitis
Sudden death reported
Telangiectasia
Thrombocytopenia
Toxic megacolon
Transient cognitive dysfunction
Ulcerative stomatitis
Unusual cranial sensations
Uraemia
Vasculitis

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: August 2018

Reference Sources

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.

The Renal Drug Handbook. Fourth Edition (2014) ed. Ashley, C and Dunleavy, A, Radcliffe Publishing Ltd, London.

Summary of Product Characteristics: Methotrexate Injection 25mg/ml. Accord Healthcare. Revised June 2018.
Summary of Product Characteristics: Methotrexate Injection 100mg/ml. Accord Healthcare. Revised June 2018.
Summary of Product Characteristics: Methotrexate Injection 2.5mg/ml. Hospira UK Ltd. Revised July 2018.
Summary of Product Characteristics: Methotrexate Injection 5mg/2ml. Hospira UK Ltd. Revised July 2018.
Summary of Product Characteristics: Methotrexate Injection 25mg/ml. Hospira UK Ltd. Revised July 2018.
Summary of Product Characteristics: Methotrexate Injection 100mg/ml. Hospira UK Ltd. Revised July 2018.
Summary of Product Characteristics: Methotrexate Injection 100mg/ml. Medac GmbH. Revised March 2018.

The Norwegian Porphyria Centre (NAPOS).
Available at: https://www.drugs-porphyria.org
Last revised: 11 January 2012.
Last accessed: 28 September 2015.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 16 August 2018