Methotrexate

Registered South African indications:

• Rheumatoid arthritis
• Psoriasis
• Neoplastic conditions

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy for non-oncological indications
• Breastfeeding
• Very severe renal impairment
• Severe hepatic impairment
• Alcohol abuse
• Pre-existing blood dyscrasias  
• Bone marrow hypoplasia
• Leukopenia
• Thrombocytopenia or significant anaemia
• Immunodeficiency syndrome/s  
• Serious, acute or chronic infections such as tuberculosis and HIV
• Stomatitis
• Ulcers of the oral cavity
• Active gastrointestinal ulcer disease
• Coadministration with live vaccines
• Coadministration with drugs with antifolate properties (e.g. co-trimoxazole)  

Cautions

• Pregnancy for oncological indications
• Male and female patients of reproductive potential
• Mild to advanced severe renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Children
• Psychiatric disorders
• Gastrointestinal toxicity
• Presence and/or history of infection, peptic ulcer, ulcerative colitis, debility
• Pleural effusions and ascites
• Folic acid deficiency
• Alcohol-related hepatic disease
• Previous hepatic disease
• Sodium controlled diet (inj)
• Doses >20mg weekly
• Skin and mucosal contact (inj)
• Diabetes mellitus (on insulin therapy)
• Haematopoietic insufficiencies
• Prior radiotherapy (especially of the pelvis)
• Psoriasis
• Conditions leading to dehydration e.g. emesis

Forms avail. in SA and covered in this monograph: tab, inj

Rheumatoid arthritis (additional agent required)

• Oral (tab): 7.5-15mg, once weekly; Titrate gradually; Max: 20mg/week

OR

• Oral (tab): 10mg, once weekly; Titrate gradually up to 20mg/week

OR

• IM/SC: 7.5mg, weekly; Titrate by 2.5mg at 6-week intervals; Max: 25mg once weekly

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Depending on the individual activity of the disease and tolerability by the patient, the initial oral or parenteral dose may be increased gradually by 2.5 mg per week

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A test dose of 5-10 mg parenterally is recommended, one week prior to therapy to detect idiosyncratic adverse events

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Monitor alanine aminotransferase and full blood count before and after 12 weekly treatments

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Psoriasis - severe

• Oral (tab): Test dose: 2.5-5mg to exclude unexpected toxic effects
• Oral (tab): 7.5-15mg, once weekly; Titrate gradually; Max: 25mg/week

OR

• IV/IM: Test dose: 5-10mg to exclude unexpected toxic effects
• IV/IM: 7.5mg, weekly; Titrate by 2.5mg at 6-week intervals; Max: 20mg/once weekly 

 

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Dosages in each schedule may be gradually adjusted to achieve optimal clinical response, but not to exceed the maximum stated for each schedule

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Once optimal clinical response has been achieved, each dosage schedule should be reduced to the lowest possible amount of medicine and to the longest possible rest period

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Mild to moderate Crohn's disease 
Breast cancer 
Osteosarcoma 
Choriocarcinoma, Chorioadenoma destruens or hydatiform mole 
Mycosis fungoides 
Other malignancies, including carcinoma of the lung, head and neck 
Acute lymphocytic leukaemias 
Meningeal leukaemia 
Lymphoblastic leukaemia 
Lymphoma 
Lymphosarcoma 

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Consult specialist for dosages and regimens

Paed. forms avail. in SA and covered in this monograph: inj, tab

Oligoarthritis (additional agent required)

• Oral (tab): 10-15mg/m²/week as single dose on empty stomach; Titrate by 1mg/kg/week at monthly intervals; Max: 25mg/week

Polyarthritis (additional agent required)

• Oral (tab): 10-15mg/m²/week as single dose on empty stomach; Max: 25mg/week

Systemic lupus erythematosis with musculoskeletal or skin disease (additional agent required)

• Oral (tab): 10-15mg/m²/week as single dose on empty stomach; Max: 25mg/week

Takayasu arteritis - Maintenance (additional agent required)

• Oral (tab): 10-15mg/m²/week as single dose on empty stomach; Max: 25mg/week

Meningeal leukaemia 
Acute lymphoblastic leukemia 
Malignant tumours of the Central Nervous System
Non-Hodgkin Lymphoma
Crohn's disease 
Osteosarcoma 
Juvenile idiopathic arthritis
Graft-versus-host disease
Severe psoriasis

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Consult specialist for dosages and regimens

Pregnancy

• Caution; positive evidence of risk; oncological indications
• Contraindicated; non-oncological indications
• Methotrexate is contraindicated during pregnancy in non-oncological indications. 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. 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. Spontaneous abortions have been reported in 42.5% of pregnant women exposed to low-dose methotrexate treatment (less than 30 mg/week), compared to a reported rate of 22.5% in disease-matched patients treated with drugs other than methotrexate
• Major birth defects occurred in 6.6% of live births in women exposed to low-dose methotrexate treatment (less than 30 mg/week) during pregnancy, compared to approximately 4% of live births in disease-matched patients treated with drugs other than methotrexate. 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 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 methotrexate 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
• When methotrexate was discontinued prior to conception, normal pregnancies have been reported
• Women must not get pregnant during methotrexate therapy, and effective contraception must be used during treatment with methotrexate and at least 6 months thereafter. 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

Breastfeeding

• Contraindicated
• Methotrexate is excreted in human milk. Because of the potential for serious adverse reactions in breastfed infants, methotrexate is contraindicated during breastfeeding. Therefore breastfeeding must be discontinued prior to and during administration

Fertility

• Methotrexate affects spermatogenesis and oogenesis and may decrease fertility. In humans, Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea. These effects appear to be reversible after discontinuation of therapy in most cases
• 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
• 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

Renal Impairment

• eGRF >10-60ml/min: Caution; dose adjustment recommended
• eGFR <10ml/min: Contraindicated

eGFR (ml/min)	Dose
> 60	Initial: Dosage should not exceed 5mg weekly; Maintenance: Dosage should not exceed 12.5mg weekly (max. 15mg/week)
30-59	Initial: Dosage should not exceed 2.5mg weekly; Maintenance: Dosage should not exceed 7.5mg weekly (max. 10mg/week)
≤29	Avoid use (only use when there are no alternatives) Initial (test): 2.5mg weekly; Maintenance: Should be guided by therapeutic plasma levels; Dosage should not exceed 5mg weekly Every-alternative week dosing frequency can be adopted in cases of deteriorated renal function
Hemodialysis	Max. 12.5mg weekly; After each dialysis session
<10	Contraindicated

Hepatic Impairment

• Mild to moderate: Caution; dose adjustment may be recommended
• Severe: Contraindicated

Bilirubin (mg/L)	Dose
<30	No adjustment necessary
31-50 (or transaminases >3 times the upper limit of normal)	Administer 75% of the recommended dose
>50	Contraindicated

Elderly

• Caution; dose adjustment recommended
  Initial: 5-7.5mg weekly; Titrate by 2.5mg at intervals of 2-4 weeks; Max dose: 20mg/week
  Concomitant use of folic acid at a dose of 5mg/week is highly recommended to prevent systemic toxicities
  Methotrexate therapy should only be used when the disease is active and less toxic, symptom-modifying therapy is ineffective

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Insomnia
• Psychoses
• Headache
• Fatigue
• Drowsiness
• Dizziness
• Aphasia
• Confusion
• Hemiparesis
• Paresis
• Depression
• Convulsions
• Encephalopathy/leukoencephalopathy
• Mood alterations
• Speech impairment
• Perception disorder
• Motor dysfunction
• Ataxia
• Pain
• Muscular asthenia
• Paresthesia of the extremities
• Irritability
• Meningism
• Acute aseptic meningitis
• Cerebral oedema
• Increased cerebrospinal fluid pressure
• Transient cognitive dysfunction
• Transient acute neurological syndrome
• Dysarthria
• Unusual cranial sensations
• Neurotoxic reactions
• Demyelination
• Chemical arachnoiditis

Cardiovascular Disorders

• Pericardial effusion
• Pericarditis
• Pericardial tamponade
• Vasculitis
• Hypotension
• Thromboembolic events
• Arterial thrombosis
• Cerebral thrombosis
• Deep vein thrombosis
• Retinal vein thrombosis
• Thrombophlebitis
• Pulmonary embolism

Respiratory Disorders

• Acute or chronic interstitial alveolitis
• Pneumonia
• Interstitial pneumonitis
• Non-specific pneumonitis
• Interstitial/pulmonary fibrosis
• Pharyngitis
• Pleurisy
• Dry, non-productive cough
• Thoracic pain
• Dyspnoea
• Bronchial asthma
• Epistaxis
• Respiratory paralysis
• Pneumocystis carinii pneumonia
• Cytomegaloviral pneumonia
• Pulmonary alveolar haemorrhage
• Chronic interstitial obstructive pulmonary disease
• Pleural effusion
• Acute pulmonary oedema
• Infiltration in lung radiography
• Norcardiosis
• Histoplasmosis
• Cryptococcosis
• Alveolitis

Gastrointestinal Disorders

• Loss of appetite
• Nausea and vomiting
• Abdominal pain
• Inflammation and ulceration of the mouth and throat
• Stomatitis
• Ulcerative stomatitis
• Ulceratic colitis
• Haemorrhagic enteritis
• Intestinal perforation
• Mucositis
• Dyspepsia
• Diarrhoea
• Gastrointestinal ulceration and bleeding
• Pancreatitis
• Gingivitis
• Enteritis
• Melena
• Malabsorption
• Haematemesis
• Haematorrhoea
• Toxic megacolon
• Enteritis
• Anorexia

Genitourinary Disorders

• Renal failure
• Inflammation and ulceration of the urinary bladder
• Disturbed micturition
• Oliguria
• Haematuria
• Dysuria
• Anuria
• Proteinuria
• Electrolyte disturbance
• Nephropathy
• Tubular necrosis
• Nepthrotoxicity
• Azotaemia
• Hyperuricaemia
• Cystitis
• Vaginal discharge
• Vaginal bleeding
• Inflammation and ulceration of the vagina
• Loss of libido
• Impotence
• Impaired menstruation
• Transient oligospermia
• Defective oogenesis or spermatogenesis
• Spermatogenesis supression
• Infertility
• Abortion
• Foetal deviations
• Foetal death

Hepatobiliary Disorders

• Increase in liver-related enzymes (ALAT, ASAT, alkaline phosphatase and bilirubin)
• Fatty degeneration of liver
• Fibrosis
• Cirrhosis
• Decreased serum albumin
• Acute hepatitis
• Periportal fibrosis
• Hepatotoxicity
• Reactivation of chronic hepatitis
• Hepatic atrophy
• Hepatic necrosis
• Herpes simplex hepatitis
• Hepatic failure

Musculoskeletal System Disorders

• Arthralgia
• Myalgia
• Osteoporosis
• Stress fracture
• Osteonecrosis of jaw (secondary to lymphoproliferative disorders)
• Osteonecrosis

Endocrine and Metabolic Disorders

• Diabetes mellitus
• Hypoxaemia

Skin and Subcutaneous Tissue Disorders

• Exanthema  
• Erythema multiform
• Erythematous rashes
• Pruritis
• Urticaria
• Photosensitivity
• Pigmentation of the skin
• Bullae
• Depigmentation
• Pigmentation of the nails
• Eccymosis
• Telaniectasia
• Acne
• Furunculosis
• Painful damage to psoriatic lesions
• Radiation dermatitis
• Inflamed/reactivated sunburn
• Onycholysis
• Petechia
• Allergic vasculitis
• Hidradenitis
• Pale skin
• Alopecia
• Skin ulceration
• Increase of rheumatic nodules
• Painful lesions of psoriatic plaque
• Herpetiform eruption
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Acute paronychia
• Cutaneous bacterial infections
• Soft tissue necrosis
• Desquamation

Immune, Blood and Lymphatic System Disorders

• Leukopenia
• Thrombocytopenia
• Anaemia
• Pancytopenia
• Agranulocytosis
• Haematopoietic disorders
• Haematopoietic suppression
• Megaloblastic anaemia
• Bone marrow depression
• Aplastic anaemia
• Lymphadenopathy
• Lymphoproliferative disorders
• Lymphomas
• Eosinophilia
• Neutropenia
• Haemorrhage
• Allergic reactions
• Anaphylactic shock
• Anaphylactic reactions
• Immunosuppression
• Hypogammaglobulinaemia
• Disseminated Herpes simplex 
• Sepsis
• Opportunistic infections
• Fever
• Chills

Sensory Disorders

• Serious impaired vision
• Blurred vision
• Conjunctivitis
• Retinopathy
• Tinnitis
• Transient blindness
• Vertigo
• Changes in sense of taste (metallic taste)
• Ocular irritation

Others

• Tumour lysis syndrome
• Impaired wound healing
• Gynaecomastia
• Paralysis
• Sudden death
• Reactivation of inactive chronic infection

• Alcohol
• Hepatotoxic agents
• Leflunomide
• Haematotoxic agents
• Azathioprine
• Retinoids
• Acitretin
• Etretinate
• Sulfasalazine
• Nitrous oxide
• Oral antibiotics
• Tetracyclines
• Chloramphenicol
• Non-absorbable broad-spectrum antibiotics
• Penicillins
• Glycopeptides
• Sulfonamides
• Ciprofloxacin  
• Cefalotin
• Salicylates
• Hypoglycaemic agents
• Sulphonamides
• P-aminobenzoic acid
• Probenecid
• Weak organic acids
• Pyrazoles
• Non-steroidal anti-inflammatory agents
• Aspirin
• Ibuprofen
• Indomethacin
• Agents affecting bone marrow
• Cotrimoxazole
• Trimethoprim
• Pyrimethamine
• Antifolate agents
• Folic acid
• Calcium folinate
• Antirheumatic agents
• Gold compounds
• Penicillamine
• Hydroxychloroquine
• Cytotoxic agents
• Ciclosporin  
• Mercaptopurine
• Proton pump inhibitors
• Omeprazole
• Pantoprazole
• Theophylline
• Insulin
• Diphenylhydantoins
• Acidic anti-inflammatory agents
• Phenylbutazone
• Phenytoin
• Barbiturates
• Tranquilisers
• Oral contraceptives
• Amidopyrine derivatives
• Pyrazols
• Weak organic acids
• Thiazide diuretics
• Doxorubicin
• Sulfinpyrazone
• Nephrotoxic chemotherapeutic agents
• Cisplatin
• Bleomycin
• 5-fluorouracil
• Cytostatic agents
• Triamterene
• Metamizole
• Anticonvulsant agents
• Levetiracetam
• Cholestyramine
• Procarbazine
• Radiotherapy
• Cytarabine
• Doxorubicin
• Cyclophosphamide
• Aminoglycosides
• Allopurinol
• Colchicine
• Vincristine
• Hydrocortisone
• Prednisone
• Asparaginase
• Cytosine arabinoside
• Aciclovir (parenteral)
• Anticoagulants
• Blood dyscrasia-causing agents
• Bone marrow depressants
• Live vaccines
• Immune-modulating agents
• Caffiene- or theophylline- containing beverages

• Hepatic function
• Renal function
• Full blood count

Specific cases may require

• Hepatitis B and C infections
• Chest x-ray
• Serum methotrexate levels

Dosing

• Methotrexate must be used only by physicians experienced in antimetabolite chemotherapy
• If changing the oral application to parenteral administration a reduction of the dose may be required due to the variable
  bioavailability of methotrexate after oral administration
• Doses exceeding 20 mg week can be associated with a substantial increase in toxicity, especially bone marrow
  depression

Toxicity

• Due to the possibility of severe and even life-threatening toxic reactions, the patient should be fully informed by the attending physician of the risks involved before onset of methotrexate treatment. The patient should be closely monitored throughout the treatment
• Patients should be informed of the signs and symptoms of toxicity, of the need to see their physician promptly if they occur, and the need for close follow-up, including regular laboratory tests for monitoring toxicity
• Complete blood count with differential blood count and platelets, liver enzymes, bilirubin, serum albumin, chest x-ray and renal function tests. If clinically indicated, exclude tuberculosis and hepatitis

Contact with the skin and mucosa 

• Methotrexate (IV)  should not come into contact with the skin or mucosa. In the event of contamination, the affected area must be rinsed immediately with ample amount of water

Rescue schedules of folinic acid following treatment with higher doses of methotrexate

Clinical situation	Laboratory findings	Dosage and duration of folinic acid
Normal methotrexate Elimination	Serum methotrexate level approx 10μmol at 24hrs after admin, 1μmol at 48hrs, and < 0.2μmol 72hrs	15mg oral/IM/IV, 6hrly for 60hrs (10 doses starting at 24hrs after start of methotrexate infusion
Delayed late methotrexate elimination	Serum methotrexate level remaining above 0.2μmol at 72hrs, and > 0.05μmol at 96hrs after admin	Continue 15mg oral/IM/IV, 6hrly, until methotrexate level is < 0.05μmol
Delayed early methotrexate Elimination and/or Evidence of Acute Renal Injury	Serum methotrexate level 50μmol or more at 24hrs, or 5μmol or more at 48hrs after admin, OR a 100% or greater increase in serum creatinine level at 24hrs after methotrexate admin	150mg IV, 3hrly, until methotrexate level <1μmol; then 15mg IV, 3hrly, until methotrexate level is < 0,05μmol

Guidelines for methotrexate rescue with calcium folinate: dosage and administration

Clinical situation	Laboratory findings	Dosage and duration of calcium folinate
Normal methotrexate elimination	Serum methotrexate level approx 10μmol at 24hrs after admin, 1μmol at 48hrs, and < 0.2μmol at 72hrs	7.5mg oral/IM/IV, 6hrly for 60hrs (10 doses starting at 24hrs after starting methotrexate infusion
Delayed late methotrexate elimination	Serum methotrexate level remaining above 0.2μmol at 72hrs, and > 0.05μmol at 96hrs after admin	Continue 7.5mg oral/IM/IV, 6hrly, until methotrexate level is < 0.05μmol
Delayed early methotrexate elimination and/or Evidence of Acute Renal Injury	Serum methotrexate level of 50μmol or more at 24hrs, or 5μmol or more at 48hrs after admin, OR a 100% or greater increase in serum creatinine level at 24hrs after methotrexate  admin	75mg IV, 3hrly, until methotrexate level is < 1μmol; Then 7.5mg IV, 3hrly until methotrexate level is < 0.05μmol

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Tablet 2.5mg - EML (Hospital)

Injection 1g, Injection 5g - EML (Tertiary)

All other formulations - EML (Section 21)

Methotrexate is a folic acid antagonist and its major site of action is the enzyme dihydrofolate reductase. Its main effect is inhibition of DNA synthesis but it also acts directly both on RNA and protein synthesis. Methotrexate is a phase specific substance, the main effect being directed during the S-phase of cell division. 

Tablet 2.5mg

• Abitrexate 2.5mg (Teva Pharmaceuticals)
• Methotrexate-Lederle (Pfizer) originator

Injection (per ml) 25mg

• Methacor (Accord)
• Abitrexate (Teva Pharmaceuticals)

Injection (per 50ml) 5g

• Abitrexate (Teva Pharmaceuticals)

Injection (per 10ml) 1g

• Abitrexate (Teva Pharmaceuticals)

Injection (per 40ml) 1g

• Emthexate Rtu 1000 (Pharmachemie)