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Methotrexate 100 Mg/Ml Concentrate For Solution For Infusion

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Methotrexate 100 mg/ml concentrate for solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains 100 mg methotrexate.

5 ml of solution contains 500 mg methotrexate.

10 ml of solution contains 1000 mg methotrexate.

50 ml of solution contains 5000 mg methotrexate.

Excipients with known effect:

10.60 mg/ml (0.461 mmol/ml) sodium.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Concentrate for solution for infusion Clear, yellow solution with pH 7.0 to 9.0.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Acute lymphocytic leukaemia, Non-Hodgkin’s lymphomas, 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.

4.2 Posology and method of administration

WARNINGS

The dose must be adjusted carefully depending on the body surface area if methotrexate is used for the treatment of tumour diseases.

Fatal cases of intoxication have been reported after administration of incorrect calculated doses. Health care professionals and patients should be fully informed about toxic effects.


Methotrexate 100mg/ml is hypertonic and must not be administered intrathecally.


Method of administration:

Treatment should be initiated by or occur in consultation with a doctor with significant experience in cytostatic treatment.

Methotrexate can be administered intramuscularly, intravenously or intra-arterial. Methotrexate 100mg/ml is hypertonic and must not be administered intrathecally.The dosage is generally calculated per m2 body surface area or body weight. Doses of over 100 mg methotrexate always require subsequent administration of folinic acid (See calcium folinate rescue).

The application and dosage recommendation for the administration of methotrexate for different indications varies considerably. Some common dosages which have been used in different indications are given below. None of these dosages can currently be described as standard therapy. Since the application and dosage recommendations for therapy with methotrexate at high and low dosages vary, only the most commonly used guidelines are given. Current published protocols should be consulted for dosages and the method and sequence of administration.

For instructions on dilution of the medicinal product before administration, see section 6.6.

Posology:

Methotrexate can be given as convention low dose therapy, intermediate dose therapy and high dose therapy..

Conventional low dose therapy: 15-50 mg/m2 body surface area per week intravenously or intramuscularly in one or more doses. 40-60 mg/m2 body surface area (for head and neck cancer) once weekly as intravenous bolus injection.

Intermediate dose therapy: Between 100 mg/m2 to 1000 mg/m2 body surface area in single dose. In advanced squamous epithelial and bladder cancer, intermediate doses of methotrexate up to 100-200 mg/m2 can be used (See calcium folinate rescue).

High dose therapy: In several malignant diseases, including malignant lymphoma, acute lymphatic leukaemia, osteogenic sarcoma and metastatic choriocarcinoma, doses of 1000 mg methotrexate or more per m2 body surface area may be used, administered over a 24-hour period. High dose methotrexate therapy has to be followed by calcium folinate rescue therapy

(further refer to therapy protocols, see calcium folinate rescue).

Calcium folinate rescue

Since the calcium folinate rescue dosage regimen depends heavily on the posology and method of the intermediate or high-dose methotrexate administration, the methotrexate protocol will dictate the dosage regimen of calcium folinate rescue. Therefore, it is best to refer to the applied intermediate or high dose methotrexate protocol for posology and method of administration of calcium folinate.

In addition to calcium folinate administration, measures to ensure the prompt excretion of methotrexate (maintenance of high urine output and alkalinisation of urine) are integral parts of the calcium folinate rescue treatment. Renal function should be monitored through daily measurements of serum creatinine.

Adults

Acute lymphocytic leukaemias (ALL)

In low doses, methotrexate is applied within the scope of complex therapy protocols for maintaining remission in adults with acute lymphocytic leukaemias. Normal single doses lie within the range of 20-40 mg/m2 methotrexate. The maintenance dose for ALL is 15-30 mg/m2 once or twice weekly.

Other examples:

•    3.3 mg/m2 in combination with other cytostatic agent once daily for 4-6 week.

•    2.5 mg/kg every week.

•    High dose regimen between 1 to 12 g/m2 (i.v. 1-6 h) repeated every 1-3 weeks.

•    20 mg/m2 in combination with other cytostatic agents once week.

Breast cancer

Cyclic combination with cyclophosphamide, methotrexate and fluorouracil has been used as adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph nodes. The dose of methotrexate is 40 mg/m2 intravenously on the first and eighth days of the cycle. The treatment is repeated at 3 week intervals. Methotrexate, in intravenous doses of 10-60 mg/m2, could be included in cyclic combination regimes with other cytotoxic drugs in the treatment of advanced breast cancer.

Osteosarcoma

Effective adjuvant chemotherapy requires the administration of several cytotoxic chemotherapeutic drugs. In addition to high dose methotrexate with calcium folinate rescue, doxorubicin, cisplatin and a combination of bleomycin, cyclophosphamide and dactinomycin (BCD) can be given. Methotrexate is used in high doses (8,00012,000 mg/m2) once weekly. If dose is insufficient to reach real serum concentration of 10-3 mol/L at the end of infusion, dose can be increased to 15 g/m2 for subsequent treatment. Calcium folinate rescue is necessary. Methotrexate has also been used as the sole treatment in metastatic cases of osteosarcoma.

Older people

Dose reduction should be considered in elderly patient due to reduced liver and kidney function as well as lower folate reserves which occur with increased age.

Patient with impaired renal function

Methotrexate should be used with caution in patients having impaired renal function. The dose regimens must be adjusted according to the creatinine clearance and serum methotrexate concentrations.

•    If creatinine clearance (ml/min) is >50, 100% MTX dose can be given

•    If creatinine clearance (ml/min) is 20-50, 50% of MTX dose can be given

•    If creatinine clearance (ml/min) is <20,MTX should not be given

Patients with impaired hepatic function

Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially when caused by alcohol. Methotrexate is contraindicated if bilirubin values are >5 mg/dl (85.5 pmol/L). In the event of a constant increase in liver related enzymes, consideration should be given to reducing the dose or discontinuing therapy.

Paediatric population

Methotrexate should be used with caution in paediatric patients. Treatment should follow currently published therapy protocols for children (see section 4.4).

4.3 Contraindications

•    Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

•    Sever liver impairment (see section 4.2).

•    Alcohol abuse.

•    Severe renal impairment (creatinine clearance below 20 mL/min, see section 4.2).

•    Pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia.

•    Serious, acute or chronic infections such as tuberculosis and HIV.

•    Ulcers of the oral cavity and known active gastrointestinal ulcer disease.

•    Pregnancy and breast-feeding (see section 4.6)

•    Concurrent vaccination with live vaccines.

4.4 Special warnings and precautions for use

Fatal toxicity in association with intravenous administration due to dose miscalculation has been reported. Particular caution should be exercised when calculating the dose (see 4.2 posology and administration).

Because of the risk of severe toxic reactions (which can be fatal), methotrexate must only be used in life-threatening neoplastic diseases. Deaths have been reported during treatment of malignancies with methotrexate. The doctor should inform the patient of the risks of treatment and the patient should be monitored constantly by the doctor.

Methotrexate has reportedly caused foetal death and/or congenital malformations. Treatment of neoplastic diseases is not recommended in women of childbearing potential unless there are clear medical indications that the benefits of treatment can be expected to outweigh the conceivable risks (see 4.6 Pregnancy and lactation). Methotrexate affects spermatogenesis and oogenesis during the period in which it is administered, which can result in reduced fertility. These effects may be reversible on discontinuing treatment.

Tumor lysis syndromeLike other cytotoxic agents, methotrexate can induce tumour lysis syndrome in patients with rapidly growing tumours. Appropriate supportive treatment and pharmacological measures can prevent or alleviate such complications.

Methotrexate and NSAIDs

Unexpected severe (including fatal) myelosuppression, aplastic anaemia and gastrointestinal toxicity have been reported in connection with concomitant treatment with methotrexate (usually at a high dose) and non-steroidal anti-inflammatory agents (NSAIDs) (see section 4.5 interaction with other medicinal products and other forms of interaction).

Concomitant methotrexate treatment and radiotherapy can increase the risk of soft tissue necrosis and osteonecrosis.

Intravenous administration of methotrexate can result in acute encephalitis and acute encephalopathy, possibly with a fatal outcome.

Methotrexate and pleural effusion/ascites

Methotrexate is eliminated slowly from collections of fluid (e.g. pleural effusion, ascites). This results in a prolonged terminal half-life and unexpected toxicity. In patients with significant collections of fluid, drainage of the fluid before treatment is started and monitoring of plasma methotrexate levels are recommended.

If stomatitis, diarrhea, haematemesis or black stool occurs, therapy with methotrexate should be discontinued due to the danger of haemorrhagic enteritis or death from intestinal perforation or dehydration (see section 4.8 undesirable side effects).

Conditions in which there is folic acid deficiency can increase the risk of methotrexate toxicity.

In high dose treatment, methotrexate must not be mixed with solutions which contain preservatives (see also 6.6).

Solutions of methotrexate which contain the preservative benzyl alcohol are not recommended for use in infants. Gasping syndrome with fatal outcome has been reported in infants following intravenous treatment with solutions containing the preservative benzyl alcohol. Symptoms include rapid onset of respiratory problems, hypotension, bradycardia and cardiovascular collapse.

Infection or immunological conditions

Methotrexate must be used with great care in connection with active infection and is usually contraindicated in patients with manifest suppression of the immune response or where immunodeficiency is demonstrated by laboratory tests.

Pneumonia (which in certain cases can lead to respiratory failure) can occur. Potentially fatal opportunistic infections including Pneumocystis carinii pneumonia can occur in association with methotrexate treatment. When a patient exhibits pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered (see section 4.8).

Immunisation

Methotrexate may interfere with results of immunological tests. Immunisation after a vaccination may be less effective in association with methotrexate treatment. Particularly caution should be excercised in the presence of inactive, chronic infections (e.g herpes zoster, tuberculosis, hepatitis B or C) due to possible activation. Immunisation with live viruses is not normally recommended.

Skin toxicity: Due to the risk of photo toxicity, the patient must avoid sunlight and solarium.

Monitoring treatment

Patients who start treatment with methotrexate must be carefully monitored so that toxic effects can be detected immediately. Analysis before treatment must include a full blood count with differential and platelet count, liver enzymes, tests for hepatitis B and C infections, renal function test and chest x-ray. Toxic effects of methotrexate can occur even at low doses and it is therefore important to monitor treated patients carefully. Most undesirable effects are reversible if detected early.

After initiation of treatment or when there is change in the dose, or during periods with an increased risk of elevated methotrexate levels (e.g. in dehydration), monitoring should be performed.

Bone marrow biopsy must be performed as necessary.

Serum methotrexate level monitoring can significantly reduce methotrexate toxicity and routine monitoring of serum methotrexate level is necessary depending on dosage or therapy protocol.

Leucopenia and thrombocytopenia occur usually 4 -14 days after administration of methotrexate. In rare cases recurrence of leucopenia may occur 12 - 21 days after administration of methotrexate. Methotrexate therapy should only be continued if the benefit outweighs the risk of severe myelosuppression (see section 4.2).

Haematopoietic suppression : Haematopoietic suppression induced by methotrexate may occur abruptly and at apparently safe doses. In the event of any significant drop in leukocytes or platelets, treatment must be discontinued immediately and appropriate supportive therapy instituted. Patients must be instructed to report all signs and symptoms suggestive of infection. In patients concomitantly taking haematotoxic medications (e.g. leflunomide, trimetoprim/co-trimoxazole and cytarabine), the blood count and platelets should be closely monitored.

Liver function tests: Particular attention should be paid to the onset of liver toxicity. Treatment should not be initiated or should be discontinued if there are any abnormalities in liver function tests or liver biopsies, or if these develop during therapy. Such abnormalities should return to normal within two weeks; after which, treatment may be resumed at the discretion of the doctor. Further research is needed to establish whether serial liver chemistry tests or propeptide of type III collagen can detect hepatotoxicity sufficiently. This assessment should differentiate between patients without any risk factors and patients with risk factors, e.g. excessive prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family history of hereditary liver disorders, diabetes mellitus, obesity and previous contact with hepatotoxic drugs or chemicals and prolonged methotrexate treatment or cumulative doses of 1.5 g or more.

Screening for liver-related enzymes in serum: A transient rise in transaminase levels to twice or three times the upper limit for normal has been reported with a frequency of 13-20%. In the event of a constant increase in liver related enzymes, consideration should be given to reducing the dose or discontinuing therapy.

Insulin-dependent diabetes

Patients suffering from insulin-dependent diabetes should be carefully monitored because liver cirrhosis and an increase in transaminase can occur.

Due to the potentially toxic effect on the liver, additional hepatotoxic medications should not be given during treatment with methotrexate unless clearly necessary and alcohol consumption should be avoided or greatly reduced (see section 4.5). Closer monitoring of liver enzymes should be undertaken in patients concomitantly taking other hepatotoxic medications (e.g. leflunomide). The same should also be taken into consideration if haematotoxic medications are co-administered.

Malignant lymphomas may occur in patients receiving low-dose methotrexate; in which case, methotrexate must be discontinued. If lymphomas should fail to regress spontaneously, initiation of cytotoxic therapy is required.

Renal function: methotrexate treatment in patients with impaired renal function should be monitored via renal function tests and urinalysis, since impaired renal function reduces the elimination of methotrexate, which may result in severe adverse reactions.

In cases of possible renal impairment (e.g. in elderly patients), close monitoring of renal function is required. This is particularly applies to the co-administration of medicinal products which affect methotrexate excretion cause kidney damage (e.g. non-steroidal anti-inflammatory drugs) or which can potentially lead to haematopoietic disorder. Dehydration may also potentiate the toxicity of methotrexate. Alkalinisation of the urine and increase a high diuresis is recommended.

Respiratory System: 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) 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.

Methotrexate should be withdrawn from patients with pulmonary symptoms and a thorough investigation (including chest x-ray) 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.

Pulmonary symptoms require a quick diagnosis and discontinuation of methotrexate therapy. Pneumonitis can occur at all doses.

Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate.

Paediatric population Methotrexate should be used with caution in paediatric patients. Treatment should follow currently published therapy protocols for paediatric population. Serious neurotoxicity, frequently manifested as generalised or focal seizures has been reported with unexpectedly increased frequency among paediatric patients with acute lymphoblastic leukaemia who were treated with intermediate-dose intravenous methotrexate (1 g/m2). Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies.

Elderly

Because of deterioration in liver and kidney function as well as reduced folic acid reserves, relatively low doses should be considered in elderly patients. These patients must be closely monitored for early signs of toxicity.

Sodium

Methotrexate injection 100 mg/ml contains 193.98 mg (8.436 mmol) of sodium per maximum daily dose. This should be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Ciprofloxacin

Excretion of methotrexate possibly reduced (increased risk of toxicity).

Non-steroidal anti-inflammatory drugs (NSAIDs).

NSAID preparations must not be given prior to or concomitantly with the high doses of methotrexate used in the treatment of conditions such as osteosarcoma . Concomitant administration of NSAIDs and methotrexate at high doses has reportedly elevated and prolonged serum methotrexate levels, resulting in deaths from severe haematological and gastrointestinal toxicity. NSAID preparations and salicylates have reportedly reduced the tubular secretion of methotrexate in animal models and may increase its toxicity by increasing methotrexate levels. Concomitant treatment with NSAIDs and low doses of methotrexate must therefore be administered with caution.

Leflunomide

Methotrexate in combination with leflunomide can increase risk of pancytopenia.

Probenecid

Renal tubular transport is diminished by probenecid, and its use together with methotrexate must be avoided.

Penicillins

Penicillins can reduce renal clearance of methotrexate. Haematological and gastrointestinal toxicity have been observed in combination with high and low dose methotrexate.

Oral antibiotics

Oral antibiotics such as tetracycline, chloramphenicol and non-absorbable broad-spectrum antibiotics may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and hence the metabolism of methotrexate by bacteria. In isolated cases, trimethoprim/sulfamethoxazole has reportedly increased myelosuppression in patients treated with methotrexate, probably due to reduced tubular secretion and/or an additive antifolate effect.

Chemotherapeutic products

An increase in renal toxicity can be observed when high doses of methotrexate are given in combination with potentially nephrotoxic chemotherapeutic agents (e.g. cisplatin).

Radiotherapy

Concurrent methotrexate and radiotherapy can increase the risk of soft tissue necrosis and osteonecrosis.

Cytarabine

Concomitant therapy with cytarabine and methotrexate can increase the risk of severe neurological side effects ranging from headache to paralysis, coma and stroke-like episodes.

Hepatotoxic products

The risk of increased hepatotoxicity when methotrexate is administered concurrently with other heptatotoxic products has not been studied. Hepatotoxicity has however been reported in such cases. Patients receiving concomitant treatment with drugs with a known hepatotoxic effect (e.g. leflunomide, azathioprine, sulfasalazine, retinoids) must be carefully monitored for signs of any increase in hepatotoxicity.

Theophylline

Methotrexate can reduce clearance of theophylline. Theophylline levels must therefore be monitored during concomitant treatment with methotrexate.

Mercaptopurine

Methotrexate increases plasma content of mercaptopurine. The combination of methotrexate and mercaptopurine can therefore require dose adjustment.

Drugs with high plasma protein binding

Methotrexate is partially bound to serum albumin. Other highly bound drugs such as salicylates, phenylbutazone, phenytoin and sulfonamides can increase the toxicity of methotrexate by means of displacement.

Furosemide

Concomitant administration of furosemide and methotrexate can result in increased levels of methotrexate due to competitive inhibition of tubular secretion.

Vitamins

Vitamin preparations containing folic acid or its derivatives can cause a reduced response to systemically administered methotrexate, however conditions in which there is a deficiency of folic acid can increase the risk of methotrexate toxicity.

Proton pump inhibitors

Literature data indicate that co-administration of proton pump inhibitors and methotrexate, especially at high dose, may result in elevated and prolonged plasma levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicity.

4.6 Fertility, pregnancy and lactation

Pregnancy:

Methotrexate is contraindicated during pregnancy (see section 4.3). Methotrexate can cause foetal death, embryotoxicity, abortion or teratogenic effects when administered to pregnant women (see section 5.3). During pregnancy, especially in the first trimester, cytotoxic drugs must only be given when strictly indicated, weighing the needs of the mother against the risks to the foetus. Treatment with methotrexate during the first trimester has resulted in a high risk of malformations (in particular cranial malformation and malformation of the extremities).

Breastfeeding:

Methotrexate passes into breast milk in quantities such that there is a risk to the child even at therapeutic doses. Breast feeding must therefore be discontinued during treatment with methotrexate (see section 4.3).

Fertility:

Methotrexate may be genotoxic. Women of childbearing potential must not be treated with methotrexate until pregnancy has been excluded. Since in men spermatogenesis can be affected by methotrexate, pregnancy should be avoided if either partner is receiving methotrexate. The optimum time interval between discontinuation of methotrexate therapy in either partner and pregnancy has not been established. The recommended interval in published literature varies between three months and one year. 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. Men should seek advice about the possibility of sperm preservation before starting therapy.

4.7 Effects on ability to drive and use machines

Since fatigue and dizziness can occur as an undesirable effect, ability to react and judgement can be impaired, which should be taken into account for example when driving or carrying out work involving a high degree of precision.

4.8 Undesirable effects

Conventional and high dose therapy

The frequency and degree of severity of undesirable effects depends on the dose administered, the duration of exposure and method of administration, but side effects have been seen at all doses and can occur at any time during treatment. Most undesirable effects are reversible when detected at an early stage. When severe reactions occur, the dose should be reduced or treatment discontinued and appropriate measures initiated (see section 4.9). If treatment with methotrexate is resumed, this should be done with caution after adequate consideration of the further need for the drug. Increased vigilance with regard to any recurrence of toxicity is required.

The most frequently reported undesirable effects include ulcerative stomatitis, leukopenia, nausea and bloating. Other frequently reported undesirable effects are feeling unwell, unusual tiredness, chills and fever, dizziness, reduced resistance to infections. Treatment with folinic acid during high dose therapy can counteract or alleviate a number of undesirable effects. Temporary discontinuation of therapy is recommended if there are signs of leukopenia.

Organ

system

class

Very

common

(>1/10)

Common

(>1/100 to <1/10 )

Uncommon

(>1/1,000 to <1/100)

Rare

(>1/10,000

to

<1/1,000)

Very rare (<1/10,000)

Not known

(Cannot be estimated from the available data)

Infections

and

infestations

Herpes zoster

Sepsis,

Opportunistic infections (may be fatal in some cases), infections caused by the cytomegaly virus

Cardiac

disorders

Pericardial

effusion,

pericarditis,

pericardial

tamponade

Blood and lymphatic

leukocypenia,

thrombocytope

Pancytopenia,

agranulocytosis,

Megaloblas tic anaemia

Severe courses ofbone

Haemorrhage,

haematoma

system

disorders

nia and anaemia

haematopoietic

disorders

marrow depression,apl astic anaemia. Lymphadenop athy,

lymphoprolifer

ative disorders

(partly

reversible),

eosinophilia

and

neutropenia

Immune

system

disorders

Anaphylactoid

reactions,

allergicvasculiti

s

Immunosuppre

ssion,

hypogammagl

obulinaemia

Metabolism

and

nutrition

disorders

Diabetes

mellitus

Psychiatric

disorders

Insomnia,

cognitive

dysfunction

psycosis

Nervous

system

disorders

Headache,

fatigue,

drowsiness

Vertigo,

confusion,

depression,

seizures,

convulsion,

encephalopathy,

Severely

impaired

vision,

mood

alterations,

paresis,

speech

impairment

incl.

dysarthria

and

aphasia,

myelopathy

Pain, muscular asthenia or paresthesia of the

extremities,

myasthenia,

changes in

sense of taste

(metallic

taste),

meningism

(paralysis,

vomiting),

acute aseptic

meningitis

Eye

disorders

visual disturbance s, blurred vision

Conjunctivitis,

Retinopathy,

transient

blindness/loss

of vision,

periorbital

oedema,

blepharitis,

epiphora,

photophobia

Neoplasms

individual cases of lymphoma,

Tumour lysis syndrome

benign,

malignant

and

unspecified

(incl cysts and

polyps)

which abated in a number of cases once methotrexate treatment had been

discontinued. In a recent study, it was not possible to establish that methotrexate therapy increases the incidence of lymphomas

Vascular

disorders

Vasculitis

hypotensio

n,

thromboem

bolic events

reactions

(incl.

arterial

thrombosis,

cerebral

thrombosis,

thrombophl

ebitis, deep

vein

thrombosis, retinal vein thrombosis, pulmonary embolism)

Cerebral

oedema,

petechie

Respiratory , thoracic and

mediastinal

disorders

Pulmonary complications due to interstitial alveolitis/pneu monitis and related deaths (independent of dose and duration of methotrexate treatment). Typical symptoms may be: general illness; dry, irritating cough; shortness of breath

progressing to

Pulmonary

fibrosis

Pharyngitis,

apnoea,

bronchial

asthma

Pneumocystis carinii pneumonia, shortness of breath, chronic

obstructive

pulmonary

disease.

Infections

including

pneumonia

have also been

observed.

Pleural

effusion

Acute

pulmonary

oedema

rest dyspnoea, chest pain, fever. If such complications are suspected, methotrexate treatment must be

discontinued

immediately

and infections

(including

pneumonia)

must be

excluded.

Gastrointes

tinal

disorders

Loss of

appetite,

nausea,

vomiting,

abdomina

l pain,

inflammat

ion and

ulceration

s of the

mucous

membran

e of

mouth

and throat

(especiall

y during

the first

24-48

hours

after

administr ation of methotrex ate).

Stomatitis

dyspepsia

Diarrhoea (especially during the first 24-48 hours after

administration

of

methotrexate)

gastrointestinal bleeding and ulcers, pancreatitis

Gingivitis,

Enteritis,

melaena

(bloody

stools),

malabsorpti

on

Haematemesis (vomiting blood), toxic megacolon

Hepato

biliary

disorders

Increase

in liver-

related

enzymes

(ALAT,

ASAT,

alkaline

phosphata

se and

bilirubin).

Development of liver fattening, fibrosis and cirrhosis (occurs frequently despite regularly monitored, normal values of liver enzymes); diabetic metabolism;

Acute

hepatitis,

and

hepatotoxic

ity

Reactivation of chronic hepatitis, acute liver

degeneration. Furthermore, herpes simplex hepatitis and liver

insufficiency have been

Metabolic

disorder

drop of serum albumin.

observed (also see the notes regarding liver biopsy in section 4.4).

Skin and subcutaneo us tissue disorders

Exanthema,

erythema,

itching

urticaria, photosensibility, pigmentation of the skin, hair loss, increase of rheumatic nodules, herpes zoster, painful lesions of psoriatic plaque; severe toxic reactions: vasculitis, herpetiform eruption of the skin, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyells syndrome)

Increased

pigmentary

changes of

nails, acne,

petechiae,

ecchymose

s, erythema

multiforme,

cutaneous

erythemato

us

eruptions.

Furunculosis,

teleangiectasis,

acute

paronychia,

Furthermore,

nocardiosis,

histoplasma

and

cryptococcus mycosis and disseminated herpes simplex have been reported. Allergic vasculitis, hidradenitis

Exfoliative dermatitis, skin necrosis

Musculosk

eletal

system,

connective

tissue and

bone

disorders

Osteoporosis,

Arthralgia,

myalgia

Stress

fracture

Renal and

urinary

disorders

Inflammation and ulceration of the urinary bladder (possibly with haematuria), dysuria.

Renal

failure,

oliguria,

anuria,

azotaemia,

hyperuricae

mia,

elevated

serum

creatinine

and urea

level

Proteinuria

Reproducti ve system and breast disorders

Inflammation and ulceration of the

vagina

Loss of libido,

impotence,

oligospermia,

impaired

menstruation,,

vaginal

discharge,

infertility,

gynaecomastia

General

disorders

and

administrati on site conditions

Severe allergic reactions progressing to anaphylactic shock;

Fever, impaired wound healing

The following undesirable effects have also been reported, but their frequency has not been established: Pneumocystis carinii pneumonia (including reversible cases),foetal death, damage to the foetus, abortion.

Systemic organ toxicity

Lymphoma

Malignant lymphoma which can go into remission after discontinuation of the treatment with methotrexate can occur in patients on low dose therapy, and may not therefore require any cytotoxic treatment. Methotrexate should be discontinued first and appropriate treatment initiated if the lymphoma does not regress.

Haematological

Methotrexate can suppress haematopoiesis and cause anaemia, aplastic anaemia, pancytopenia, leukopenia, neutropenia and/or thrombocytopenia. Methotrexate must be administered with caution to patients with malignancies and underlying factors affecting haematopoiesis. When treating neoplastic conditions, treatment with methotrexate should only be given provided the potential benefits outweigh the risk of myelosuppression.

Lungs

Lung disease caused by methotrexate, including acute or chronic interstitial pneumonitis, is a potentially dangerous complication, which can occur at any time during the course of treatment. This undesirable effect has been reported at low doses and is not always totally reversible. Deaths have been reported. Signs of pulmonary involvement or symptoms such as dry non-productive cough, fever, chest pains, dyspnoea, hypoxemia and infiltrate on x-ray of the lungs, or non-specific pneumonitis which occurs in connection with methotrexate therapy, may indicate potentially serious damage and requires discontinuation of treatment and careful investigation. Lung changes can occur at all doses. The possibility of infection (including pneumonia) must be excluded.

Gastrointestinal

If vomiting, diarrhoea or stomatitis occur, with resulting dehydration, methotrexate therapy must be discontinued until the patient has recovered. Haemorrhagic enteritis and deaths caused by intestinal perforation can occur. Methotrexate must be used with great caution in patients with peptic ulcers or ulcerative colitis. Stomatitis can be prevented or alleviated by folinic acid mouthwashes.

Liver

Methotrexate involves a potential risk of acute hepatitis and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal and occurs commonly after long-term use (in general after 2 years or more) and after a total cumulative dose greater than 1.5 g. In studies of psoriasis patients hepatotoxicity was seen to be proportional to the cumulative dose and was potentiated by alcoholism, overweight, diabetes and age.

Transient deterioration in liver enzyme values is frequently seen after methotrexate treatment and does not usually necessitate adjustment of treatment. Existing abnormal liver values and/or reduction in serum albumin can indicate severe hepatotoxicity.

Methotrexate has caused reactivation of hepatitis B infections and exacerbation of hepatitis C infections, in some cases with fatal outcome. Some cases of hepatitis B reactivation have occurred following discontinuation of methotrexate. Clinical and laboratory tests should be performed to investigate any occurrence of liver disease in patients with prior hepatitis B or C infections. Based on these investigations, treatment with methotrexate may prove unsuitable for certain patients.

In the event of impaired liver function, the undesirable effects of methotrexate (in particular stomatitis) can be exacerbated.

Kidneys

Methotrexate can cause kidney damage which can result in acute renal failure. Renal function can be exacerbated following high dose therapy to such an extent that the excretion of methotrexate is inhibited, as a result of which systemic methotrexate toxicity can occur. In order to prevent renal failure, alkalinisation of the urine and adequate fluid intake (at least 3 l/day) are recommended. Measurement of serum methotrexate and renal function is recommended.

Skin

Serious, in some cases fatal skin reactions, including toxic epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome and erythema multiforme have been reported within a few days of oral, intramuscular or intravenous treatment with methotrexate in single or repeat doses. Radiation dermatitis and sunburn can be accentuated after use of methotrexate.

CNS

There are reports of leukoencephalopathy after intravenous treatment with methotrexate in patients who have undergone craniospinal radiotherapy. Severe neurotoxicity, often manifested as generalised or focal seizures have been reported with an unexpected increase in frequency in children with acute lymphoblastic leukaemia treated with a moderately high dose of intravenous methotrexate (1 g/m2). Symptomatic patients frequently had leukoencephalopathy and/or microangiopathic calcifications in x-ray investigations.

Chronic leukoencephalopathy has also been reported in patients treated with repeated high doses of methotrexate together with folinic acid, even without concomitant cranial radiotherapy. Discontinuation of the methotrexate therapy did not always result in full recovery. Leukoencephalopathy has also been reported in patients treated with methotrexate tablets.

One transient acute neurological syndrome has been observed in patients undergoing high dose therapy. Manifestations of this neurological syndrome can include abnormal behaviour, focal sensorimotor symptoms including transient blindness, and abnormal reflexes. The exact cause is unclear.

Cases of neurological side effects ranging from headache to paralysis, coma and stroke-like episodes have been reported, primarily in children and adolescents receiving concomitant medication with cytarabine.

Intrathecal therapy

The subacute neurotoxicity is usually reversible after discontinuing methotrexate.

Organ system class

Common (>1/100)

Central and peripheral nervous system disorders

Headache, chemical arachnoiditis, subacute neurotoxicity, necrotising demyelinating leukoencephalopathy

Gastrointestinal disorders

Nausea and vomiting

General disorders and administration site conditions

Fever

Chemical arachnoiditis, which can occur a few hours after intrathecal administration of methotrexate is characterised by headache, back pain, stiff neck, vomiting, fever, meningism and pleocytosis in the cerebrospinal fluid similar to that in bacterial meningitis. Arachnoiditis generally disappears within a few days.

Subacute neurotoxicity, common after frequently repeated intrathecal administration, mainly affects the motor functions in the brain or spinal cord. Paraparesis/paraplegia, with involvement of one or more spinal nerve roots, tetraplegia, cerebellar dysfunction, cranial nerve paralysis and epileptic seizures can occur.

Necrotising demyelinating leukoencephalopathy can occur several months or years after starting intrathecal therapy. The condition is characterised by progressive neurological deterioration with insidious onset, confusion, irritability and somnolence. Ultimately severe dementia, dysarthria, ataxia, spasticity, seizures and coma can occur. The condition can be fatal. Leukoencephalopathy occurs primarily in patients who have received large quantities of intrathecal methotrexate in combination with cranial radiotherapy and/or systemically administered methotrexate.

Signs of neurotoxicity (meningeal inflammation, transient or permanent paresis, encephalopathy) must be followed up after intrathecal administration of methotrexate.

Reporting of suspected adverse reactions

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 Yellow Card Scheme

Website: www.mhra.gov .uk/yellowcard

4.9 Overdose

Experience of overdose with the product has in general been associated with oral and intrathecal treatment, although overdose in association with intravenous and intramuscular administration has also been reported.

Reports of oral overdose have often been due to accidental daily instead of weekly ingestion. Commonly reported symptoms following oral overdose include the symptoms and signs seen at pharmacological doses, in particular haematological and gastrointestinal reactions such as leukopenia, thrombocytopenia, anaemia, pancytopenia, neutropenia, myelosuppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In certain cases no symptoms were reported. There are reports of deaths associated with overdose. In these cases there were also reports of conditions involving sepsis or septic shock, renal failure and aplastic anaemia.

The most common symptoms of intrathecal overdose are CNS symptoms including headache, nausea and vomiting, seizures or convulsions and acute toxic encephalopathy. In certain cases, no symptoms were reported. There have been reports of deaths following intrathecal overdose. In these cases there were also reports of cerebellar herniation accompanying elevated intracranial pressure and toxic encephalopathy.

Recommended treatment

Antidote therapy: Folinic acid should be given parenterally at a dose at least the size of the methotrexate dose and should wherever possible be administered within an hour. Folinic acid is indicated to minimise toxicity and counter the effect of methotrexate overdose. Folinic acid treatment should be initiated as soon as possible. The longer the interval between the administration of methotrexate and the initiation of folinic acid, the less the effect of folinic acid in suppressing the toxic effect. Monitoring of serum methotrexate concentrations is necessary to be able to determine the optimum dose of folinic acid and the length of the treatment.

In the event of a major overdose, hydration and alkalinisation of the urine may be required to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Neither standard haemodialysis nor peritoneal dialysis have been shown to

increase the elimination of methotrexate. Acute intermittent haemodialysis with the use of highly permeable dialyser may be attempted for methotrexate intoxication.

Intrathecal overdose may require intensive systemic supportive measures such as systemic administration of high doses of folinic acid, alkaline diuresis, acute CSF drainage and ventricular lumbar perfusion.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Cytostatic agent: folic acid analogue ATC code: L01BA01

Mechanism of action:

Methotrexate is a folic acid antagonist with a cytostatic effect. Methotrexate inhibits the conversion of folic acid to tetrahydrofolic acid since the compound has a greater affinity for the enzyme dihydrofolate reductase than the natural substrate folic acid. As a result, DNA synthesis and new cell formation are inhibited. Methotrexate is s-phase specific.

Clinical efficacy and safety:

Actively proliferating tissues such as malignant cells, bone marrow, foetal cells, epithelium and buccal and intestinal mucosa are generally most susceptible to methotrexate.

5.2 Pharmacokinetic properties

Absorption:

Following intravenous administration, peak serum concentrations of methotrexate are reached after approx. 0.5 - 1 hour. There is wide inter-individual and intra-individual variation, especially with repeated doses. Saturation of oral absorption occurs at doses above 30 mg/m2.

Distribution:

About half of the absorbed methotrexate is bound to plasma proteins, but binding is reversible, and methotrexate is easily diffused into the cells with the highest concentrations reached in the liver, spleen and kidneys in the form of polyglutamate can be found which can be retained for few weeks or months. Methotrexate also passes to a lesser degree into cerebrospinal fluid.

Biotransformation and elimination:

The half-life is approx. 3 to 10 hours with low dose therapy and approx. 8 to 15 hours with high dose therapy. Elimination from plasma is triphasic and the majority of the methotrexate is excreted unchanged in urine within 24 hours.

5.3 Preclinical safety data

Animal studies show that methotrexate impairs fertility and that it is embryotoxic, foetotoxic and teratogenic. Methotrexate is mutagenic in vivo and in vitro, but the clinical significance is unknown since rodent carcinogenicity studies have produced differing results.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium hydroxide, Water for Injections-

6.2 Incompatibilities

Owing to the absence of compatibility studies, this medicine should not be mixed with other medicines except those mentioned in section 6.6.

6.3 Shelf life

Unopened vials -24 months

Vial after first opening - Use immediately after opening.

After dilution

Chemical and physical stability of the diluted solution have been demonstrated in glucose solution (5%) and sodium chloride solution (0.9%) at concentrations of 5mg/ml and 20mg/ml for 36 hours at 20-25°C and 35 days at 2-8°C. Diluted product is stable in both diluents at both concentrations for 36 hours at 20-25°C and 35 days at 2-8°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and condition prior to use are the responsibility of the user and would not longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled validated aseptic condition.

6.4 Special precautions for storage

Do not store above 30°C.

For storage conditions after dilution, see section 6.3.

6.5 Nature and contents of container

5 ml: 5 ml Type I clear tubular glass vial, sealed with a grey butyl rubber stopper and aluminium flip-off royal blue seal.

10 ml: 10 ml Type I clear tubular glass vial, sealed with a grey butyl rubber stopper and aluminium flip-off red seal.

50 ml: 50 ml Type I clear tubular glass vial, sealed with a grey butyl rubber stopper and aluminium flip-off yellow seal.

Pack size: 1 vial in carton for 5 ml, 10 ml and 50 ml pack size.

5 vials in a carton for 5 ml, 10 ml & 50 ml pack size

Not all the pack size may be marketed .

6.6 Special precautions for disposal

The solution should be visually inspected prior to use. Only clear solution practically free from particles should be used.

Methotrexate injection may be further diluted with an appropriate preservative-free medium such as glucose solution (5%) or sodium chloride solution (0.9%).

With respect to the handling the following general recommendations should be considered: The product should be used and administered only by trained personnel; the mixing of the solution should take place in designated areas, designed to protect personnel and the environment (e.g safety cabins); protective clothing should be worn (including gloves, eye protection, and masks if necessary).

Pregnant healthcare personnel should not handle and/or administer Methotrexate injection.

Methotrexate should not come into contact with the skin or mucosa. In the event of contamination, the affected area must be irrigated immediately with copious quantities of water at least ten minutes.

For single use only. Any unused solution should be discarded. Waste should be disposed of carefully in suitable separate containers, clearly labelled as to their contents (as the patient's body fluids and excreta may also contain appreciable amounts of antineoplastic agents and it has been suggested that they, and material such as bed linen contaminated with them, should also be treated as hazardous waste). Any unused product or waste should be disposed of in accordance with local requirements by incineration.

Adequate procedures should be in place for accidental contamination due to spillage; staff exposure to antineoplastic agents should be recorded and monitored.

7    MARKETING AUTHORISATION HOLDER

Accord Healthcare Limited Sage House

319 Pinner Road

North Harrow

Middlesex

HA1 4HF

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 20075/0378

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

06/08/2014

10    DATE OF REVISION OF THE TEXT

01/06/2015