METHOTREXATE 100 MG / ML INJECTION BP - patient leaflet, side effects, dosage

Methotrexate 100mg/ml Injection BP

Methotrexate

Read all of this leaflet carefully before you are given this medicine.Keep this leaflet. You may need to read it again.If you have further questions, please ask your doctor or nurse.

In this leaflet:

• 1. What is methotrexate and what is it used for?

• 2. Before you are given methotrexate

• 3. How methotrexate will be given to you

• 4. Possible side effects

• 5. Storing methotrexate

The active substance in the injection is methotrexate.

The other ingredients are sodium hydroxide and water for injections.

Marketing Authorisation Holder and Manufacturer:

EBEWE Pharma Ges.m.b.H. Nfg.KG

A-4866 Unterach, AUSTRIA

1. WHAT IS METHOTREXATE AND WHAT IS IT USED FOR?

Methotrexate 100mg/ml Injection BP is a solution for injection. It is available as a single 10ml vial containing 1000mg of methotrexate and a single 50ml vial containing 5000mg of methotrexate.

Methotrexate 100mg/ml Injection BP is a clear yellow solution free from particles.

Methotrexate belongs to a group of medicines known as cytotoxics, which are used in the treatment of cancer. Methotrexate may be used to treat tumours of the placenta, breast cancer, leukaemia and lymphomas. It is also used in the treatment of mycosis fungoides (a type of skin cancer) and severe psoriasis (a skin condition) which has not responded to other treatments.

Methotrexate helps the patients with psoriasis by killing the cells in the skin which are growing too quickly. It is these fast growing cells which cause the raised patches of skin in psoriasis. Methotrexate can also be used to treat several kinds of cancer. It prevents cancer cells from growing and eventually kills them, by stopping a chemical called dihydrofolate reductase from working.

• 2. BEFOREYOU ARE GIVEN METHOTREXATE

You will not be given methotrexate:

• if you are allergic to methotrexate or any of the other ingredients,
• if you have severe liver problems,
• if you have severe kidney problems,
• if you have serious blood disorders including certain types of anaemia or a reduction in white blood cell numbers (leucopenia) or platelet numbers

(thrombocytopenia)

• if you are breast-feeding and additionally, for non-oncologic indications (for non-cancer treatment) if you are pregnant (see section “Pregnancy, breast-feeding and fertility”)"

Your doctor will take special care when giving you methotrexate:

• if you are using other medication, because they may either increase the toxicity of methotrexate or reduce the effectiveness of methotrexate (e.g. penicillamine),
• if you have mild to moderate liver or kidney problems or blood disorders
• if you are have stomach ulcers or ulcerative colitis
• if you have excess fluid on the lungs or in the abdomen (ascites)
• if you are suffering from an infection or you are generally ‘run down’
• if you are very young or very old
• if you are also receiving radiotherapy
• if you need to be vaccinated as methotrexate can reduce the effect of vaccines

Consult your doctor if any of the above warnings applies to you or has applied to you in the past.

Before your treatment starts you will be given a chest X-ray.Your doctor will check your kidney function, liver function and blood before, during and after every treatment cycle and may repeat the chest X-ray. If the results of any of these tests are abnormal treatment will only be resumed when all readings are back to normal.

Methotrexate temporarily affects sperm and egg production. Methotrexate can cause miscarriage and severe birth defects. You and your partner should avoid having a baby if you are being given methotrexate at the time and for at least 6 months after the end of your treatment with methotrexate. See also section “Pregnancy, breast-feeding and fertility”.

Pregnancy

Do not use Methotrexate during pregnancy except if your doctor has prescribed it for oncology treatment. Methotrexate can cause birth defects, harm the unborn child or cause miscarriage. It is associated with malformations of the skull, face, heart and blood vessels, brain, and limbs. It is therefore very important that methotrexate is not given to pregnant women or to women who are planning to become pregnant unless used for oncology treatment.

For non-oncological indications, in women of child-bearing age the possibility of a pregnancy must be ruled out, e.g. by pregnancy tests, before treatment is started.

Do not use Methotrexate if you are trying to become pregnant. You must avoid becoming pregnant during treatment with methotrexate and for at least 6 months after the end of treatment. Therefore, you must ensure that you are taking effective contraception for the whole of this period (see also section „Warnings and precautions“).

If you become pregnant during treatment or suspect you might be pregnant, speak to your doctor as soon as possible. If you do become pregnant during treatment, you should be offered advice regarding the risk of harmful effects on the child through treatment.

If you want to become pregnant, you should speak with your doctor, who may refer you for specialist advice before the planned start of treatment.

Male fertility

The available evidence does not indicate an increased risk of malformations or miscarriage if the father takes methotrexate less than 30 mg/week. However, a risk cannot be completely excluded and there is no information regarding higher methotrexate doses. Methotrexate can have a genotoxic effect. This means that the medicine can cause genetic mutations. Methotrexate can affect the production of sperm, which is associated with the possibility of birth defects.

You should avoid fathering a child or to donate semen during treatment with methotrexate and for at least 6 months after the end of treatment. As treatment with methotrexate at higher doses commonly used in cancer treatment can cause infertility and genetic mutations, it may be advisable for male patients treated with methotrexate doses higher than 30 mg/week to consider sperm preservation before the beginning of treatment (see also section „Warnings and precautions“).

Breast-feeding

Methotrexate should not be given to you if you are breast-feeding, because methotrexate passes into breast milk and may affect the baby.

Driving and using machines:

If you are experiencing side-effects which could affect your ability to drive, you should avoid driving or operating machinery until these have worn off.

Being given methotrexate at the same time as other medication

Taking methotrexate at the same time as NSAIDs (e.g. aspirin, ibuprofen), antidiabetic agents, diuretics (water tablets), certain antibiotics (e.g. trimethoprim, co-trimoxazole, penicillin, tetracyclines, chloramphenicol), phenytoin (used to treat epilepsy), probenecid (for gout) and nitrous oxide can increase the toxic effects of methotrexate.

The use of methotrexate with drugs which affect the functioning of the liver or kidneys, including alcohol, should be avoided.

The use of methotrexate with etretinate (used in psoriasis) should be avoided.

Taking folic acid (in some vitamin preparations) at the same time as methotrexate may make it less effective.

Having radiation therapy or taking bone marrow function suppressing medicines at the same time as methotrexate may enhance the suppression of the bone marrowfunction.

Tell your doctor or pharmacist about medicines you are currently taking or have taken recently. This also applies to medicines you may have bought yourself from a pharmacy or supermarket.

• 3. HOW METHOTREXATE WILL BE GIVEN TO YOU

Methotrexate will only be given to you under the supervision of a doctor specialised in this type of treatment.

Important warning about the dose of Methotrexate:

Use Methotrexate only once a week for the treatment of psoriasis. Using too much of Methotrexate may be fatal.

Please read section 3 of this leaflet very carefully. If you have any questions, please talk to your doctor or pharmacist before you take this medicine.

Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation of therapy. In addition, methotrexate causes embryotoxicity, abortion and foetal defects in humans. Therefore the possible risk of effects on reproduction should be discussed with patients of childbearing potential (see ,Warnings‘).

Patients undergoing therapy should be subject to appropriate supervision so that signs or symptoms of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay. Pretreatment and periodic haematological studies are essential to the use of methotrexate in chemotherapy because of its common adverse effect of haematopoietic suppression. This may occur abruptly and on apparent safe dosage, and any profound drop in blood cell count indicates immediate stopping of the drug and appropriate therapy. In patients with malignant disease who have pre-existing bone marrow aplasia, leukopenia, thrombocytopenia or anaemia, methotrexate should be used with caution, if at all.

In general, the following laboratory tests are recommended as part of essential clinical evaluation and appropriate monitoring of patients chosen for or receiving methotrexate therapy: complete haemogram; haematocrit; urinalysis; renal function tests; liver function tests and chest X-ray.

The purpose is to determine any existing organ dysfunction or system impairment.The tests should be performed prior to therapy, at appropriate periods during therapy and after termination of therapy.

Liver biopsy may be considered after cumulative doses >1.5g have been given, if hepatic impairment is suspected.

After absorption, methotrexate is bound in part to serum albumin and toxicity may be increased because of displacement by certain drugs such as salicylates, sulphonamides, phenytoin, and some antibacterials such as tetracycline, chloramphenicol and para-aminobenzoic acid (see 4.5 Interactions with other Medicaments and other forms of Interaction). These drugs, especially salicylates and sulphonamides, whether antibacterial, hypoglycaemic or diuretic, should not be given concurrently until the significance of these findings is established.

Vitamin preparations containing folic acid or its derivatives may alter response to methotrexate.

Methotrexate should be used with extreme caution in the presence of infection, peptic ulcer, ulcerative colitis, debility, and in extreme youth and old age. If profound leukopenia occurs during therapy, bacterial infection may occur or become a threat. Cessation of the drug and appropriate antibiotic therapy is usually indicated. In severe bone marrow depression, blood or platelet transfusions may be necessary.

Since it is reported that methotrexate may have an immunosuppressive action, this factor must be taken into consideration in evaluating the use of the drug where immune responses in a patient may be important or essential.

In all instances where the use of methotrexate is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse reactions. Most such adverse reactions are reversible if detected early. When such effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgement of the physician. Reinstitution of methotrexate therapy should be carried out with caution, with adequate consideration of further need for the drug and alertness as to the possible recurrence of toxicity.

Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

781816-Reg

When receiving methotrexate for breast cancer

The usual dosage of methotrexate is 40mg per square metre of body surface area, calculated from your height and weight. The dosage will be given on the first and eighth days as a single intravenous infusion.

When receiving methotrexate for leukaemia

The usual dose of methotrexate is 20–30mg per square metre of body surface area, by intramuscular injection twice a week. Alternatively, you may be given 2.5mg per kg bodyweight intravenously every 14 days.

When receiving methotrexate for leukaemia affecting the nervous system

The usual dose of methotrexate is 200–500 micrograms per kg bodyweight given intrathecally as a single dose every two to five days, until the spinal fluid is normal. At this point an additional dose is given. Alternatively, 12mg per square metre of body surface area can be given once a week for two weeks and then once a month.

When receiving methotrexate for lymphomas

The usual dose of methotrexate for Stage 3 tumours is 0.625–2.5mg/kg daily, several courses being given, with 7–10 day rest periods in between them.

When receiving methotrexate for mycosis fungoides

The usual dose of methotrexate is 50mg once a week or 25mg twice a week by intramuscular injection.

When receiving methotrexate for psoriasis

A test dose of 5–10mg by intramuscular or intravenous injection is given one week before the treatment and, if there are no adverse reactions, the treatment dose is 10–25mg by intramuscular or intravenous injection per week.

If you suffer from kidney problems or if methotrexate is being given to you in combination with other treatments, the dosage of methotrexate may be adjusted.

Your general condition and your response to the treatment will be closely observed before, during and after the methotrexate treatment.

4. possible side effects

Like any other medication, methotrexate may cause side-effects.

The most common unwanted effects are nausea, stomach pains, mouth ulcers and a tendency to get infections. If you think you have an infection or have mouth ulcers, a sore throat, fever, chills, achiness or diarrhoea during treatment you should tell your doctor immediately.

Less commonly, methotrexate causes malaise (generally feeling unwell), dizziness, sore eyes, excessive tiredness, drowsiness, rash, itchiness, reddening, blistering or discolouration of the skin, increased sensitivity to sunlight, skin ulcers, vaginal or anal soreness, acne, boils, hair loss, headache, blurred vision, sore gums, loss of appetite, vomiting and thinning of the bones.

In a small number of patients methotrexate may cause serious side effects and, on rare occasions, death. You should contact your doctor immediately if you notice any of the following:

• unusual bleeding (including vomiting blood) or bruising
• black or tarry stools
• blood in the urine or stools
• tiny red spots on the skin
• a serious skin rash with reddening and flaking
• yellowing of the skin or of the whites of the eyes
• pain in the shoulders or back
• pain or difficulty in passing urine
• needing to pass urine more often than usual
• needing to drink much more than usual
• a dry cough
• pain or difficulty breathing or shortness of breath
• numbness or tingling
• confusion
• fits (convulsions)
• general weakness or paralysis
• unusual body movements or a lack of balance
• difficulty with speech
• loss of consciousness
• an allergic reaction which may cause a skin rash or swelling of your lips, eyes or tongue
• tissue destruction at injection site (Not known: frequency cannot be estimated from the available data Tissue destruction at injection site)

Methotrexate can cause inflammation of the lung with breathlessness. If you develop a persistent cough, experience pain or difficulty breathing or become breathless, you should seek medical attention.

Methotrexate can harm unborn babies or cause miscarriage (see section on pregnancy). Methotrexate can affect women’s periods – they may become less frequent or stop completely. It can also affect fertility in men and women.

Certain other unwanted side effects can only be detected by your doctor testing your blood, liver and kidney function and bone density.

Methotrexate can potentially cause Non-Hodgkin’s lymphoma, a type of cancer, to develop. Symptoms include: lumps (swollen glands) in the neck, armpits or groin, weakness and tiredness that do not go away, unexplained weight loss, fever, coughing and trouble breathing.

During the treatment with methotrexate your general condition will be closely monitored.

If you notice any side-effects not mentioned in this leaflet, please tell your doctor or nurse.

• 5. STORING METHOTREXATE

Keep out of the reach and sight of children

Do not store above 25°C.

Store in the original container

Do not use after the expiry date stated on the label.

After dilution, the product should be used within 24 hours if stored at 2–8oC.

This leaflet was last revised: July 2007.

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Product name	Reference number
Methotrexate 100mg/ml Injection BP (1,000mg in 10ml):	14510/0030
Methotrexate 100mg/ml Injection BP (5,000mg in 50ml):	14510/0029

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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 should be made to exclude infection. If methotrexate induced lung disease is suspected treatment with corticosteroids should be initiated and treatment with methotrexate should be restarted.

• 4.5. Interactions with other medicinal products and other forms of interaction

Methotrexate is extensively protein bound and may be displaced by certain drugs such as salicylates, hypoglycaemics, diuretics, sulphonamides, diphenylhydantoins, tetracyclines, chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents, so causing a potential for increased toxicity when used concurrently (see 4.4. Special Warnings and Precautions for Use).

Concomitant use of other drugs with nephrotoxic or hepatotoxic potential (including alcohol) should be avoided.

Vitamin preparations containing folic acid or its derivatives may decrease the effectiveness of methotrexate.

Caution should be used when NSAIDs and salicylates are administered concomitantly with methotrexate (see 4.4. Special Warnings and Precautions for Use). These drugs have been reported to reduce the tubular secretion of methotrexate and thereby may enhance its toxicity. Concomitant use of NSAIDs and salicylates has been associated with fatal methotrexate toxicity.

However, patients using constant dosage regimens of NSAIDs have received concurrent doses of methotrexate without any problems being observed.

Renal tubular transport is also diminished by probenecid and penicillins; use of these with methotrexate should be carefully monitored.

Severe bone marrow depression has been reported following the concurrent use of methotrexate and co-trimoxazole or trimethoprim. Concurrent use should probably be avoided.

Methotrexate-induced stomatitis and other toxic effects may be increased by the use of nitrous oxide.

An increased risk of hepatitis has been reported following the use of methotrexate and the acitretin metabolite, etretinate. Consequently, the concomitant use of methotrexate and acitretin should be avoided.

The use of nitrous oxide potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe, unpredictable myelosuppression, stomatitis and neurotoxicity with intrathecal administration. Whilst this effect can be reduced by administering calcium folinate, the concomitant use should be avoided.

• 4.6. Pregnancy and lactation

Abortion, foetal death, and/or congenital anomalies have occurred in pregnant women receiving methotrexate, especially during the first trimester of pregnancy. Methotrexate is contraindicated in the management of psoriasis or rheumatoid arthritis in pregnant women.

Women of childbearing potential/Con­traception in males and females

Women must not get pregnant during methotrexate therapy, and effective contraception must be used during treatment with methotrexate and at least 6 months thereafter (see section 4.4). Prior to initiating therapy, women of childbearing potential must be informed of the risk of malformations associated with methotrexate and any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. a pregnancy test. During treatment pregnancy tests should be repeated as clinically required (e.g. after any gap of contraception). Female patients of reproductive potential must be counselled regarding pregnancy prevention and planning.

Contraception in males

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.

Pregnancy

Methotrexate is contraindicated during pregnancy in non-oncological indications (see section 4.3). If pregnancy occurs during treatment with methotrexate and up to six months thereafter, medical advice should be given regarding the risk of harmful effects on the child associated with treatment and ultrasonography examinations should be performed to confirm normal foetal development. In animal studies, methotrexate has shown reproductive toxicity, especially during the first trimester (see section 5.3). Methotrexate has been shown to be teratogenic to humans; it has been reported to cause foetal death, miscarriages and/or congenital abnormalities (e.g. craniofacial, cardiovascular, central nervous system and extremity-related).

Methotrexate is a powerful human teratogen, with an increased risk of spontaneous abortions, intrauterine growth restriction and congenital malformations in case of exposure during pregnancy.

• 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 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 methotrexate was discontinued prior to conception, normal pregnancies have been reported.

When used in oncological indications, methotrexate should not be administered during pregnancy in particular during the first trimester of pregnancy. In each individual case the benefit of treatment must be weighed up against the possible risk to the foetus. If the drug is used during pregnancy or if the patient becomes pregnant while taking methotrexate, the patient should be informed of the potential risk to the foetus.

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. In oncologic indications, women who are planning to become pregnant are advised to consult a genetic counselling centre, if possible, prior to therapy and men should seek advice about the possibility of sperm preservation before starting therapy as methotrexate can be genotoxic at higher doses (see section 4.4).

• 4.7. Effects on ability to drive and use machines

Methotrexate is not known to affect ability to drive or use machines.

• 4.8. Undesirable effects

The most common adverse reactions include ulcerative stomatitis, leukopenia, nausea and abdominal distress. Although very rare, anaphylactic reactions to methotrexate have occurred. Others reported are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. Opportunistic infections (sometimes fatal e.g. fatal sepsis) have also been reported in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases, Pneumocystis carinii pneumonia being the most common. Other reported infections include, pneumonia, nocardiosis, histoplasmosis, cryptococcosis, Herpes Zoster, Herpes Simplex, hepatitis and disseminated Herpes Simplex and cytomegalovirus infection, including cytomegaloviral pneumonia. In general, the incidence and severity of side effects are considered to be dose-related. Adverse reactions as reported for the various systems are as follows:

Skin and subcutaneous tissue disorders : Stevens-Johnson syndrome, epidermal necrolysis, erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration in psoriatic patients and rarely painful erosion of psoriatic plaques have been reported. The recall phenomenon has been reported in both radiation and solar damaged skin. Skin exfoliation / dermatitis exfoliative has also been reported (not known frequency).

Blood and lymphatic system disorders : Bone marrow depression, leukopenia, thrombocytopenia, pancytopenia, anaemia, hypogammaglobu­linaemia, haemorrhage from various sites, septicaemia. Lymphoproliferative disorders (see “description” below), very rare

Musculoskeletal and connective tissue: Osteonecrosis of jaw (secondary to lymphoproliferative disorders), frequency unknown

Alimentary System: Gingivitis, pharyngitis, stomatitis, anorexia, vomiting, diarrhoea, haematemesis, melaena, gastrointestinal ulceration and bleeding, enteritis, hepatic toxicity resulting in active liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis, or hepatic cirrhosis. In rare cases the effect of methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon.

Hepatic: Hepatic toxicity resulting in significant elevations of liver enzymes, acute liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis or cirrhosis or death may occur, usually following chronic administration.

Urogenital System: Renal failure, azotaemia, cystitis, haematuria, defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, abortion, foetal defects, severe nephropathy. Vaginitis, vaginal ulcers, and nephropathy have also been reported.

Pulmonary System: Infrequently an acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Acute pulmonary oedema has also been reported after intrathecal use. Pulmonary fibrosis is rare. A syndrome consisting of pleuritic pain and pleural thickening has been reported following high doses.

Central Nervous System: Headaches, drowsiness, blurred vision, aphasia, hemiparesis and convulsions have occurred possibly related to haemorrhage or to complications from intra-arterial catheterization. Convulsion, paresis, Guillain-Barre syndrome and increased cerebrospinal fluid pressure have followed intrathecal administration.

Other reactions related to, or attributed to the use of methotrexate such as pneumonitis, metabolic changes, precipitation of diabetes, osteoporotic effects, abnormal changes in tissue cells, abnormal (usually ‘megaloblastic’) red cell morphology and even sudden death have been reported.

There is the potential for Non-Hodgkin’s lymphoma to develop through the use of methotrexate.

There have been reports of leukoencephalopathy following intravenous methotrexate in high doses, or low doses following cranial-spinal radiation.

Adverse reactions following intrathecal methotrexate are generally classified into three groups, acute, subacute, and chronic. The acute form is a chemical arachnoiditis manifested by headache, back or shoulder pain, nuchal rigidity, and fever. The subacute form may include paresis, usually transient, paraplegia, nerve palsies, and cerebellar dysfunction. The chronic form is a leukoencephalopathy manifested by irritability, confusion, ataxia, spasticity, occasionally convulsions, dementia, somnolence, coma, and rarely, death.There is evidence that the combined use of cranial radiation and intrathecal methotrexate increases the incidence of leukoencephalo­pathy.

Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. (see Section 4.4 Warnings And Precautions for Use)

• 4.9. Overdose

Calcium Folinate (Calcium Leucovorin) is a potent agent for neutralizing the immediate toxic effects of methotrexate on the haematopoietic system. Where large doses or overdoses are given, calcium folinate may be administered by intravenous infusion in doses up to 75mg within 12 hours, followed by 12mg intramuscularly every six hours for four doses. Where average doses of methotrexate appear to have an adverse effect, 6–12mg of calcium folinate may be given intramuscularly every six hours for four doses. In general, where overdosage is suspected, the dose of calcium folinate should be equal to, or higher than, the offending dose of methotrexate and should be administered as soon as possible; preferably within the first hour and certainly within four hours, after which it may not be effective.

Other supporting therapy such as blood transfusion and renal dialysis may be required. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser.

• 5. PHARMACOLOGICAL PROPERTIES

  • 5.1. Pharmaco­dynamic properties

Methotrexate is an antimetabolite which acts principally by competitively inhibiting the enzyme, dihydrofolate reductase. In the process of DNA synthesis and cellular replication, folic acid must be reduced to tetrahydrofolic acid by this enzyme, and inhibition by methotrexate interferes with tissue cell reproduction. Actively proliferating tissues such as malignant cells are generally more sensitive to this effect of methotrexate. It also inhibits antibody synthesis.

Methotrexate also has immunosuppressive activity, in part possibly as a result of inhibition of lymphocyte multiplication. The mechanism(s) of action of the drug in the management of rheumatoid arthritis is not known, although suggested mechanisms have included immunosuppressive and/or anti-inflammatory effect.

hieved within 0.5–2 hours following I.V. / I.M. or intra-arterial administration.

Methotrexate is actively transported across cell membranes. The drug is widely distributed into body tissues with highest concentrations in the kidneys, gall bladder, spleen, liver and skin. Methotrexate is retained for several weeks in the kidneys and for months in the liver. Sustained serum concentrations and tissue accumulation may result from repeated daily doses. Methotrexate crosses the placental barrier and is distributed into breast milk. Approximately 50% of the drug in the blood is bound to serum proteins.

In one study, methotrexate had a serum half-life of 2–4 hours following I.M. administration.

Methotrexate does not appear to be appreciably metabolised. The drug is excreted primarily by the kidneys via glomerular filtration and active transport. Small amounts are excreted in the faeces, probably via the bile. Methotrexate has a biphasic excretion pattern. If methotrexate excretion is impaired accumulation will occur more rapidly in patients with impaired renal function. In addition, simultaneous administration of other weak organic acids such as salicylates may suppress methotrexate clearance.

• 5.3. Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to those included in other sections.

• 6. PHARMACEUTICAL PARTICULARS

  • 6.1. List of excipients

Sodium hydroxide

Water for injections

• 6.2. Incompati­bilities

Immediate precipitation or turbidity results when combined with certain concentrations of droperidol, heparin sodium, metoclopramide hydrochloride or ranitidine hydrochloride in the syringe.

As with all parenteral solutions, incompatibility of the additive medications with the solution must be addressed before addition. In the absence of compatibility studies, this solution must not be mixed with other medicinal products, except sodium chloride solution 0.9% and glucose solution 5% (see Section 6.4, Special precautions for storage).

• 6.3 Shelf life

Two years

After dilution (see section 6.4. and 6.6.): 24 hours.

Any unused solution should be discarded immediately after use.

• 6.4 Special precautions for storage

Do not store above 25°C. Store in the original container.

After dilution (see section 6.6.):

Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C for solutions with a final concentration of methotrexate 5mg/ml or 20mg/ml after dilution of the methotrexate 100mg/ml with one of the following solutions:

• sodium chloride solution 0.9%;
• glucose solution 5%

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

• 6.5. Nature and contents of container

Colourless vials of hydrolytic type I glass, packed in a carton.

Vials are closed with a rubber stopper with an aluminium crimp cap with flip-off.

Packs of 1 vial containing 1000mg/10ml or 5000mg/50ml of methotrexate.

• 6.6. Special precautions for disposal

Cytotoxic drugs should only be handled by trained personnel in a designated area. The work surface should be covered with disposable plastic-backed absorbent paper. Protective gloves and goggles should be worn to avoid the drug accidentally coming into contact with the skin or eyes. Methotrexate is not a vesicant and should not cause harm if it comes into contact with the skin. It should of course be washed off with water immediately. Any transient stinging may be treated with bland cream. If there is any danger of systemic absorption of significant quantities of methotrexate, by any route, calcium folinate cover should be given.

Cytotoxic preparations should not be handled by pregnant staff.

Adequate care should be taken in the disposal of any unwanted product, syringes and containers. Any spillage or waste material may be disposed of by incineration. We do not make any specific recommendations with regard to the temperature of the incinerator.

• 7. MARKETING AUTHORISATION HOLDER

CP Pharmaceuticals Ltd

Ash Road North

Wrexham LL13 9UF

United Kingdom

• 8. MARKETING AUTHORISATION NUMBER (S)

PL 14510/0030 (1,000mg in 10ml)

PL 14510/0029 (5,000mg in 50ml)

• 9. DATE OF FIRST AUTHORISATION/RE­NEWAL OFTHE AUTHORISATION

• 10. DATE OF REVISION OFTHETEXT