26 Jun 2009

Methotrexate 10mg (Generic) - United Kingdom

Updated: 26 Jun 2009

Methotrexate 10mg tablets

- Active rheumatoid arthritis in adult patients. - Severe forms of psoriasis vulgaris, particularly of the plaque type, which cannot be sufficiently treated with conventional therapy such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis.

Methotrexate 10mg Description, Presentation and Dosage

Methotrexate 10mg Description

Methotrexate 10mg Drug Class Description

Folic acid antagonists (DMARDs).

Methotrexate 10mg Drug Description

One tablet contains 10 mg methotrexate. Excipients: 36.6 mg lactose (as lactose monohydrate)).

Methotrexate 10mg Generic Name

Generic

Methotrexate 10mg Presentation

Methotrexate 10mg Presentation

Tablet. Yellow, convex, capsule-shaped tablet, scored on one side, engraved with M 10 on one side, length 8 mm, breadth 4.5 mm. The tablet can be divided into equal halves

Methotrexate 10mg Manufacturer

Orion Pharma (UK) Limited

Free Medical Education Resources

Methotrexate 10mg Dosage

Methotrexate 10mg Adult Dosage

For doses not realisable/practicable with this strength, another strength of this medicinal product is available.

Rheumatoid arthritis

The usual dose is 7.5 - 15 mg once weekly. The planned weekly dose may be administered in three divided doses over 36 hours. The schedule may be adjusted gradually to achieve an optimal response but should not exceed a total weekly dose of 20 mg. Thereafter the dose should be reduced to the lowest possible effective dose which in most cases is achieved within 6 weeks.

Psoriasis

Before starting treatment it is advisable to give the patient a test dose of 2.5–5.0 mg to exclude unexpected toxic effects. If, one week later, appropriate laboratory tests are normal, treatment may be initiated. The usual dose is 7.5–15 mg taken once weekly. The planned weekly dose administered as three divided doses over 24 hours. As necessary, the total weekly dose can be increased up to 25 mg. Thereafter the dose should be reduced to the lowest effective dose according to therapeutic response which in most cases is achieved within 4 to 8 weeks.

The patient should be fully informed of the risks involved and the clinician should pay particular attention to the appearance of liver toxicity by carrying out liver function tests before starting methotrexate treatment, and repeating these at 2 to 4 month intervals during therapy. The aim of therapy should be to reduce the dose to the lowest possible level with the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy which should be encouraged.

Patients with hepatic impairment

Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially if due to alcohol.

Methotrexate 10mg Child Dosage

Not recommended.

Methotrexate 10mg Elderly Dosage

Methotrexate should be used with extreme caution in elderly patients, a dose reduction should be considered due to reduced liver and kidney function as well as lower folate reserves which occur with increased age.

Methotrexate 10mg Precautions, Reactions and Contraindications

Methotrexate 10mg Special Precautions

Methotrexate 10mg Special Precautions

Warnings

Methotrexate must be used only by physicians experienced in antimetabolite chemotherapy.

Concomitant administration of hepatotoxic or haematotoxic DMARDs (disease-modifying antirheumatic drug, e.g. leflunomide) is not advisable.

Due to the possibility of fatal or severe toxic reactions, the patient should be fully informed by the physician of the risks involved and be under constant supervision.

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 undertaken to exclude infection. If methotrexate induced lung disease is suspected treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted.

Deaths have been reported associated with the use of methotrexate in the treatment of psoriasis.

For the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established by biopsy and/or after dermatological consultation.

The patient should be informed clearly that in the treatment of psoriasis and rheumatoid arthritis the administration is in most cases once weekly and that wrong daily administration can result in severe toxic reactions.

Full blood counts should be closely monitored before, during and after treatment. If a clinically significant drop in white-cell or platelet count develops, methotrexate should be withdrawn immediately. Patients should be advised to report all symptoms or signs suggestive of infection.

Methotrexate may be hepatotoxic, particularly at high doses or with prolonged therapy. Liver atrophy, necrosis, cirrhosis, fatty changes, and periportal fibrosis have been reported. Since changes may occur without previous signs of gastrointestinal or haematological toxicity, it is imperative that hepatic function be determined prior to initiation of treatment and monitored regularly throughout therapy.

Liver function tests: Particular attention should be given to the appearance of liver toxicity. Treatment should not be instituted or should be discontinued if any abnormality of liver function tests, or liver biopsy, is present or develops during therapy. Such abnormalities should return to normal within two weeks after which treatment may be recommenced at the discretion of the physician.

Check of liver-related enzymes in serum: Temporary increases in transaminases to twice or three times of the upper limit of normal have been reported by patients at a frequency of 13 - 20 %. In the case of a constant increase in liver-related enzymes, a reduction of the dose or discontinuation of therapy should be taken into consideration.

Due to its potentially toxic effect on the liver, additional hepatotoxic medicinal products should not be taken during treatment with methotrexate unless clearly necessary and the consumption of alcohol should be avoided or greatly reduced. Closer monitoring of liver enzymes should be exercised in Patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide). The same should be taken into account with the simultaneous administration of haematotoxic medicinal products (e.g. leflunomide).

There is no evidence to support use of a liver biopsy to monitor hepatic toxicity in rheumatological indications. In case of longer-term treatment of severe forms of psoriasis with methotrexate, liver biopsies should be performed on account of the hepatotoxic potential.

It has proven useful to differentiate between patients with normal and elevated risk of hepatotoxicity.

a) Patients without risk factors

According to current medical standard of knowledge, liver biopsy is not necessary before a cumulative dose of 1.0-1.5 g is reached.

b) Patients with risk factors

These primarily include

- anamnestic alcohol abuse

- persistent increase in liver enzymes

- anamnestic hepatopathy including chronic hepatitis B or C

- familial anamnesis with hereditary hepatopathy

and secondarily (with possibly lower relevance):

- diabetes mellitus

- adiposity

- anamnestic exposure to hepatotoxic medicines or chemicals.

Liver biopsy is recommended for these patients during or shortly after initiation of therapy with methotrexate. Since a small percentage of patients discontinue therapy for various reasons after 2-4 months, the first biopsy can be delayed to a time after this initial phase. It should be performed when longer-term therapy can be assumed.

Repeated liver biopsies are recommended after a cumulative dose of 1.0-1.5 g is achieved.

No liver biopsy is necessary in the following cases:

- elderly patients

- patients with an acute disease

- patients with contraindication for liver biopsy (e.g. cardiac

instability, altered blood coagulation parameters)

- patients with poor expectance of life

More frequent check-ups may become necessary:

- during the initial phase of treatment

- when the dose is increased

- during episodes of a higher risk of elevated methotrexate blood levels (e.g. dehydration, impaired renal function, additional or elevated dose of medicines administered concomitantly, such as non-steroidal anti-inflammatory drugs).

Methotrexate has been shown to be teratogenic; it has caused foetal death and/or congenital anomalies. Therefore it is not recommended in women of childbearing potential unless there is appropriate medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant psoriatic patients must not receive methotrexate.

Renal function should be closely monitored before, during and after treatment. Caution should be exercised if significant renal impairment is disclosed. The dose of methotrexate in patients with renal impairment should be reduced. High doses may cause the precipitation of methotrexate or its metabolites in the renal tubules. A high fluid throughput and alkalinisation of the urine to pH 6.5 – 7.0, by oral or intravenous administration of sodium bicarbonate (5 x 625 mg tablets every three hours) or acetazolamide (500 mg orally four times a day) is recommended as a preventative measure. Methotrexate is excreted primarily by the kidneys. Its use in the presence of impaired renal function may result in accumulation of toxic amounts or even additional renal damage.

Diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.

Methotrexate affects gametogenesis during the period of its administration and may result in decreased fertility which is thought to be reversible on discontinuation of therapy.

Methotrexate has some immunosuppressive activity and immunological responses to concurrent vaccination may be decreased. Vaccination with live vaccines should be avoided during therapy.

The immunosuppressive effect of methotrexate should be taken into account when immune responses of patients are important or essential. Special attention should be paid in cases of inactive chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) because of their potential activation.

A chest X-ray is recommended prior to initiation of methotrexate therapy.

Pleural effusions and ascites should be drained prior to initiation of methotrexate therapy.

Serious adverse reactions including deaths have been reported with concomitant administration of methotrexate (usually in high doses) along with some non-steroidal anti-inflammatory drugs (NSAIDs).

In the treatment of rheumatoid arthritis, treatment with acetylsalicylic acid and non-steroidal anti-inflammatory drugs (NSAID) as well as small-dose steroids can be continued. One has to take into consideration, however, that coadministration of NSAIDs and methotrexate may involve an increased risk of toxicity. The steroid dose can be reduced gradually in patients who exhibit therapeutic response to methotrexate therapy.

Interaction between methotrexate and other antirheumatic agents, such as gold, penicillamin, hydroxychloroquine, sulphasalazine or other cytotoxic agents, have not been studied comprehensively, and coadministration may involve an increased frequency of adverse reactions. Rest and physiotherapy can be continued as previously.

Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.

If acute methotrexate toxicity occurs, patients may require folinic acid.

 

Precautions

Before beginning methotrexate therapy or reinstituting methotrexate after a rest period, assessment of renal function, liver function and a bone marrow function should be made by history, physical examination and laboratory tests.

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

Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires the initiation of cytotoxic therapy.

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 risks of effects on reproduction should be discussed with patients of childbearing potential.

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. Pre-treatment and periodic haematological studies are essential for the safe use of methotrexate in chemotherapy because of its common effect of haematopoietic suppression. This may occur without warning when a patient is on an apparently safe dose, and any profound drop in blood cell count indicates immediate stopping of the drug and appropriate therapy.

In general, the following laboratory tests are recommended as part of essential clinical evaluation and appropriate monitoring of patients chosen for or receiving methotrexate: 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.

Methotrexate is bound in part to serum albumin after absorption, 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. 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.

The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine

Methotrexate 10mg Adverse Reactions

Methotrexate 10mg Adverse Reactions

Generally the frequency and severity of adverse reactions are dependent of the size of the dose, the dosing frequency, the method of administration and the duration of exposure.

If adverse reactions occur, the dose should be reduced or therapy discontinued and necessary corrective therapeutic measures undertaken, such as administration of calcium folinate.

The most common adverse reactions of methotrexate are bone marrow suppression and mucosal damage which manifest as ulcerative stomatitis, leucopaenia, nausea and other gastrointestinal disorders. These adverse reactions are generally reversible and corrected in about two weeks after the single dose of methotrexate has been reduced or dose interval increased and/or calcium folinate is used. Other frequently occurring adverse reactions include e.g. malaise, abnormal fatigue, chills and fever, dizziness and reduced immunity to infections.

Methotrexate causes adverse reactions most at high and frequently repeated doses, e.g. in the treatment of cancer diseases. Adverse reactions reported on methotrexate are given below according to organ systems.

The frequencies of the adverse reactions are classified as follows: Very common (GREATER-THAN OR EQUAL TO (8805) 1/10); common (GREATER-THAN OR EQUAL TO (8805) 1/100 to < 1/10); uncommon (GREATER-THAN OR EQUAL TO (8805) 1/1000 to < 1/100); rare (GREATER-THAN OR EQUAL TO (8805) 1/10000 to < 1/1000); very rare (< 1/10000), not known (cannot be estimated from the available data).

 

 

Common

Uncommon

Rare

Very rare

Infections and infestations

Infections

Opportunistic infections

Herpes zoster

Sepsis

 

 

Neoplasms benign,malignant and unspecified (including cysts and polyps)

 

 

Lymphoma1

 

 

 

 

Blood and lymphatic system disorders

Leucopaenia

Bone marrow depression

Thrombocytopaenia

Anaemia

 

 

Hypogammaglobulinaemia

Immune system disorders

 

 

Anaphylactic-type reaction

 

 

 

 

Endocrine disorders

 

 

 

 

Diabetes mellitus

 

 

 

Psychiatric disorders

 

 

 

 

Depression

Confusion

 

 

Nervous system disorders

Headache

Dizziness

Fatigue

 

 

Hemiparesis

Irritation

Dysarthria

Aphasia

Lethargy

 

Eye disorders

 

 

 

 

 

 

Conjunctivitis

Blurred vision

Cardiac disorders

 

 

 

 

 

 

Pericardial effusion

Pericarditis

Vascular disorders

 

 

Nosebleed

Hypotension

Thromboembolism

 

Vasculitis

Respiratory, thoracic and mediastinal disorders

 

 

Pneumonitis

Interstitial pneumonitis (can be fatal)

Interstitial fibrosis

Dyspnoea

Pharyngitis

Pneumocystis carinii – pneumonia

Chronic interstitial obstructive lung disease

Pleuritis

Dry cough

Gastrointestinal disorders2

Stomatitis

Anorexia

Nausea

Vomiting

Diarrhoea

 

 

Gingivitis

Gastrointestinal ulcerations and haemorrhage

Enteritis

Haematemesis

Hepatobiliary disorders

Elevated transaminase concentrations

 

 

Hepatotoxicity

Periportal fibrosis

Liver cirrhosis

Acute hepatitis

 

 

Skin and subcutaneous tissue disorders

Erythematous rash

Alopaecia

Pruritus

Stevens-Johnson´s syndrome

Toxic epidermal necrolysis

Photohypersensitivity

Acne

Depigmentation

Urticaria

Erythema multiforme

Painful damage to psoriatic lesion

Skin ulceration

Telangiectasis

Furunculosis

Ecchymoses

Musculoskeletal and connective tissue disorders

 

 

 

 

Osteoporosis

Arthralgia

Myalgia

Increased rheumatic nodules

 

 

Renal and urinary disorders

 

 

Renal insufficiency

Nephropathy

 

 

Dysuria

Azotaemia

Cystitis

Haematuria

Reproductive system and breast disorders

 

 

Vaginal ulceration

Decreased libido

Impotence

Menstrual disorders

 

Formation of defective oocytes or sperm cells

Transient oligospermia, infertility

Vaginal bleeding

Gynaecomastia

1 Can be reversible.

Gastrointestinal severe adverse reactions require often dose reduction. Ulcerative stomatitis and diarrhoea require discontinuation of methotrexate therapy because of the risk of ulcerative enteritis and fatal intestinal perforation.

The following adverse reactions have also been reported, but their frequency is not known: pancytopaenia, sepsis resulting in death, miscarriage, fetal damages, increased risk of toxic reactions (soft tissue necrosis, osteonecrosis) during radiotherapy, eosinophilia, alveolitis.

The psoriatic lesions may get worse from simultaneous exposure to methotrexate and ultraviolet radiation

Methotrexate 10mg Contraindications

Methotrexate 10mg Contraindications

• Significantly impaired hepatic function

• Significantly impaired renal function

• Pre-existing blood dycrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anaemia

• Alcoholism

• Severe acute or chronic infections and immunodeficiency syndrome

• Pregnancy and breast-feeding.

• Hypersensitivity to methotrexate or to any of the excipients

• During methotrexate therapy concurrent vaccination with live vaccines must not be carried out.

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