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Azathioprine 25mg Film-Coated Tablets

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Azathioprine 25 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 25 mg azathioprine.

Excipient: contains Lactose

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Film-coated tablet.

White to yellowish-white film-coated tablet, biconvex, no score-line.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Azathioprine is indicated in combination with other immunosuppressive agents for the prophylaxis of transplant rejection in patients receiving allogenic kidney, liver, heart, lung or pancreas transplants.

Azathioprine is usually indicated in immunosuppressive regimens as an adjunct to immunosuppressive agents that form the mainstay of treatment (basic immunosuppression).

Therapeutic effect may be evident only after weeks or months and can include a steroid-sparing effect, thereby reducing the toxicity associated with high dosage and prolonged usage of corticosteroids.

Azathioprine is indicated in severe cases of the following diseases in patients who are intolerant to steroids or who are dependent on steroids and in whom the therapeutic response is inadequate despite treatment with high doses of steroids:

•    Severe active rheumatoid arthritis that cannot be kept under control by less toxic agents (disease-modifying anti-rheumatic drugs (DMARDs),

•    Severe or moderately severe inflammatory intestinal diseases (Crohn’s disease or ulcerative colitis),

•    Systemic lupus erythematosus,

•    Dermatomyositis and polymyositis,

Auto-immune hepatitis,

Polyarteritis nodosa,

Refractory warm auto-immune haemolytic anaemia, Chronic refractory idiopathic thrombocytopenic purpura.

4.2 Posology and method of administration

Azathioprine film-coated tablets are supplied for oral administration, and the tablet should be taken with at least a glass of liquid (200 ml). Azathioprine film-coated tablets should be taken during meals.

Transplantation

Depending on the immunosuppressive regimen selected, a loading dose of up to 5 mg/kg bodyweight/day orally is usually given. The maintenance dose can range from 1-4 mg/kg bodyweight per day, and must be adjusted according to clinical requirements and haematological intolerance.

Other conditions

In general, the starting dosage is 1-3 mg/kg bodyweight/day, and should be adjusted according to the clinical response (which may be evident only after weeks or months) and haematological tolerance. For the treatment of chronic active hepatitis the dosage is usually between 1.0 and 1.5 mg/kg bodyweight/day. When the therapeutic response is evident, consideration should be given to reducing the maintenance dosage to the lowest level compatible with maintenance of the response. If no improvement occurs in the patient's condition within three to six months, consideration should be given to withdrawing the medicinal product. The maintenance dosage required may range from less than 1 mg/kg bodyweight/day to 3 mg/kg bodyweight/day, depending on the clinical condition being treated and the individual patient response, including haematological tolerance.

Use in patients with renal and/or hepatic impairment

In patients with renal and/or mild to moderate hepatic dysfunction, dosages should be given at the lower end of the normal range. Azathioprine is contraindicated in severe hepatic impairment (see Section 4.3).

Use in Children and Adolescents

There are insufficient data to recommend the use of Azathioprine for the treatment of juvenile chronic arthritis, systemic lupus erythematosus, dermatomyositis, and polyarteritis nodosa (in children and adolescents < 18 years).

Concerning the other indications the given dose recommendations apply for children and adolescents as well as for adults.

Use in the elderly:

There is no specific information available on how elderly patients tolerate azathioprine. It is recommended that the dosages used should be at the lower end of the normal range (for controls of blood count see section 4.4).

When allopurinol, oxipurinol or thiopurinol is given concomitantly with azathioprine, the dose of azathioprine must be reduced to a quarter of the original dose (see section 4.4 and 4.5).

It can take weeks or months before a therapeutic effect is seen.

The medicinal product may be given over the long term unless the patient cannot tolerate the preparation.

In cases, such as rheumatoid arthritis and certain haematological conditions, the treatment can be stopped after a certain period without problems.

4.3


Contraindications

a)    Hypersensitivity to azathioprine, 6-mercaptopurine (metabolite of azathioprine) or to any of the excipients.

b)    Severe infections.

c)    Severely impaired hepatic or bone-marrow function.

d)    Pancreatitis.

e)    Any live vaccine especially BCG, smallpox, yellow fever.

f)    Pregnancy unless the benefits outweigh the risks (see section 4.6)

g)    Lactation (see Section 4.6).

4.4 Special warnings and precautions for use

a)    There are potential dangers in the use of azathioprine tablets; they should therefore not be prescribed unless the patient can be adequately monitored for toxic effects throughout the duration of treatment.

During the first eight weeks of treatment, a complete blood count, including platelet count, should be performed at least once weekly. It should be controlled more frequently

•    if high dosages are used

•    in elderly patients

•    if renal function is impaired

•    if hepatic function is mildly to moderately impaired (see also sections 4.2 and 5.2)

•    if bone marrow function is mildly to moderately impaired (see also section 4.2)

•    in patients with hypersplensim.

The frequency of the blood counts control may be reduced after 8 weeks. It is recommended that complete blood counts be repeated monthly, or at least at intervals of not longer than 3 months.

Patients must be advised to inform their doctor immediately about ulcerations of the throat, fever, infections, bruising, bleeding or other signs of myelosuppression.

b)    Especially in patients with hepatic dysfunction, liver function should be controlled regularly.

c)    Close monitoring of blood counts is required if azathioprine is given together with

•    allopurinol, oxipurinol or thiopurinol (see section 4.2 and 4.5)

•    derivatives of aminosalicylic acid, such as mesalazine, olsalazine or suphasalazine (see section 4.5)

•    ACE inhibitors, trimethoprim/sulphamethoxazole, cimetidine or indomethacin (see section 4.5)

•    agents with cytotoxic/myelosuppressive properties (see section 4.5)

d)    About 10 % of patients have a thiopurine methyltransferase deficiency due to genetic polymorphism. They may therefore be unable to metabolise azathioprine completely. Consequently they may be exposed to an increased myelotoxic effect. Special care should therefore be taken during co-administration of aminosalicylate derivatives, including sulphasalazine, which are inhibitors of the TPMT enzyme. Phenotyping or genotyping of the patient is desirable before administration of the medicinal product in order to investigate a possible thiopurine transferase deficiency.

e)    Limited data indicate that azathioprine is not effective in patients with hereditary hypoxanthine-guanine-phosphoribosyl transferase deficiency (Lesch-Nyhan syndrome). Therefore azathioprine should not be used in these patients.

f)    If allopurinol, oxipurinol and/or thiopurinol are given concomitantly with azathioprine, the dosage of azathioprine must be reduced (see section 4.2 and 4.5).

g)    Special care is necessary when azathioprine is given concomitantly with neuromuscular acting agents, like tubocurarine or succinylcholine. It can also potentiate the neuromuscular block that is produced by depolarising agents such as succinylcholine (see section 4.5). Patients should be advised to inform their anaesthesiologist of their treatment with azathioprine prior to surgery.

h)    Coagulation should be closely monitored when anticoagulants of the coumarin type are given concomitantly with azathioprine (see section 4.5)

i)    Withdrawal of azathioprine can result in a severe worsening of the condition, e.g. SLE with nephritis, Crohn's disease, ulcerative colitis or autoimmune hepatitis.

j)    Withdrawal of azathioprine should always be a gradual process performed under close monitoring.

k)    If inactivated or toxoid vaccines are applied together with azathioprine, immune response should always be controlled by means of titre determination.

l)    An increased number skin tumours have occurred in patients during treatment with azathioprine. They have been observed mainly on areas of skin exposed to the sun. Patients should be warned about undue exposure to the sun or UV rays, and the skin should be examined at regular intervals (see section 4.8).

m)    Particular caution should be exercised in patients with untreated acute infections (see section 4.3).

n)    Patients with concomitant cytotoxic therapy may only be given azathioprine under supervision.

Effects on fertility

Relief of chronic renal insufficiency by renal transplantation involving the administration of azathioprine has been accompanied by increased fertility in both male and female transplant recipients (for contraceptive measures see section 4.6).

Note for handling the drug:

Azathioprine is mutagenic and potentially carcinogenic. When handling this substance appropriate precautions must be taken. This should be especially considered in pregnant nurses (see also section 6.6).

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

a)    Allopurinol, oxipurinol and thiopurinol have an inhibitory effect on the metabolism of azathioprine by blocking the enzyme xanthinoxidase. (see sections 4.2 and 4.4)

b)    There is clinical evidence that azathioprine antagonises the effect of nondepolarising muscle relaxants such as curare, d-tubocurarine and pancuronium. Experimental data confirm that azathioprine reverses the neuromuscular blockade produced by d-tubocurarine, and show that azathioprine potentiates the neuromuscular blockade produced by succinylcholine (see section 4.4).

c)    If azathioprine is combined with other immunosuppressants, such as cyclosporin or tacrolimus, excessive immunosuppression must be taken into consideration.

d)    There is a risk of an increased myelosuppressive effect of azathioprine, as a result of inhibition of its hepatic metabolism, if azathioprine is administered concomitantly with aminosalicylic acid derivatives such as olsalazine, mesalazine and sulphasalazine (see section 4.4).

e)    Inhibition of the anticoagulant effect of warfarin has been reported if administered concomitantly with azathioprine.

f)    Concomitant therapy with azathioprine and ACE inhibitors, trimethoprim/sulphamethoxazole, cimetidine or indomethacin increases the risk of myelosuppression (see section 4.4).

g)    Concomitant therapy with azathioprine and agents with myelosuppressive/cytotoxic properties effect may enhance the myelotoxic effect. This applies also to myelosuppressive therapies completed only shortly before initiation of treatment with azathioprine (see section 4.4).

h)    It has been shown that furosemide reduced the metabolism of azathioprine by human hepatic tissue in vitro. The clinical relevance of this is not known.

i)    The immunosuppressive activity of azathioprine can lead to an atypical and possibly harmful response to live vaccines, and therefore, for theoretical reasons, the administration of live vaccines to patients being treated with azathioprine is contraindicated (see section 4.3).

j) A diminished response to killed vaccines is likely and such a response to hepatitis B vaccine has been observed among patients treated with a combination of azathioprine and corticosteroids.

A small clinical study has indicated that standard therapeutic doses of Azathioprine do not deleteriously affect the response to polyvalent pneumococcal vaccine, as assessed on the basis of mean anti-capsular specific antibody concentration (see section 4.4).

4.6 Pregnancy and lactation

Pregnancy

Azathioprine must not be used during pregnancy without careful assessment of risks and benefits. In animal studies Azathioprine was teratogenic and embryotoxic (see section 5.3). Azathioprine and its metabolites have been found in low concentrations in foetal blood and amniotic fluid after administration to the mother. Leukopenia and/or thrombocytopenia have been reported in a number of neonates whose mothers received azathioprine during pregnancy. Extra care in haematological monitoring is advised during pregnancy. Contraceptive measures should be taken by both male and female patients of reproductive age during, and for at least 3 months after the end of, azathioprine therapy. This applies also to patients with impaired fertility due to chronic uraemia, since that usually returns to normal after transplantation. Azathioprine has been reported to interfere with effectiveness of intrauterine contraceptive devices. Therefore, it is recommended to use other or additional contraceptive measures.

After in utero exposure to azathioprine in combination with prednisone, a temporary reduction of immune function is observed. Intra-uterine growth retardation and premature birth have been reported in cases of treatment with azathioprine together with prednisolone. The long-term consequences of these properties of azathioprine are not known, but many children exposed to the substance in utero have now reached the age of ten years without any problems being reported.

Lactation

6-Mercaptopurine, the active metabolite of azathioprine, has been identified in the colostrum and breast-milk of women receiving azathioprine treatment. Breast-feeding and concomitant use of azathioprine are contraindicated (see section 4.3).

4.7 Effects on ability to drive and use machines

Studies of the effects of azathioprine on the ability to drive and use machines have not been performed.

4.8 Undesirable effects

Frequencies are defined as: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000, < 1/100), rare (> 1/10,000, <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Approximately 15 % of patients can be expected to experience adverse effects. The type, frequency and severity of adverse reactions may depend on the dose of azathioprine and duration of therapy as well as on the patient’s underlying disease or concomitant therapies.

The principal undesirable effect of azathioprine is a dose-related, generally reversible, depression of bone marrow function expressed mainly as leukopenia (50 % in transplant patients).

Although adverse effects on haematopoiesis occur most commonly at the beginning of the treatment with azathioprine, late occurrence has been reported. Therefore, careful monitoring of the blood cell counts is recommended even in patients on stable long-term therapy (see section 4.4).

Type and frequency of undesirable effects of azathioprine are listed under the system organ classes.

Infections and infestations

Very common

Infections in 20 % of renal homographs (RH) patients

Common

Susceptibility to infection in patients with inflammatory bowel disease.

Uncommon

Infections in rheumatoid patients (< 1 %)

Neoplasms benign, malignant and unspecified

Common

In up to 2.8 % of renal homograft patients (in decreasing frequency): squamous cell carcinoma at the skin, non-Hodgkin’s lymphoma, cervical cancer, Kaposi’s sarcoma, vulval cancer.

Uncommon

Lymphoproliferative diseases after transplantation

Very rare

Acute myeloic leukaemia and myelodysplastic syndromes.

Use in indications other than prevention of transplant rejection increases the risk of the development of tumours. This risk is lower than when used for the indication organ transplantation because, in this indication, weaker immune suppression is used than in the indication organ transplantation. However, the type of tumours is not different from the above-mentioned, which typically occur under conditions of immunosuppression (induced by oncovirus or natural radiation).

Blood and the lymphatic system disorders

Very common

Leukopenia in transplant recipients (50 %) and patients with rheumatoid arthritis (28 %)

Common

Leucopoenia in patients with inflammatory bowel disease (5-10 %)

Anaemia, thrombocytopenia

Rare

Granulocytopenia, pancytopenia and aplastic anaemia Megaloblastic anaemia, erythroid hypoplasia

TPMP deficiency, hepatic and renal impairment predispose for myelosuppression.

Immune system disorders

Uncommon

Hypersensitivity reactions including general malaise, rigor, chills, hypotension, dizziness, leukocytosis, exanthema, severe nausea and vomiting, diarrhoea, fever, rash, myalgia, arthralgia, vasculitis, renal dysfunction, elevations in liver enzymes. Immediate discontinuation of azathioprine and, where necessary, measures to support the circulation have led to improvement in most cases. After a hypersensitivity reaction to azathioprine therapy with azathioprine should not be reinstated.

Very rare

Hypersensitivity reactions with lethal outcome.

Respiratory, thoracic and mediastinal disorders

Rare

Reversible interstitial pneumonitis

Gastroinstestinal disorders

Very common

Nausea and anorexia with occasional vomiting (10% in patients with rheumatoid arthritis)

Common

Pancreatitis (0.2-8 % most commonly in organ recipients and patients with Crohn’s disease).

Uncommon

Steatorrhoea

Diarrhoea

Severe diarrhoea in patients with inflammatory bowel disease. The possibility that exacerbation of symptoms might be drug-related should be borne in mind when treating such patients.

Rare

Gastrointestinal ulcers, intestinal haemorrhage, necrosis, colitis, diverticulitis or intestinal perforation

These are complications that are only encountered after transplantation. The aetiology is not clear. However concomitant treatment with steroids may play a role.

Gastrointestinal disturbance may be reduced by administering azathioprine in divided doses and/or during meals.

Hepatobiliary disorders

Common

hepatic dysfunction

Different pathologies including cholestasis, destructive cholangitis, bacillary angiomatosis (peliosis hepatitis), disse space fibrosis and nodular regenerative hyperplasia in 3-10 % in patients after organ transplantation

Uncommon

Hepatotoxicity occur in < 1 % of patients with rheumatoid arthritis

Rare

Veno-occlusive hepatic disease

A rare, but life-threatening veno-occlusive hepatic disease during chronic administration of azathioprine has been described, mainly in transplant patients. In occasional cases discontinuation of azathioprine led to either a temporary or permanent recovery from the liver histology and the symptoms.

Cholestasis and deterioration of liver function are usually reversible on withdrawal of azathioprine therapy.

Skin and subcutaneous tissue disorders

Common

Alopecia

Hair loss has been described a number of times in patients receiving azathioprine alone or in combination with other immunosuppressive agents. In many cases this symptom disappeared spontaneously despite continuing therapy.

4.9 Overdose

In the event of overdose the most likely effect is bone marrow suppression, reaching its maximum mostly 9-19 days after dosing. The principal signs of bone marrow suppression are ulcerations in the throat, fever and infections. Furthermore, bruising, bleeding and fatigue may occur. These signs are more likely to be manifest following chronic overdosage, rather than after a single acute overdose. Although improvement may be delayed, it usually occurs from the twelfth day after overdose, provided that the patient has not taken a high dose in the meantime.

There is no specific antidote for azathioprine. In the event of overdose, blood count and hepatic function in particular should be monitored. Azathioprine is known to be dialysable, and in severe cases dialysis may be used.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other immunosuppressive agents, azathioprine ATC code: L04AX01

Azathioprine is used as an immunosuppressant antimetabolite either alone or, more commonly, in combination with other agents (usually corticosteroids) which influence the immune response.

Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP). It is rapidly broken down in vivo into 6-MP and 1-methyl-4-nitro-5-thiomidazole. 6-MP readily crosses cell membranes and is converted intracellularly into a number of purine thioanalogues, which include the main active nucleotide, thioinosinic acid. The activity of the methylnitroimidazole moiety has not been defined clearly. However, in various systems it appears to modify the activity of azathioprine, compared with that of 6-MP.

Azathioprine has an effect on both immunological reaction and tumour growth. Its major role has been as an agent for suppressing the immune response, and although the precise mechanism by which this effect is achieved is not known, the following mechanisms of action have been suggested:

i.    The action of the released 6-MP as a purine antimetabolite.

ii.    The possible blockade of -SH groups by alkylation.

iii.    The inhibition of many pathways in nucleic acid biosynthesis, hence preventing proliferation and activity of immuncompetent cells (B- and T-lymphocytes).

iv.    Damage to deoxyribonucleic acid (DNA) through incorporation of purine thio-analogues.

5.2 Pharmacokinetic properties

Azathioprine is readily absorbed following oral administration. Peak plasma concentrations are reached 1-2 hours after taking a dose. Azathioprine is distributed rapidly through the body. The plasma half-life is 3-5 hours. Only small amounts of the medicinal product bind to plasma proteins, a maximum of 30 %. 12.5 % enter the cerebrospinal fluid.

Azathioprine is extensively metabolised to 6-thioinosinic acid and methylmercaptopurine-ribonucleotide, which, in part, are responsible for the effect of the medicinal product.

The effect in vivo is made more difficult by the action of methyl-nitroimidazole, which is also found.

Up to 50 % of a dose are excreted in urine during the first 24 hours after administration, with approximately 10 % as unchanged substance. Only 12.6 % of the dose appearing in the stool after 48 hours. There is no evidence of enterohepatic circulation. A lowered dosage for patients with reduced renal function may be necessary, probably as a result of reduced elimination of the active metabolites of azathioprine.

Also in patients with hepatic impairment the metabolism of azathioprine is altered. Conversion into the active form is reduced and especially the breakdown to eliminable metabolites is diminished.

Mercaptopurine, an active metabolite of azathioprine, has been identified in the colostrum and breast-milk of women receiving azathioprine treatment.

5.3 Preclinical safety data

Teratogenicity or embryolethality has been seen in a number of animal species, with a varying degree of susceptibility.

In rabbits, a dose of 5-15mg/kg body weight daily on days 6-14 of pregnancy produced skeletal abnormalities; in mice and rats, doses of 1-2mg/kg body weight daily on days 3-12 were lethal to the embryos.

Azathioprine was mutagenic in a number of in-vitro and in-vivo genotoxicity assays.

In long-term carcinogenicity studies of azathioprine in mice and rats, an increased incidence of lymphosarcomas (mice) and epithelial tumours and carcinomas (rats) were observed at dosages that were up to 2-fold the human therapeutic dosage.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core:

Lactose monohydrate maize starch povidone

colloidal silicon dioxide magnesium stearate

Coating: hypromellose microcrystalline cellulose polyoxyl 8 stearate talc

Colouring agent: titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5    Nature and contents of container

The film-coated tablets are packed in either polypropylene-aluminium blister or PVC/PVDC-aluminium blister in a carton box.

The pack contains 20, 28, 30, 50 or 100 film-coated tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

Provided that the film-coating is intact, there is no risk in handling film-coated azathioprine tablets and no additional precautions are required.

However, azathioprine tablets should be handled in strict accordance with guidance for handling cytotoxic agents when people have crushed the tablets (see section 4.4).

Surplus medical products as well as contaminated appliances should be temporarily stored in markedly labelled containers and then discarded safely. High-temperature incineration is recommended.

7    MARKETING AUTHORISATION HOLDER

Sandoz Limited Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04416/1247

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

08/07/2007

10    DATE OF REVISION OF THE TEXT

06/05/2013