What is the safety and efficacy of off-label treatment with azathioprine in patients with dermatological diseases?

General treatment considerations

Dosage in other conditions then organ transplant patients - adults and children

• In general, starting dosage is from 1 to 3 mg/kg body weight/day, and should be adjusted, within these limits, depending on the clinical response (which may not be evident for weeks or months) and haematological tolerance.
• When therapeutic response is evident, consideration should be given to reducing the maintenance dosage to the lowest level compatible with the maintenance of that response. If no improvement occurs within 3 months, consideration should be given to withdrawing azathioprine.

• The maintenance dosage required may range from less than 1 mg/kg body weight/day to 3 mg/kg body weight/day, depending on the clinical condition being treated and the individual patient response, including haematological tolerance.
• In patients with renal and/or hepatic insufficiency, dosages should be given at the lower end of the normal range (see Special Warnings and Precautions for Use for further details).

Use in the elderly (see also renal and/or hepatic insufficiency)

There is limited experience of azathioprine in elderly patients. Although the available data do not provide evidence that the incidence of side effects among elderly patients is higher than that among other patients treated with azathioprine, it is recommended that the dosages used should be at the lower end of the range.

Particular care should be taken to monitor haematological response and to reduce the maintenance dosage to the minimum required for clinical response.

Contraindications

Azathioprine is contra-indicated in patients known to be hypersensitive to azathioprine. Hypersensitivity to 6-mercaptopurine (6-MP) should alert the prescriber to probable hypersensitivity to azathioprine. Azathioprine therapy should not be initiated in patients who may be pregnant, or who are likely to become pregnant without careful assessment of risk versus benefit (see Special Warnings and Precautions for Use and Pregnancy and Lactation).

Special warnings and precautions for use

Monitoring

There are potential hazards in the use of azathioprine. It should be prescribed only if the patient can be adequately monitored for toxic effects throughout the duration of therapy. It is suggested that during the first 8 weeks of therapy, complete blood counts, including platelets, should be performed weekly and more frequently if high dosage is used or if severe renal and/or hepatic disorder is present. The blood count frequency may be reduced later in therapy, but it is suggested that complete blood counts are repeated monthly or at least at intervals of not longer than 3 months.

Patients receiving azathioprine should be instructed to immediately consult their doctor in case of evidence of fever, chills , unexpected bruising or bleeding or other manifestations of bone marrow depression (e.g. chest pain, dizziness, fatigue, petechiae).

There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effect of azathioprine and prone to developing rapid bone marrow depression following the initiation of treatment with azathioprine. This problem can be exacerbated by co-administration with drugs that inhibit TPMT, such as sulfasalazine.

It has been reported that decreased TPMT activity increases the risk of secondary leukaemias and myelodysplasia in individuals receiving 6-mercaptopurine (the active metabolite of azathioprine) in combination with other cytotoxic drugs (see section Undesirable effects).

Renal and/or hepatic insufficiency

It has been suggested that the toxicity of azathioprine may be enhanced in the presence of renal insufficiency, but it has not been supported by controlled studies. Nevertheless, it is recommended that the dosages used should be at the lower end of the normal range and that haematological response should be carefully monitored. Dosage should be further reduced if haematological toxicity occurs. During the administration of azathioprine to patients with hepatic dysfunction, regular (two times a week in the first 8 weeks) complete blood counts and liver function tests should be undertaken. In such patients the metabolism of azathioprine may be impaired, and the dosage of azathioprine should therefore be reduced if hepatic or haematological toxicity occurs.

Limited evidence suggests that azathioprine is not beneficial to patients with hypoxanthine-guanine-phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). Therefore, it is not recommended to give these patients azathioprine.

Carcinogenicity (see also section Undesirable Effects)

• Patients receiving immunosuppressive therapy are at an increased risk of developing non-Hodgkin's lymphomas and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. It has been reported that reduction or discontinuation of immunosuppression may be associated with partial or complete regression of non-Hodgkin's lymphomas and Kaposi's sarcomas.
• Patients receiving multiple immunosuppressive agents may be at risk of over-immunosuppression, therefore such therapy should be maintained at the lowest effective level.
• Exposure to sunlight and UV light should be limited and patients should wear protective clothing and use a sunscreen with a high protection factor to minimize the risk of skin cancer and photosensitivity (see also section Undesirable Effects).
• Infection with varicella zoster virus (VZV; chickenpox and herpes zoster) may have a severe clinical outcome during the administration of immunosuppressants. Caution should be exercised especially with respect to the following: Before starting the administration of immunosuppressants, the prescriber should check if the patient has a history of VZV. Serologic testing may be useful in determining previous exposure. Patients who have no history of exposure should avoid contact with individuals with chickenpox or herpes zoster. If the patient is exposed to VZV, special care must be taken to avoid patients developing chickenpox or herpes zoster and passive immunisation with varicella zoster immunoglobulin (VZIG) may be considered. If the patient becomes infected with VZV, appropriate measures should be taken, which may include antiviral therapy and supportive care.

Interaction with other medicinal products and other forms of interaction

• Allopurinol

Xanthine oxidase activity is inhibited by allopurinol which results in reduced conversion of biologically active 6 thioinosinic acid to biologically inactive 6-thiouric acid. When allopurinol is given concomitantly with azathioprine, the dose of azathioprine should be reduced to one-quarter of the original dose.

• Neuromuscular blocking agents

Azathioprine can potentiate the neuromuscular blockade produced by depolarising agents such as suxamethonium and can reduce the blockade produced by non-depolarising agents such as tubocurarine. There is considerable variation in the potency of this interaction.

• Cytostatic/myelosuppressive agents

Where possible, concomitant administration of cytostatic drugs, or drugs which may have a myelosuppressive effect, such as penicillamine, should be avoided. There are conflicting clinical reports of interactions, resulting in serious haematological abnormalities, between azathioprine and co-trimoxazole. There has been a case report suggesting that haematological abnormalities may develop due to the concomitant administration of azathioprine and ACE inhibitors. It has been suggested that cimetidine and indometacin may have myelosuppressive effects, which may be enhanced by concomitant administration of azathioprine.

• Other interactions

As there is in vitro evidence that aminosalicylate derivatives (eg. sulfasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent azathioprine therapy (see Special Warnings and Special Precautions for Use). Furosemide has been shown to impair the metabolism of azathioprine by human hepatic tissue in vitro. The clinical significance is unknown.

• Vaccines

The immunosuppressive activity of azathioprine could result in an atypical and potentially deleterious response to live vaccines and the administration of live vaccines to patients receiving Azathioprine therapy is contra-indicated on theoretical grounds. 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 by mean anti-capsular specific antibody concentration.

Use in Pregnancy and Lactation

Azathioprine should not be given to patients who are pregnant or likely to become pregnant without careful assessment of risk versus benefit. There have been reports of premature birth and low birth weight following maternal exposure to azathioprine, particularly in combination with corticosteroids. There have also been reports of spontaneous abortion following either maternal or paternal exposure. Azathioprine and/or its metabolites have been found in low concentrations in foetal blood and amniotic fluid after maternal administration of azathioprine. Leucopenia and/or thrombocytopenia have been reported in a proportion of neonates whose mothers took azathioprine throughout their pregnancies. Extra care in haematological monitoring is advised during pregnancy. 6-Mercaptopurine has been found in the colostrum and breast-milk of women receiving azathioprine treatment. Treatment with azathioprine is therefore not recommended during lactation.

The need for anti-conception in men during treatment is unclear and is currently subject of debate.

Undesirable effects

There is no modern clinical documentation that can be used for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the indication. The following convention has been utilised for the classification of frequency: Very common,  1/10; common,  1/100 and < 1/10; uncommon,  1/1000 and < 1/100; rare,  1/10000 and < 1/1000; very rare, < 1/10000.

Azathioprine may be associated with a dose-related, generally reversible, depression of bone marrow function, most frequently as leucopenia, but also sometimes as anaemia and thrombocytopenia, and rarely as agranulocytosis, pancytopenia and aplastic anaemia. These occur particularly in patients predisposed to myelotoxicity, such as those with TPMT deficiency and renal or hepatic insufficiency and in patients failing to reduce the dose of azathioprine when receiving concurrent allopurinol therapy.

Reversible, dose-related increases in mean corpuscular volume and red cell haemoglobin content have occurred in association with azathioprine therapy. Megaloblastic bone marrow changes have also been observed but severe megaloblastic anaemia and erythroid hypoplasia is rare.

A minority of patients experience nausea when first given azathioprine. This appears to be relieved by administering the tablets after meals. Pancreatitis has been reported in a small percentage of patients on azathioprine therapy, particularly in renal transplant patients and patients with inflammatory bowel disease. There are difficulties relating pancreatitis to the administration of one particular drug, although re-challenge has confirmed an association with azathioprine .

Cholestasis and deterioration of liver function have occasionally been reported in association with azathioprine therapy and are usually reversible on withdrawal. This may be associated with symptoms of a hypersensitivity reaction (see hypersensitivity reactions).

Rare, but life-threatening hepatic damage associated with chronic administration of azathioprine has been described primarily in transplant patients. In some cases withdrawal of azathioprine has resulted in either a temporary or permanent improvement in symptoms and histological changes.

Several different clinical syndromes, which appear to be idiosyncratic manifestations of hypersensitivity, have been described occasionally following administration of azathioprine. Clinical features include general malaise, dizziness, nausea, vomiting, diarrhoea, fever, rigors, exanthema, rash, vasculitis, myalgia, arthralgia, hypotension, renal dysfunction, hepatic dysfunction and cholestasis (see hepato-biliary disorders). In many cases, re-challenge has confirmed an association with azathioprine. Immediate withdrawal of azathioprine and institution of circulatory support where appropriate have led to recovery in the majority of cases. Other marked underlying pathology has contributed to the very rare deaths reported. Following a hypersensitivity reaction to azathioprine, the necessity for continued administration of azathioprine should be carefully considered on an individual basis.

Overdose 

• Symptoms and signs

Unexplained infection, ulceration of the throat, bruising and bleeding are the main signs of overdosage with azathioprine and result from bone marrow depression which may be maximal after 9 to 14 days after overdosage. These signs are more likely following chronic overdosage, than after a single acute overdose.

• Treatment

There is no specific antidote. Gastric lavage has been used for acute overdose. Subsequent monitoring, including haematological monitoring, is necessary to allow prompt treatment of any adverse effects which may develop. The value of dialysis in patients who have taken an overdose of azathioprine is not known, though azathioprine is partially dialysable.

Safety data off-label azathioprine

The safety data described here are derived from all the identified studies reporting about safety (see section ’Methodology’ for more information. The total number of patients treated with azathioprine in studies that mentioned adverse events was 877. The individual studies and tables can be found in section IV: Tables.

Adverse events

Serious adverse events

• Atopic dermatitis

Four serious adverse events (SAE) were described, 2 of which occurred during treatment with AZA, leading to discontinuation of AZA.^1-3 One subject experienced a severe pancytopenia, which required blood transfusion. The time between initiating AZA and the occurrence of the severe pancytopenia was not reported. It is noteworthy that in this study the TPMT activity was not measured prior to initiation of AZA. Another subject developed pancreatitis after 15 days of treatment, which resolved after discontinuation. Two SAE occurred in the follow up period. A non Hodgkin Lymphoma emerged 8 months after treatment with AZA (duration of treatment 12 months). A fatal event due to a ruptured cerebral aneurysm occurred 7 years after AZA treatment.

• Bullous pemphigoid

Due to the mean age of the subjects and the severity of the disease, serious adverse events were not uncommon. Beissert et al. reported 2 deaths, 2 cases of severely raised liver enzymes and 1 severe infection.⁴Guillaume et al. reported 15serious adverse events, 6 of which deaths, 4 cases of severe cytopenia and 3 hepatitis.⁵ The remaining 2 adverse events were not further specified. The causes of death were unspecified. Burton et al. described 3 deaths, 2 due to cerebrovascular accidents (CVA) and one due to heart failure.⁶Another study by Burton et al. reported 4 serious adverse events , all occurring during treatment with AZA and leading to death .⁷ The causes of death were adenocarcinoma, a pre-exisisting mammacarcinoma, myocardal infarction and CVA.

• Psoriasis

Three serious adverse events were described which occurred during treatment with AZA, leading to discontinuation of the treatment.^8,9 One patient died due to respiratory insufficiency 6 years after AZA treatment was stopped. In that same study (Le Quintrec et al.) another subject died due to a pulmonary embolus. The time between initiating AZA and the pulmonary embolus was not reported. In the publication of Hewitt et al., one subject experienced a severe anemia, which required blood transfusions. The time between initiating AZA and the occurrence of the severe anemia was not reported. Another subject had a myocard infarction in the third week of the third treatment course of AZA.

• Chronic actinic dermatitis

Three subjects died: CVA (1), airway disease (1) and heart disease (1) after 15, 15 and 12 months of AZA treatment respectively.¹⁰

• Cutaneous vasculitis

Two serious adverse events occurred, both of infectious origin; a septic arthritis and an epidural abcess.¹¹ One subject with severe and rapid onset of vasculitis died during treatment with AZA due to renal failure, which could be attributed to the natural course of the underlying disease.

• Cutaneous lupus erythematosus

One serious adverse event occurred; pancreatitis.¹²

Evidence on safety derived from included RCT’s

There is a limited number of eligible RCT’s comparing one treatment with another. However, the relative risk of specific adverse events from a particular RCT could be of value in formulating a recommendation for a therapy.

In the study of Beissert et al. the subjects randomized to the AZA group had significant higher elevated liver enzymes than the mycofenolaat group; the number of subjects having elevated liver enzymes was comparable (Table 7).

Adverse events that occurred during AZA treatment compared to betamethasone treatment are shown in Table 30. There were statistically significant (Fisher exact < 0.05) more AE’s related to corticosteroid use (acne, striae, Cushingoid features, weight gain, rise in blood pressure) in the group B. However, there was no difference in the other AE’s. Adverse events that occurred during AZA treatment compared to CYC are shown in Table 38.