Imuran Side Effects

Generic Name: azathioprine

Please note - some side effects for Imuran may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Imuran - for the Consumer

Imuran

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Imuran:

Mild nausea or vomiting.

Severe allergic reactions (rash; itching; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain or tightness; dizziness; fatty stools; fever, chills, or persistent sore throat; increased or painful urination; muscle pain or aches; painful, red bumps or blisters on the arms, face, neck, or back; severe or persistent nausea, vomiting, or diarrhea; shortness of breath; stomach pain; symptoms of liver problems (eg, dark urine, loss of appetite, pale stools, right-sided stomach pain, yellowing of the eyes or skin); unusual bleeding or bruising; unusual growths or lumps; unusual weakness or tiredness.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

Imuran Side Effects - for the Professional

Imuran

The principal and potentially serious toxic effects of Imuran are hematologic and gastrointestinal. The risks of secondary infection and malignancy are also significant. The frequency and severity of adverse reactions depend on the dose and duration of Imuran as well as on the patient's underlying disease or concomitant therapies. The incidence of hematologic toxicities and neoplasia encountered in groups of renal homograft recipients is significantly higher than that in studies employing Imuran for rheumatoid arthritis. The relative incidences in clinical studies are summarized below:

Hematologic: Leukopenia and/or thrombocytopenia are dose-dependent and may occur late in the course of therapy with Imuran. Dose reduction or temporary withdrawal may result in reversal of these toxicities. Infection may occur as a secondary manifestation of bone marrow suppression or leukopenia, but the incidence of infection in renal homotransplantation is 30 to 60 times that in rheumatoid arthritis. Anemias, including macrocytic anemia, and/or bleeding have been reported.

TPMT genotyping or phenotyping can help identify patients with low or absent TPMT activity (homozygous for non-functional alleles) who are at increased risk for severe, life-threatening myelosuppression from Imuran. See CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS:Laboratory Tests. Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving azathioprine. 6, 20

Gastrointestinal: Nausea and vomiting may occur within the first few months of therapy with Imuran, and occurred in approximately 12% of 676 rheumatoid arthritis patients. The frequency of gastric disturbance often can be reduced by administration of the drug in divided doses and/or after meals. However, in some patients, nausea and vomiting may be severe and may be accompanied by symptoms such as diarrhea, fever, malaise, and myalgias. Vomiting with abdominal pain may occur rarely with a hypersensitivity pancreatitis. Hepatotoxicity manifest by elevation of serum alkaline phosphatase, bilirubin, and/or serum transaminases is known to occur following azathioprine use, primarily in allograft recipients. Hepatotoxicity has been uncommon (less than 1%) in rheumatoid arthritis patients. Hepatotoxicity following transplantation most often occurs within 6 months of transplantation and is generally reversible after interruption of Imuran. A rare, but life-threatening hepatic veno-occlusive disease associated with chronic administration of azathioprine has been described in transplant patients and in one patient receiving Imuran for panuveitis.21, 22, 23 Periodic measurement of serum transaminases, alkaline phosphatase, and bilirubin is indicated for early detection of hepatotoxicity. If hepatic veno-occlusive disease is clinically suspected, Imuran should be permanently withdrawn.

Others: Additional side effects of low frequency have been reported. These include skin rashes, alopecia, fever, arthralgias, diarrhea, steatorrhea, negative nitrogen balance, reversible interstitial pneumonitis, hepatosplenic T-cell lymphoma, and Sweet's Syndrome (acute febrile neutrophilic dermatosis).

Side Effects by Body System - for Healthcare Professionals

General

The principal and potentially serious toxic effects of azathioprine are hematologic and gastrointestinal. Risk of secondary infection and malignancy is also significant. Frequency and severity of side effects depend on dose and duration of azathioprine as well as on underlying disease or concomitant therapies. Hematologic toxicities and neoplasia were reported more often in renal homograft recipients than in patients using azathioprine for rheumatoid arthritis.

Hematologic

Bone marrow suppression is dose related and is the most common cause for dosage reductions.

Leukopenia (any degree) has been reported in greater than 50% of renal homograft recipients and 28% of rheumatoid arthritis patients. Leukopenia (less than 2500/mm3) has been reported in 16% of renal homograft recipients and 5.3% of rheumatoid arthritis patients.

There are data to support an increased risk of bone marrow aplasia in patients with very low or absent thiopurine methyltransferase (TPMT) activity. The majority of the population has high TPMT activity, 11% have moderate activity, and approximately one in 300 persons has very low to no activity. The main metabolic pathway of azathioprine, conversion to 6-MP, involves TPMT. Limitations in this pathway lead to increased metabolism via alternate pathways. In patients with low TPMT activity, there is an increase in 6-thioguanine nucleotide (6-TGN) concentrations, a cytotoxic metabolite which suppresses purine synthesis. Despite these findings, bone marrow aplasia has been reported in patients with normal TPMT activity.

A 55-year-old male with pompholyx and deficiency of erythrocyte thiopurine methyltransferase experienced pancytopenia coincident with azathioprine therapy. Ten weeks after starting azathioprine 100 mg per day, a full blood count (during routine monitoring) showed moderate pancytopenia. Azathioprine was discontinued. Ten days later he was admitted to the hospital with malaise, lethargy, and deterioration in blood count. He was treated with blood and platelet transfusions and discharged eight days later with modest improvement in peripheral blood count.

Hematologic side effects have included reversible bone marrow suppression, severe leukopenia, thrombocytopenia, and anemia. Macrocytosis, hemolytic anemia, pure red cell aplasia, and pancytopenia have been reported. Anemias (including macrocytic anemia) and/or bleeding have been reported. Fatal myelosuppression has been reported in a carrier of heterozygous thiopurine S-methyl transferase *1/*3C.

Gastrointestinal

Gastrointestinal side effects tend to be more problematic in the first few months of therapy.

A 20-year-old man developed severe small-bowel villus atrophy and chronic diarrhea after starting azathioprine 50 mg per day. Diarrhea completely resolved within 2 weeks after azathioprine discontinuation. Mucosal biopsies at 4 months post azathioprine discontinuation showed complete reversal of severe duodenal villus atrophy.

Gastrointestinal (GI) side effects have included nausea, vomiting, diarrhea, and anorexia. Severe villus, chronic malabsorption syndrome, acute pancreatitis, GI discomfort, and steatorrhea have been reported. Vomiting with abdominal pain has been reported with hypersensitivity pancreatitis. Case reports of patients with symptoms that imitate viral gastroenteritis (nausea, vomiting, diarrhea, and fever) hours after a single dose of azathioprine have also been reported.

Oncologic

Oncologic side effects have included an increased risk of cancer, particularly lymphomas and leukemias. Case reports of common de novo tumors that have developed in renal transplant patients have included basal cell, squamous cell carcinomas of the skin, urogenital malformations, lung malformations, and Kaposi's sarcoma (cutaneous and visceral). Lymphoproliferative disease in azathioprine-treated rheumatoid arthritis patients have been reported in approximately 1.8 cases per 1000 patient years of follow-up compared to an incidence of 0.8 cases per 1000 patient years of follow-up in the normal population. Epstein-Barr virus-positive lymphoma and hepatosplenic T-cell lymphoma have also been reported.

The increased risk of cancer may be more pronounced when azathioprine is used concomitantly with other immunosuppressive agents.

Renal transplant patients may have a higher risk of developing lymphoproliferative disorders, lymphomas, and leukemia, as well as some solid tumors while receiving azathioprine.

Transplant patients as well as those with rheumatoid arthritis are often treated with multiple immunosuppressants; therefore, the true risk of neoplasia associated with azathioprine alone has yet to be determined.

A small increase in the risk of Epstein-Barr virus-positive lymphoma was seen in a study of patients with inflammatory bowel disease treated with azathioprine.

Other

Other side effects have included infection in up to 20% of patients, even with therapeutic doses of azathioprine. These have included fungal, protozoal, viral, and uncommon bacterial infections, some of which have been fatal. Fever, delayed wound healing, oral lesions, fatigue, and malaise have also been reported.

Hepatic

Hepatic side effects have included elevations in alkaline phosphatase, bilirubin, and/or serum transaminases, cholestatic jaundice, hepatitis, and hepatic veno-occlusive disease. Other hepatotoxic side effects have included cirrhosis, perisinusoidal fibrosis, hepatic peliosis, sinusoidal dilatation, cholestasis, and acute focal hepatocellular necrosis. In addition, several cases of nodular regenerative hyperplasia of the liver and at least one case of destructive cholangitis have been reported.

Hepatotoxicity usually occurs within the first six months of therapy and is more common in patients requiring immunosuppression following transplant than in patients requiring therapy for rheumatoid arthritis. Hepatotoxicity, often manifest as cholestasis and/or acute focal hepatocellular necrosis, is generally reversible following discontinuation of azathioprine therapy. However, permanent hepatic damage associated with cirrhosis, perisinusoidal fibrosis, hepatic peliosis, sinusoidal dilatation, and veno-occlusive disease is also reported.

Veno-occlusive disease of the hepatic veins is due to an unknown mechanism, may affect males more often, usually precedes portal hypertension, and carries a poor prognosis. Numerous fatalities have been reported. Permanent discontinuation of azathioprine therapy is indicated if hepatic veno-occlusive disease is suspected.

A 51-year-old man developed jaundice and diffuse abdominal pain two months after the start of azathioprine 1.4 mg/kg/day. Biopsy reports confirmed destruction of the bile ducts consistent with destructive cholangitis. After discontinuation of azathioprine, the abdominal pain disappeared within 2 days; and liver function tests improved and returned to normal values 8 weeks later.

Hypersensitivity

Hypersensitivity side effects have included hypersensitivity rash, leukocytoclastic vasculitis, skin rash, fever, chills, malaise, diarrhea, nausea, hepatitis, hypotension, and circulatory collapse. Hypersensitivity has also been implicated in cases of hepatotoxicity, interstitial nephritis, interstitial pneumonitis, pancreatitis, and vasculitis. As azathioprine is metabolized to 6-mercaptopurine, rechallenge with both agents should be avoided. Hypersensitivity reactions which manifest from mild gastrointestinal disturbances, fever, and myalgias to severe hypotension and shock have been reported. Rhabdomyolysis has been reported as part of an azathioprine hypersensitivity syndrome. At least 3 cases of erythema nodosum, 2 cases of pustules, and 1 case of contact dermatitis have been reported.

Erythema nodosum and pustules are rarely reported manifestations of azathioprine hypersensitivity. Both types of skin lesions may be related to the clinical activity of inflammatory bowel disease. Relapse of such lesions shortly after rechallenge should raise the hypothesis of hypersensitivity rather than pharmacological manifestations.

Gastrointestinal hypersensitivity is characterized by severe nausea and vomiting which may be accompanied by diarrhea, rash, fever, malaise, myalgias, elevated liver function tests, and hypotension.

Cardiovascular

A 52-year-old male with steroid-dependent ulcerative colitis experienced atrial fibrillation coincident with azathioprine therapy. The drug had been started 3 years earlier, but discontinued after a few months because the patient reported palpitations, lipothymia, nausea, and vomiting. Upon a rechallenge with 50 mg of azathioprine, the patient showed general malaise, nausea, and vomiting. An ECG showed atrial fibrillation, and the patient reported that the symptoms were similar to those experienced previously.

Azathioprine-induced hypotension is independent of dose and may accompany signs and symptoms of hypersensitivity. Hypotension may be profound, although it is usually responsive to intravenous fluids and, if hypersensitivity is suspected, corticosteroids.

Cardiovascular side effects have included rare cases of hypotension, including cardiogenic shock. At least three cases of atrial fibrillation have been reported (one case involving a patient with ulcerative colitis), although causality is unknown.

Respiratory

Respiratory side effects have included reversible interstitial pneumonitis. Interstitial pneumonitis associated with a restrictive pattern on pulmonary function tests has been reported.

Review of seven rare cases of azathioprine-associated interstitial pneumonitis revealed that the progression from alveolitis to pulmonary fibrosis may be dose-related.

Renal

A reduction in the incidence of chronic allograft nephropathy has been reported during the extended follow-up (greater than or equal to 10 years) of patients (n=128) participating in a randomized trial that examined the conversion from cyclosporine to azathioprine as early as three months after renal transplantation.

A 47-year-old female with Wegener's granulomatosis experienced rapid progression of renal failure within 10 days of starting azathioprine for vasculitis. Her creatinine was 119 mcmol/L at the time of presentation. Acute tubulointerstitial nephritis and no active glomerulonephritis were observed on renal biopsy. Her renal function started improving by day 6 post-admission and at one month post-admission her serum creatinine was 116 mcmol/L. She continued to have reasonable renal function and 16 months later had creatinine of 104 mcmol/L with no clinical evidence of recurrent interstitial nephritis.

Renal side effects have included elevation in serum creatinine and BUN accompanied by oliguria, but are usually associated with hypotension, and normalize after treatment with intravenous hydration and steroids. Rare cases of hematuria secondary to azathioprine-induced crystalluria have been reported, and may be less common with high urine output. Chronic allograft nephropathy and at least one case of acute interstitial nephritis have been reported.

Dermatologic

Dermatologic side effects have included skin rashes, alopecia, verrucae, zoster, increased skin color, malignant neoplasms, Kaposi sarcoma, dermatomycoses, cytomegalovirus infection, scabies, skin lesions, Sweet's syndrome (acute febrile neutrophilic dermatosis), and at least one case of skin peeling syndrome.

A female patient developed skin peeling syndrome eight months after the dosage of azathioprine was reduced to 25 mg daily. Skin lesions resolved 30 days after drug withdrawal.

Excess sun exposure, pale skin types, and duration of allograft seem to be important risk factors in the development of skin lesions.

Immunologic

Immunologic side effects have included at least one case of bilateral cytomegalovirus (CMV) retinitis.

A patient with systemic lupus erythematosus and end-stage renal disease experienced CMV retinitis coincident with azathioprine therapy. It is theorized that immunosuppressive therapy may have a role in the development of CMV retinitis in this population. The patient responded to discontinuation of azathioprine, lowering of the corticosteroid dose, and systemic administration of ganciclovir.

Metabolic

Metabolic side effects have included negative nitrogen balance.

Musculoskeletal

Musculoskeletal side effects have included arthralgias.

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