Azasan Side Effects

Generic Name: azathioprine

Note: This page contains information about the side effects of azathioprine. Some of the dosage forms included on this document may not apply to the brand name Azasan.

Not all side effects for Azasan may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

For the Consumer

Applies to azathioprine: oral tablet

In addition to its needed effects, some unwanted effects may be caused by azathioprine (the active ingredient contained in Azasan). In the event that any of these side effects do occur, they may require medical attention.

You should check with your doctor immediately if any of these side effects occur when taking azathioprine:

More common
  • Black, tarry stools
  • bleeding gums
  • blood in the urine or stools
  • chest pain
  • cough or hoarseness
  • fever or chills
  • lower back or side pain
  • painful or difficult urination
  • pinpoint red spots on the skin
  • shortness of breath
  • sore throat
  • sores, ulcers, or white spots on the lips or in the mouth
  • swollen glands
  • unusual bleeding or bruising
  • unusual tiredness or weakness
Rare
  • Abdominal or stomach pain or tenderness
  • clay-colored stools
  • dark urine
  • decreased appetite
  • fast heartbeat
  • fever (sudden)
  • headaches
  • itching
  • loss of appetite
  • muscle or joint pain
  • nausea, vomiting, and diarrhea (severe)
  • redness or blisters on the skin
  • swelling of the feet or lower legs
  • unusual feeling of discomfort or illness (sudden)
  • yellow eyes or skin
Incidence not known
  • Abdominal or stomach cramps
  • diarrhea
  • difficulty with breathing
  • difficulty with moving
  • fat in the stool
  • general feeling of illness
  • pale skin
  • sores on the skin
  • sudden loss of weight
  • troubled breathing with movement
  • weight loss

Some of the side effects that can occur with azathioprine may not need medical attention. As your body adjusts to the medicine during treatment these side effects may go away. Your health care professional may also be able to tell you about ways to reduce or prevent some of these side effects. If any of the following side effects continue, are bothersome or if you have any questions about them, check with your health care professional:

More common
  • Nausea or vomiting (mild)
  • swollen joints
Incidence not known
  • Hair loss or thinning of the hair

For Healthcare Professionals

Applies to azathioprine: compounding powder, intravenous powder for injection, oral tablet

General

The principal and potentially serious toxic effects of azathioprine (the active ingredient contained in Azasan) 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

Very common (10% or more): Depression of bone marrow function, leukopenia
Common (1% to 10%): Thrombocytopenia, anemia
Rare (Less than 0.1%): Agranulocytosis, pancytopenia, aplastic anemia, megaloblastic anemia, erythroid hypoplasia
Frequency not reported: Bleeding, increased mean corpuscular volume and red cell hemoglobin content (reversible, dose-related)

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 [2.5 x 10(9)/L]) 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. In patients with low TPMT activity, there is an increase in 6-thioguanine nucleotide (6-TGN) concentrations, a cytotoxic metabolite which suppresses purine synthesis. Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving azathioprine. 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.

Gastrointestinal

Very common (10% or more): Nausea, vomiting, anorexia
Uncommon (0.1% to 1%): Pancreatitis, steatorrhea, diarrhea
Rare (less than 0.1%): Gastrointestinal ulcers (transplant recipients), intestinal hemorrhage (transplant recipients), necrosis (transplant recipients), colitis (transplant recipients), diverticulitis or intestinal perforation (transplant recipients), and severe diarrhea (inflammatory bowel disease patients)
Frequency not reported: Severe villus, sores in the mouth and on the lips

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.

Complications such as colitis, diverticulitis, and bowel perforation have been primarily reported in transplant patients, and may be related to concomitant high-dose corticosteroid therapy. Pancreatitis occurs most commonly in organ recipients and patients with Crohn's disease.

There have been case reports of patients with symptoms that imitate viral gastroenteritis (nausea, vomiting, diarrhea, and fever) occurring hours after a single dose of azathioprine.

Oncologic

Common (1% to 10%): Squamous cell carcinoma of the skin, non-Hodgkin's lymphoma, cervical cancer, Kaposi's sarcoma, vulval cancer (renal homograft patients)
Uncommon (0.1% to 1%): Lymphoproliferative diseases after transplantation
Rare (0.01% to 0.1%): Melanoma, non-Kaposi's sarcoma
Very rare (less than 0.01%): Acute myeloid leukemia and myelodysplastic syndromes
Frequency not reported: Hepatosplenic T-cell lymphoma

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.

The majority of reported cases of hepatosplenic T-cell lymphoma have bee in patients with Crohn's disease or ulcerative colitis, and were adolescent and young adult males.

Hepatic

Common (1% to 10%): hepatic dysfunction (including cholestasis, destructive cholangitis, peliosis hepatitis, perisinusoidal fibrosis, nodular regenerative hyperplasia) (organ transplant recipients)
Uncommon (0.1% to 1%): Hepatotoxicity, including elevation of serum alkaline phosphatase, bilirubin, and/or serum transaminases
Rare (Less than 0.1%): Life-threatening hepatic damage, hepatic veno-occlusive disease
Frequency not reported: Sinusoidal dilatation, acute focal hepatocellular necrosis, acute focal hepatocellular necrosis

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 is often manifest as cholestasis and/or acute focal hepatocellular necrosis, and 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. Several cases of nodular regenerative hyperplasia of the liver and at least one case of destructive cholangitis have been 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

Uncommon (0.1% to 1%): Hypersensitivity reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis
Very rare (less than 0.01%): Hypersensitivity reactions with fatal outcome

Idiosyncratic manifestations of hypersensitivity include general malaise, headache, dizziness, nausea, vomiting, diarrhea, fever, rigors, exanthema, rash, vasculitis, myalgia, arthralgia, hypotension, renal dysfunction, hepatic dysfunction, cardiac dysrhythmia, and cholestasis. 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 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.

Azathioprine should be permanently withdrawn after occurrence of hypersensitivity reactions.

Cardiovascular

At least three cases of atrial fibrillation have been reported (one case involving a patient with ulcerative colitis), although causality is unknown. A 52-year-old male with steroid-dependent ulcerative colitis experienced atrial fibrillation coincident with azathioprine (the active ingredient contained in Azasan) 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.

Rare (less than 0.01%): Hypotension, including cardiogenic shock
Frequency not reported: Atrial fibrillation

Dermatologic

Alopecia has been reported in patients on azathioprine (the active ingredient contained in Azasan) monotherapy or in combination with other immunosuppressants. This side effect may resolve spontaneously despite ongoing therapy.

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.

Common (1% to 10%): Alopecia
Frequency not reported: Skin rashes, Sweet's syndrome (acute febrile neutrophilic dermatosis), exacerbation of dermatomyositis

Genitourinary

Rare (less than 0.1%): Hematuria secondary to azathioprine-induced crystalluria

Immunologic

Very common (10% or more): Viral, fungal, and bacterial infections (transplant recipients also receiving other immunosuppressants)
Common (1% to 10%): Susceptibility to infection in patients with inflammatory bowel disease
Uncommon (0.1% to 1%): Viral, fungal, and bacterial infections (other indications)
Frequency not reported: Protozoal and opportunistic infections, including reactivation of latent infections, increased susceptibility to varicella and herpes zoster progressive multifocal leukoencephalopathy

Metabolic

Frequency not reported: Negative nitrogen balance

Musculoskeletal

Frequency not reported: Arthralgias, myalgias, exacerbation of myasthenia gravis

Nervous system

Frequency not reported: Meningitis

Ocular

Frequency not reported: 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.

Renal

Elevation in serum creatinine and BUN accompanied by oliguria are usually associated with hypotension, and normalize after treatment with intravenous hydration and steroids. Cases of hematuria secondary to azathioprine-induced crystalluria may be less common with high urine output.

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 (the active ingredient contained in Azasan) 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.

Frequency not reported: Elevation in serum creatinine and BUN accompanied by oliguria, chronic allograft nephropathy, acute interstitial nephritis

Respiratory

Rare (less than 0.01%): Reversible interstitial pneumonitis

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

Other

There have been reports of fungal, protozoal, viral, and uncommon bacterial infections, some of which have been fatal, in patients who are receiving azathioprine (the active ingredient contained in Azasan)

Frequency not reported: Fever, malaise, alterations in sense of smell or taste, delayed wound healing, oral lesions, fatigue

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