Imruza

Imruza is used as an immunosuppressant antimetabolite either alone or, more commonly, in combination with other agents (usually corticosteroids) and procedures which influence the immune response. Therapeutic effect may be evident only after weeks or months and can include a steroid-sparing effect
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Imruza is used as an immunosuppressant antimetabolite either alone or, more commonly, in combination with other agents (usually corticosteroids) and procedures which influence the immune response. 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.
Imruza, combination with corticosteroids and/or other immunosuppressive agents and procedures, is indicated to enhance the survival of organ transplants, such as renal transplants, cardiac transplants, and hepatic transplants. It also reduces the corticosteroid requirements of renal transplant recipients.
Imruza is indicated for the treatment of moderate to severe inflammatory bowel disease (IBD) (Crohn's disease or ulcerative colitis) in patients in whom corticosteroid therapy is required, in patients who cannot tolerate corticosteroid therapy, or in patients whose disease is refractory to other standard first line therapy.
Imruza either alone or more usually in combination with corticosteroids and/or other medicinal products and procedures, has been used with clinical benefit (which may include reduction of dosage or discontinuation of corticosteroids) in a proportion of patients suffering from the following:
Severe active rheumatoid arthritis;
Systemic lupus erythematosus;
Dermatomyositis and polymyositis;
Auto-immune chronic active hepatitis;
Pemphigus vulgaris
Polyarteritis nodosa;
Auto-immune haemolytic anaemia;
Chronic refractory idiopathic thrombocytopenic purpura

For Imruza there is no modern clinical documentation that can be used as support for determining the frequency of undesirable effects
Infections and infestations
: Very common: viral, fungal and bacterial infections in transplant patients receiving Imruza in combination with other immunosuppressants
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
: Rare: neoplasms including lymphoproliferative disorders, skin cancers (melanomas and non-melanomas), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ, acute myloid leukaemia and myelodysplasia
Blood and lymphatic system disorders
: Very common: depression of bone marrow function; leucopenia. Common: thrombocytopenia
Immune system disorders
:Uncommon: hypersensitivity reactions
Respiratory, thoracic and mediastinal disorders
: Very rare
Gastrointestinal disorders
: Common: nausea

Monitoring
: There are potential hazards in the use of Imruza. 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 or 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. At the first signs of an abnormal fall in blood counts, treatment should be interrupted immediately as leucocytes and platelets may continue to fall after treatment is stopped. Patients receiving Imruza should be instructed to report immediately any evidence of infection, unexpected bruising or bleeding or other manifestations of bone marrow depression. Bone marrow suppression is reversible if Imruza is withdrawn early enough. There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effect of Imruza and prone to developing rapid bone marrow depression following the initiation of treatment with Imruza. This problem could be exacerbated by co-administration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulfasalazine. Also 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 Imruza) in combination with other cytotoxics. Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore close monitoring of blood counts is still necessary. The dosage of Imruza may need to be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression.
Hepatotoxicity
: Imruza is hepatotoxic and liver function tests should be routinely monitored during treatment.
Renal and/or hepatic insufficiency
: Caution is advised during the administration of Imruza in patients with renal impairment and/or hepatic impairment.
Lesch-Nyhan syndrome
: Mutagenicity: Chromosomal abnormalities have been demonstrated in both male and female patients treated with Imruza.
Effects on fertility
: Relief of chronic renal insufficiency by renal transplantation involving the administration of Imruza has been accompanied by increased fertility in both male and female transplant recipients.
Carcinogenicity
: Patients receiving immunosuppressive therapy, including Imruza are at an increased risk of developing lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ. The increased risk appears to be related to the degree and duration of immunosuppression. It has been reported that discontinuation of immunosuppression may provide partial regression of the lymphoproliferative disorder.A treatment regimen containing multiple immunosuppressants (including thiopurines) should therefore be used with caution as this could lead to lymphoproliferative disorders, some with reported fatalities. A combination of multiple immunosuppressants, given concomitantly increases the risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders. Reports of hepatosplenic T-cell lymphoma have been received when Imruza is used alone or in combination with anti-TNF agents or other immunosuppressants. Although most reported cases occurred in the IBD population, there have also been cases reported outside of this population.Patients receiving multiple immunosuppressive agents may be at risk of over-immunosuppression, therefore such therapy should be maintained at the lowest effective level.
Photosensitivity and risk of skin cancer
: 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
Varicella Zoster Virus Infection
: Infection with varicella zoster virus (VZV; chickenpox and herpes zoster) may become severe during the administration of immunosuppressants. Caution should be exercised.
Progressive Multifocal Leukoencephalopathy (PML)
: PML, an opportunistic infection caused by the JC virus, has been reported in patients receiving Imruza with other immunosuppressive agents. Immunosuppressive therapy should be withheld at the first sign or symptoms suggestive of PML and appropriate evaluation undertaken to establish a diagnosis.
Hepatitis B
: Hepatitis B carriers (defined as patients positive for hepatitis B surface antigen [HBsAg] for more than six months), or patients with documented past. HBV infection, who receive immunosuppressive drugs are at risk of reactivation of HBV replication, with asymptomatic increases in serum HBV DNA and ALT levels. Local guidelines may be considered including prophylactic therapy with oral anti-HBV agents.
Macrophage activation syndrome
: Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with autoimmune conditions, in particular with inflammatory bowel disease (IBD), and there could potentially be an increased susceptibility for developing the condition with the use of Imruza.

Azathioprine is an immunosuppressive antimetabolite, chemically 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine. It is an imidazolyl derivative of 6-mercaptopurine and many of its biological effects are similar to those of the parent compound.
Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP). It is rapidly broken down in vivo into 6-MP and amethylnitroimidazole moiety. The 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 rate of conversion varies from one person to another. Nucleotides do not traverse cell membranes and therefore do not circulate in body fluids. Irrespective of whether it is given directly or is derived in vivo from azathioprine, 6-MP is eliminated mainly as the inactive oxidised metabolite thiouric acid. This oxidation is brought about by xanthine oxidase, an enzyme that is inhibited by allopurinol. The activity of the methylnitroimidazole moiety has not been defined clearly. However, in several systems it appears to modify the activity of azathioprine as compared with that of 6-MP. Determination of plasma concentrations of azathioprine or 6-MP have no prognostic value as regards effectiveness or toxicity of these compounds.
Because of these mechanisms, the therapeutic effect of azathioprine may be evident only after several weeks or months of treatment. Azathioprine appears to be well absorbed from the upper gastro-intestinal tract. Plasma levels of azathioprine and 6-mercaptopurine do not correlate well with the therapeutic efficacy or toxicity of azathioprine.
Absorption
: Azathioprine is well absorbed following oral administration. Although there are no food effect studies with azathioprine, pharmacokinetic studies with 6-mercaptopurine have been conducted that are relevant to azathioprine. The mean relative bioavailability of 6-mercaptopurine was approximately 27% lower following administration with food and milk compared to an overnight fast. 6-mercaptopurine is not stable in milk due to the presence of xanthine oxidase (30% degradation within 30 minutes). Azathioprine may be taken with food or on an empty stomach, but patients should standardise the method of administration. The dose should not be taken with milk or dairy products.
After oral administration of [35S]-azathioprine, the maximum plasma radioactivity occurs at 1-2 hours and decays with a half-life of 4-6 hours. This is not an estimate of the half-life of azathioprine itself, but reflects the elimination from plasma of azathioprine and the [35S]-containing metabolites of the drug.
Azathioprine is principally excreted as 6-thiouric uric acid in the urine. 1-methyl-4-nitro-5-thioimidazole has also been detected in urine as a minor excretory product. A small proportion of the drug may be cleaved between the S atom and the purine ring. Only a small amount of the dose of azathioprine administered is excreted unmetabolised in the urine.
Biotransformation
: Thiopurine S-Methyl Transferase (TPMT): TPMT activity is inversely related to red blood cell 6-mercaptopurine derived thioguanine nucleotide concentration, with higher thioguanine nucleotide concentrations resulting in greater reductions in white blood cell and neutrophil counts. Individuals with TPMT deficiency develop very high cytotoxic thioguanine nucleotide concentrations.