Imruza50 mg

Imruza is an immunosuppressive antimetabolite with the following evidence-based uses:

Established / FDA-approved indications

• Prevention of kidney (renal) transplant rejection - used, usually in combination with corticosteroids and/or other immunosuppressants, to reduce the risk of the immune system rejecting a transplanted kidney.
• Rheumatoid arthritis (moderate to severe, active) - used in adults who have not responded adequately to conventional first-line disease-modifying antirheumatic drugs (DMARDs).

Guideline-supported / off-label uses

• Inflammatory bowel disease (Crohn's disease and ulcerative colitis) - used as a steroid-sparing maintenance agent, generally as part of combination management.
• Autoimmune hepatitis - used, typically combined with corticosteroids, to maintain remission.
• Systemic lupus erythematosus (SLE) and other autoimmune conditions such as autoimmune hemolytic anemia and myasthenia gravis - used off-label under specialist supervision when other therapies are inadequate.

Use of Imruza for any indication should be directed and monitored by a physician experienced in immunosuppressive therapy.

Each tablet contains Azathioprine as the active ingredient, commonly available in 25 mg and 50 mg strengths. Formulations may also include standard pharmaceutical excipients such as lactose, microcrystalline cellulose, povidone, and magnesium stearate. Refer to the specific product's package insert for exact excipient composition.

Imruza is a purine analog and antimetabolite immunosuppressant. Chemically, it is an imidazolyl derivative of 6-mercaptopurine (6-MP), from which it is enzymatically converted in the body. It has been used for decades in solid organ transplantation and in the management of severe autoimmune and inflammatory disorders where suppression of an overactive immune response is required.

Imruza carries a boxed warning for increased risk of malignancy (including lymphoma and skin cancers) with chronic use, and for genotoxicity; genetic testing for thiopurine methyltransferase (TPMT) and NUDT15 enzyme activity is recommended before starting therapy because patients with reduced enzyme activity are at significantly higher risk of severe, potentially life-threatening bone marrow suppression at standard doses.

Imruza belongs to the immunosuppressant therapeutic class, specifically the purine analog / antimetabolite subclass, and is also classified as a disease-modifying antirheumatic drug (DMARD) when used for rheumatoid arthritis.

Mechanism of action

Azathioprine is metabolized in the body, largely via non-enzymatic and enzymatic pathways, to 6-mercaptopurine and subsequently to active thioguanine nucleotides (TGNs). These nucleotide metabolites are incorporated into cellular DNA and RNA, inhibiting purine synthesis and interfering with DNA replication and cell division. This selectively suppresses the proliferation of rapidly dividing lymphocytes (T- and B-cells), producing an overall immunosuppressive effect that reduces the activity of the immune system responsible for graft rejection and autoimmune tissue damage.

Pharmacokinetics

Azathioprine is well absorbed after oral administration, though bioavailability is variable between individuals. It is extensively metabolized in the liver and red blood cells via three competing pathways: thiopurine methyltransferase (TPMT), xanthine oxidase, and hypoxanthine-guanine phosphoribosyltransferase (the pathway leading to active TGNs). Metabolites are excreted mainly in urine. Individuals with genetically reduced TPMT or NUDT15 activity accumulate higher levels of active metabolites and are at markedly increased risk of toxicity.

Imruza tablets are usually taken orally, once daily or in divided doses as directed by the physician. Taking it with food or immediately after a meal may help reduce nausea and stomach upset. Tablets should be swallowed whole with water; do not crush, split, or handle crushed/broken tablets unnecessarily, as Imruza is a cytotoxic agent. Pregnant or breastfeeding caregivers should avoid handling crushed or broken tablets. Take the medicine at the same time(s) each day and do not stop or adjust the dose without consulting the prescribing physician, even if feeling well, as abrupt discontinuation can affect transplant/disease control.

The following are well-established, clinically significant interactions with Imruza:

• Allopurinol (and other xanthine oxidase inhibitors, e.g., febuxostat): Xanthine oxidase inhibition markedly reduces the breakdown of Imruza, increasing active metabolite levels and the risk of severe, potentially life-threatening myelosuppression. If co-administration cannot be avoided, the dose of Imruza must be reduced to about one-quarter to one-third of the usual dose, with close blood count monitoring.
• ACE inhibitors: Concurrent use has been associated with severe leukopenia and anemia; monitor blood counts closely.
• Warfarin and other oral anticoagulants: Imruza may reduce anticoagulant effect; monitor INR/coagulation status more closely when starting, stopping, or changing the dose of Imruza.
• Ribavirin: Inhibits the enzyme pathway that inactivates Imruza metabolites, increasing the risk of severe pancytopenia; avoid combination where possible, or monitor blood counts (including weekly CBC) closely if used together.
• Other myelosuppressive drugs (e.g., co-trimoxazole, methotrexate) and other immunosuppressants: Additive bone marrow suppression and infection risk; requires closer monitoring.
• Vaccines: Immune response to vaccines may be reduced; live/live-attenuated vaccines should generally be avoided during Imruza therapy due to risk of disseminated infection.

Always inform the physician or pharmacist about all other medicines, supplements, and vaccines before starting or while taking Imruza.

Side effects of Imruza are generally dose-related and reversible with dose reduction or discontinuation, but some are serious.

Common

• Nausea, vomiting, loss of appetite, abdominal discomfort
• Leukopenia (low white blood cell count)
• Increased susceptibility to infections

Less common but significant

• Thrombocytopenia and anemia
• Hepatotoxicity (elevated liver enzymes, cholestasis)
• Pancreatitis
• Hair thinning

Serious/rare

• Severe bone marrow suppression (agranulocytosis, pancytopenia), particularly in patients with reduced TPMT/NUDT15 enzyme activity
• Increased long-term risk of malignancy, including lymphoma and non-melanoma skin cancers (see boxed warning)
• Hypersensitivity reactions (fever, rash, myalgia, hypotension, malaise) - typically require immediate discontinuation
• Serious opportunistic infections due to immunosuppression

Patients should seek urgent medical attention for fever, unusual bruising/bleeding, signs of infection, jaundice, or severe abdominal pain while taking Imruza.

Imruza crosses the placenta and has been associated with fetal harm in animal and human data; it is classified under FDA pregnancy category D. It should not be used in pregnant patients being treated for rheumatoid arthritis. For other indications (e.g., transplant recipients, severe inflammatory bowel disease) where discontinuation poses a significant risk to the mother, Imruza may be continued only if a specialist judges that the potential benefit clearly justifies the potential risk to the fetus, with close monitoring; this decision should always be made in consultation with the treating physician and should not be self-initiated or self-discontinued.

Small amounts of Imruza metabolites pass into breast milk. Breastfeeding while on Imruza should only be undertaken after specialist evaluation of the risks and benefits, with monitoring of the infant. Adequate contraceptive precautions are advised for patients (and partners) of reproductive potential while receiving Imruza.

Boxed warning

Chronic immunosuppressive therapy with Imruza increases the risk of malignancy, including lymphoma (notably post-transplant lymphoproliferative disorder and hepatosplenic T-cell lymphoma in inflammatory bowel disease patients) and skin cancers. Imruza is also genotoxic.

TPMT and NUDT15 testing

Testing for thiopurine methyltransferase (TPMT) and NUDT15 enzyme activity/genotype is recommended before starting Imruza where available. Patients with reduced or absent enzyme activity are at significantly increased risk of severe, potentially fatal myelosuppression at standard doses and require substantial dose reduction or an alternative agent.

Myelosuppression

Regular complete blood count (CBC) monitoring is required, especially during the first months of therapy and after any dose change, and periodically thereafter, due to the risk of leukopenia, thrombocytopenia, and anemia.

Hepatotoxicity

Liver function should be monitored periodically; dose reduction or discontinuation may be needed if significant hepatotoxicity develops.

Infection risk

Immunosuppression increases susceptibility to bacterial, viral, fungal, and opportunistic infections, including reactivation of latent infections (e.g., tuberculosis, hepatitis B/C); screening prior to therapy is advisable.

Alkylating agent history

Prior treatment with alkylating agents increases carcinogenic risk when combined with Imruza (see Contraindications).

Allopurinol and other interacting drugs

Concurrent allopurinol significantly increases Imruza toxicity and requires major dose reduction (see Interactions).

Imruza must only be used under regular medical and laboratory supervision. Do not stop or change the dose without consulting your physician.

Overdose of Imruza can cause profound bone marrow suppression (leukopenia, thrombocytopenia, anemia), infection, bleeding, and gastrointestinal upset (nausea, vomiting, diarrhea), with effects sometimes delayed. There is no specific antidote. In case of suspected overdose, seek immediate medical attention or contact a poison control center/emergency services; do not attempt to manage overdose at home. Management in a medical facility typically involves close monitoring of blood counts for an extended period, supportive care, and treatment of any resulting infection or bleeding as needed.

Store at room temperature, below 30°C, protected from light and moisture. Keep the container tightly closed and out of the reach and sight of children.

Renal impairment

Use lower doses with caution, as clearance of Imruza and its metabolites may be reduced; monitor closely.

Hepatic impairment

Use with caution and enhanced monitoring; dose reduction may be required.

Elderly

May be more susceptible to infections and bone marrow suppression; use the lowest effective dose with close monitoring.

Pediatric

Used off-label in pediatric transplant recipients and select severe autoimmune/inflammatory conditions under specialist supervision, generally using weight-based dosing; safety and efficacy for rheumatoid arthritis have not been established in children (see Pediatric Uses).

TPMT/NUDT15-deficient patients

Require substantial dose reduction and close monitoring, or consideration of an alternative agent, due to markedly increased risk of severe myelosuppression.

Duration of treatment with Imruza depends on the indication: in transplant recipients it is typically continued long-term (often indefinitely) as part of maintenance immunosuppression to prevent graft rejection. For rheumatoid arthritis, a therapeutic trial of at least 12 weeks is generally required to assess benefit, and if effective and tolerated, treatment is usually continued long-term at the lowest effective dose. For inflammatory bowel disease and other guideline-supported uses, duration is individualized by the treating specialist based on disease control and tolerability. Treatment should never be stopped or extended without medical advice.

Azathioprine: Immunosuppressant; Purine analog / Antimetabolite; Disease-modifying antirheumatic drug (DMARD).

Azathioprine is converted in the body to 6-mercaptopurine and then to active thioguanine nucleotides, which are incorporated into DNA and RNA, inhibiting purine synthesis and blocking replication of rapidly dividing lymphocytes. This suppresses T- and B-lymphocyte proliferation, reducing the immune-mediated processes responsible for transplant rejection and autoimmune inflammation.

D

Safety and efficacy of Imruza for rheumatoid arthritis have not been formally established in pediatric patients. Imruza is used off-label in pediatric solid organ transplant recipients (as part of standard pediatric transplant immunosuppression protocols) and in selected severe pediatric autoimmune/inflammatory conditions (e.g., inflammatory bowel disease, autoimmune hepatitis) under the supervision of a pediatric specialist, generally using weight-based dosing analogous to adult regimens with close monitoring of blood counts and growth/development. Use in children should always be directed by a pediatric specialist.