Drugs affecting the immune response

Immunosuppressants are used to suppress rejection in organ transplant recipients and to treat a variety of chronic inflammatory and autoimmune diseases. Solid organ transplant patients are usually maintained on a corticosteroid combined with a calcineurin inhibitor (ciclosporin or tacrolimus), or with an antiproliferative drug (azathioprine or mycophenolate mofetil), or with both. Specialist management is required and other immunomodulators may be used to initiate treatment or to treat rejection. Modification of tissue reactions caused by corticosteroids and other immunosuppressants may result in the rapid spread of infection. Corticosteroids may suppress clinical signs of infection and allow diseases such as septicaemia or tuberculosis to reach an advanced stage before being recognised. Transplant patients immunosuppressed with azathioprine should not discontinue it on becoming pregnant; there is no evidence that azathioprine is teratogenic. However, there have been reports of premature birth and low birth-weight following exposure to azathioprine, particularly in combination with corticosteroids. Spontaneous abortion has been reported following maternal or paternal exposure.

Antiproliferative immunosuppressants

AZATHIOPRINE:

Indications: Azathioprine Tablet is indicated as an adjunct for the prevention of rejection in renal homotransplantation. It is also indicated for the management of active rheumatoid arthritis to reduce signs and symptoms.

Contraindications: Bone Marrow Depression, Pregnancy, Bacterial Infection, Disease of Liver, Fungal Infections, Neoplasm, Portal Hypertension, Protozoal Infection, Renal Disease with Moderate to Severe Function Impairment, Severe Leukopenia, Thiopurine S-Methyltransferase Deficiency, Thrombocytopenic Disorder, Viral Infection.

Dose and Administration: Autoimmune conditions, 1–3 mg/kg daily, adjusted according to response (consider withdrawal if no improvement in 3 months). Suppression of transplant rejection, initially up to 5 mg/kg then 1–4 mg/kg daily according to response.

MYCOPHENOLATE MOFETIL:

Indications: prophylaxes of acute renal, cardiac, or hepatic transplant rejection (in combination with ciclosporin and corticosteroids).

Contraindications: pregnancy (exclude before starting and avoid for 6 weeks after discontinuation) and breast-feeding.

Dose and Administration: Renal transplantation, by mouth, 1 g twice daily starting within 72 hours of transplantation or by intravenous infusion, 1 g twice daily starting within 24 hours of transplantation for max. 14 days (then transfer to oral therapy); child and adolescent 2–18 years, by mouth 600 mg/m² twice daily (max. 2 g daily).

Corticosteroids and other Immunosuppressants

Prednisolone:

widely used in oncology. It has a marked antitumour effect in acute lymphoblastic leukaemia, Hodgkin’s disease, and the non-Hodgkin lymphomas. It has a role in the palliation of symptomatic end-stage malignant disease when it may enhance appetite and produce a sense of well-being. See under corticosteroides.

CICLOSPORIN (Cyclosporin):

Indications: Organ Transplant Rejection, Prevention of Cardiac Transplant Rejection, Prevention of Kidney Transplant Rejection, Prevention of Liver Transplant Rejection, Graft Versus Host Disease, Prevention of Graft Versus Host Disease, Prevention of Lung Transplant Rejection, Pure Red Cell Aplasia associated with Chronic Lymphocytic Leukemia.

Contraindications: Lactating Mother, Malignancy, Severe Uncontrolled Hypertension, BK Polyomavirus Reactivation Nephropathy, Cyclosporine Toxicity, Disease of Liver, Encephalopathy, Hyperkalemia, Hyperuricemia, Hypomagnesemia, Infection, Metabolic Acidosis, Neoplasm, Nephrotoxicity, Renal Disease, Thrombotic Thrombocytopenic Purpura.

Dose and Administration: Organ transplantation, used alone, adult and child over 3 months 10–15 mg/kg by mouth 4–12 hours before transplantation followed by 10–15 mg/kg daily for 1–2 weeks postoperatively then reduced gradually to 2–6 mg/kg daily for maintenance (dose should be adjusted according to blood-ciclosporin concentration and renal function); dose lower if given concomitantly with other immunosuppressant therapy (e.g. corticosteroids). Bone-marrow transplantation, prevention and treatment of graft-versus-host disease, adult and child over 3 months 3–5 mg/kg daily by intravenous infusion over 2–6 hours from day before transplantation to 2 weeks postoperatively (or 12.5–15 mg/kg daily by mouth) then 12.5 mg/kg daily by mouth for 3–6 months then tailed off.

TACROLIMUS:

Indications: prophylaxis of organ rejection in liver, kidney, and heart allograft recipients and allograft rejection resistant to conventional immunosuppressive regimens.

Contraindications: hypersensitivity to macrolides; pregnancy (exclude before starting—if contraception needed non-hormonal methods should be used; breast-feeding; avoid concurrent administration with ciclosporin.

Dose and Administration: Liver transplantation, starting 12 hours after transplantation, by mouth, 100–200 micrograms/kg daily in 2 divided doses; child by mouth, 300 micrograms/kg daily in 2 divided doses. Renal transplantation, starting within 24 hours of transplantation, by mouth, 200–300 micrograms/kg daily in 2 divided doses; child by mouth, 300 micrograms/kg daily in 2 divided doses.

Rituximab

RITUXIMAB:

Indications: CD20 Positive Non-Hodgkin’s Lymphoma, Chronic Lymphoid Leukemia, Diffuse Large B-Cell Lymphoma, Follicular B-Cell Lymphoma, Mantle Cell Lymphoma, Progressive Chronic Lymphocytic Leukemia, Relapse or Refractory Non-Hodgkin’s Lymphoma, Rheumatoid Arthritis. Burkitt’s Lymphoma, Relapsing and Remitting Multiple Sclerosis, Waldenstrom’s Macroglobulinemia.

Contraindications: Lactating Mother, Angina, Chemotherapy-Induced Hyperuricemia, Conduction Disorder of the Heart, Cytomegalovirus Disease, Disease due to West Nile Virus, Gastrointestinal Obstruction, Gastrointestinal Perforation, Herpes Simplex Infection, Hyperkalemia, Hyperphosphatemia, Hypocalcemia, Neutropenic Disorder, Parvovirus Infection, Progressive Multifocal Leukoencephalopathy, Renal Disease, Thrombocytopenic Disorder, Varicella Zoster Virus Infection, Viral Hepatitis C.

Dose and Administration: IV 375 mg/m ² infused on day 1 of each chemotherapy cycle for up to 8 infusions.

Other immunomodulating drugs

PEGINTERFERON ALFA

PEGINTERFERON ALFA-2a:

Indications: Treatment of hepatitis B e antibody (HBeAg) positive and HBeAg negative chronic hepatitis B virus (HBV) in patients who have compensated liver disease and evidence of viral replication and liver inflammation; alone or in combination with ribavirin tablets for the treatment of chronic hepatitis C virus (HCV) in patients with compensated liver disease and those not treated previously with interferon alfa.

Contraindications: Autoimmune hepatitis; patients with decompensated hepatic disease prior to or during treatment with interferon alfa-2a; hypersensitivity to any component of the product; because peginterferon alfa-2a contains benzyl alcohol, it is contraindicated in neonates and infants. Acute Pancreatitis, Aplastic Anemia, Autoimmune Hepatitis, Hemorrhagic Colitis, Ischemic Colitis, Pregnancy, Severe Infection.

Dose and Administration: Subcutaneous 180 mcg once weekly for 48 wk. For patients with hepatitis C, consider discontinuing therapy after 12 to 24 wk of therapy if patient has failed to demonstrate an early virologic response.

PEGINTERFERON ALFA-2b:

Indications: For use alone (in patients 18 yr of age and older) or in combination with ribavirin (in patients 3 yr of age and older) for the treatment of chronic hepatitis C in patients not previously treated with interferon alfa who have compensated liver disease.

Contraindications: Acute Pancreatitis, Autoimmune Hepatitis, Hepatic Failure, Pregnancy, And Ulcerative Colitis.

Dose and Administration: Subcutaneous For patients weighing 45 kg or less, administer 40mcg; 46 to 56kg, administer 50mcg; 57 to 72kg, administer 64mcg; 73 to 88kg, administer 80mcg; 89 to 106kg, administer 96mcg; 107 to 136kg, administer 120mcg; 137 to 160kg, administer 150mcg.

INTERFERON BETA

INTERFERON BETA-1a:

Indications: Treatment of relapsing forms of multiple sclerosis to slow accumulation of physical disability and decrease the frequency of clinical exacerbations.

Contraindications: Pregnancy, Suicidal Ideation, Bone Marrow Depression, Depression, Disease of Liver, Epilepsy, Leukopenia, Neutropenic Disorder, Psychiatric Disturbance, Severe Anemia, Thrombocytopenic Disorder.

Dose and Administration: Adults Avonex IM 30 mcg once weekly. Rebif Subcutaneous Titrate dose to 22 or 44 mcg 3 times/wk. Titration schedule for 22 mcg Wk 1 and 2, administer 4.4 mcg 3 times/wk. Wk 3 and 4, administer 11 mcg 3 times/wk. Wk 5 and on, administer 22 mcg 3 times/wk. Titration schedule for 44 mcg Wk 1 and 2, administer 8.8 mcg 3 times/wk. Wk 3 and 4, administer 22 mcg 3 times/wk. Wk 5 and on, administer 44 mcg 3 times/wk.

INTERFERON BETA-1b:

Indications: Multiple Sclerosis, Relapsing and Remitting Multiple Sclerosis.

Contraindications: Pregnancy, Depression, Disease of Liver, Psychiatric Disturbance, Suicidal Ideation.

Dose and Administration: Subcutaneous Titrate to 0.25 mg every other day over a 6-wk period according to the following schedule: wk 1 and 2, 0.0625 mg every other day; wk 3 and 4, 0.125 mg every other day; wk 5 and 6, 0.1875 mg every other day; wk 7 and on, 0.25 mg every other day.

Natalizumab

NATALIZUMAB:

Indications: Relapsing and Remitting Multiple Sclerosis, Severe Crohn’s Disease.

Contraindications: Lactating Mother, Progressive   Multifocal
Leukoencephalopathy, Disorder of Immune Function.

Dose and Administration: IV 300 mg infused over 1 h every 4 wk.