Immunosuppressant drugs

Immunosuppression is the suppression of the body’s immune system and its ability to fight infections and other diseases. Immunosuppression may be deliberately induced with immunosuppressant drugs, as in preparation for bone marrow or other organ transplantation, to prevent rejection of the donor tissue. Immunosuppression may also result from certain diseases such as AIDS or lymphoma or from anticancer drugs.

Immunosuppressants are drugs used to suppress your immune system commonly used in the treatment of autoimmune diseases, immune-mediated diseases and in transplantation to prevent rejection of transplanted organs. Another term for immunosuppressant drugs is anti-rejection drugs. There are 2 types of immunosuppressants:

1. Induction drugs: Powerful antirejection medicine used at the time of transplant
2. Maintenance drugs: Antirejection medications used for the long term.

Induction drugs serve to eliminate alloreactive lymphocytes when the host’s immune system is first exposed to alloantigens following transplantation ¹. Several of the biologics such asrabbit anti-thymocyte globulin (rATG) and muromonab-CD3 (OKT3) were approved for use as antirejection therapy rather than as induction agents. Maintenance agents provide continuous prophylaxis against rejection. Approved and off-label use of specialty drugs exert their effects against B cells and plasma cells or directly inhibit downstream complement activation following antibody binding.

There are usually 4 classes of induction drugs:

• Rabbit anti-thymocyte globulin (rATG): Polyclonal antibodies against CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, HLA-DR, HLA I heavy chain
  • FDA approved as antirejection drug
  • Off label as induction agent
• Basiliximab: Chimeric human/murine monoclonal IgG1κ against CD25/Tac subunit
  • FDA approved as antirejection drug
• Alemtuzumab: Humanized monoclonal IgG1κ against CD52
  • Off label as induction agent
• Muromonab-CD3 (OKT3): Murine monoclonal antibody against CD3 of T-cell receptor complex
  • FDA approved as antirejection drug
  • Off label as induction agent

There are usually 4 classes of maintenance drugs:

• Calcineurin Inhibitors: Tacrolimus and Cyclosporine
• Antiproliferative agents: Mycophenolate Mofetil, Mycophenolate Sodium and Azathioprine
• mTOR inhibitor: Sirolimus
• Steroids: Prednisone
• Belatacept: Fusion protein of modified CTLA-4-human Ig, blocks B7/CD28 costimulatory proteins
• Leflunomide: Inhibits dihydroorotate dehydrogenase and pyrimidine biosynthesis

Agents with activities against B cell, plasma cell, and complement components:

• Bortezomib: Proteasome inhibitor
• Eculizumab: Monoclonal antibody against complement C5
• Rituximab: Monoclonal antibody against CD20 glycoprotein on B cells
• Intravenous immune globulins (IVIG): Suppress autoantibodies, cytokines, neutralize complements, up-regulate FcγRIIB, immunomodulation

These “immunosuppressive” drugs make the immune system less able to detect and destroy cancer cells or fight off infections that cause cancer.

Induction Agents

Antithymocyte Globulin

Antithymocyte globulin (ATG) is produced by immunizing rabbits or horses with human thymocytes generating polyclonal antithymocyte antibodies. The major mode of action for ATG is the depletion of T cells. Antithymocyte globulin (ATG) also targets a wide range of antigens displayed on B cells, dendritic cells, NK cells, and endothelial cells, and disrupts cell trafficking ². The equine ATG (eATG) product ATGAM became available in the 1980s, whereas rabbit-ATG (rATG) or thymoglobulin was introduced commercially in 1999. Rabbit-ATG (rATG) or equine ATG (eATG) are used both as induction agents, especially in high-risk renal transplant recipients, and for the treatment of moderate to severe acute rejection. Head-to-head comparison study of rabbit versus equine ATG preparations in a randomized double-blinded fashion showed that the acute rejection rate was lower with rATG compared to equine ATG (eATG) (4% vs. 25%) ³. At 10 years, the acute rejection rate was 11% for rATG arm and 42% for eATG arm ⁴. Currently, rATG is the most common induction agent in kidney graft recipients.

Anti-thymocyte globulin (rabbit) injection is used together with other medicines to prevent and treat the body from rejecting a transplanted kidney.

The effect of anti-thymocyte globulin (rabbit) on the white blood cells may also reduce the body’s ability to fight infections. Before you begin treatment, you and your doctor should talk about the benefits of this medicine as well as the risks of using it.

This medicine is to be given only by or under the direct supervision of your doctor.

Interleukin (IL)-2 Receptor Antagonists: Basiliximab and Daclizumab

Both basiliximab and daclizumab are monoclonal antibodies (mAbs) directed at the IL-2 receptor α (CD25 antigen); basiliximab is a chimeric mAb, whereas daclizumab is a humanized mAb. Both antibodies received U.S. Food and Drug Administration (FDA) approval as an induction agent for renal transplantation. A meta-analysis showed that when combined with a standard double or triple immunosuppressive regimen, these antibodies reduced the incidence of acute rejection by 34% and the incidence of steroid-resistant rejection by 49%, and that their efficacy in preventing acute rejection was similar to that of OKT3 and polyclonal antibody preparations and, importantly, with fewer side effects ⁵. A prospective randomized international trial tested the efficacy of a 5-day course of ATG versus two doses of basiliximab therapy in 278 deceased-donor renal transplants at risk for acute rejection or delayed graft function (DGF) ⁶. Participants in the ATG group (n = 141) had a lower incidence of acute rejection (15.6% vs. 25.5%) at 12 mo compared to the basiliximab group (n = 137). The incidence of DGF, death, and graft loss was similar in the two groups. A Cochrane systematic review of 71 studies (10,537 participants) compared the effects of IL-2Ra to placebo in kidney graft recipients found reduced graft loss because of death with a functioning graft by 25% at 1 yr ⁷. The incidence of biopsy-proven acute rejection at 1 yr was also reduced by 28% (RR 0.72, 95% CI, 0.64–0.81). Compared to ATG, induction with IL-2Ra resulted in similar rate of graft loss at any time point and an equivalent incidence of clinical rejection. However, ATG was superior to IL-2Ra when comparing biopsy-proven acute rejection at 1 yr, but at a cost of 75% increase in malignancy and 32% increase in cytomegalovirus (CMV) disease.

Alemtuzumab

Alemtuzumab is a recombinant humanized monoclonal antibody to human CD52 which is used in the therapy of chronic lymphocytic leukemia, and off-label for induction regimens for solid organ transplantation and for resistant or relapsing multiple sclerosis.

Alemtuzumab is a recombinant, humanized IgG1 kappa monoclonal antibody which is directed at and binds avidly to the human cell surface marker CD52 which is present on T and B cells, monocytes, macrophages and other bone marrow cells. Alemtuzumab therapy leads to depletion of lymphocytes with suppression of B cells for 6 to 12 months and T cells for 12 to 24 months. Alemtuzumab was approved in the United States in 2004 for use in chronic lymphocytic leukemia. It has also been used extensively off-label as a part of induction therapy for prevention of rejection after solid organ transplantation. It is currently under evaluation in several autoimmune diseases including resistant or relapsing multiple sclerosis. Alemtuzumab is available in single use vials of 30 mg/mL under the brand name Campath. The typical dose and regimen varies with indication. Alemtuzumab has significant adverse side effects, largely due to the profound immunosuppression. Common adverse events include epistaxis, headache, hypertension, rhinitis, dry skin, back pain, excessive bleeding and skin rash. Uncommon, but serious complications include severe infusions reactions, cytopenias (including fatal autoimmune anemia and thrombocytopenia) and opportunistic infections.

Alemtuzumab (Campath-1H), a humanized monoclonal IgG1κ directed against the CD52 glycoprotein and developed by the pathology department at Cambridge University, was approved by the FDA for B-cell chronic lymphocytic leukemia. The INTAC study group tested alemtuzumab against conventional induction agents in a randomized prospective multicenter trial of kidney graft recipients ⁸. All participants received Tac and MMF maintenance immunosuppression with rapid steroid discontinuation after 5 days of therapy. Compared to basiliximab, alemtuzumab induction in the low-risk group resulted in a lower rate of biopsy-proven acute rejection at 6 months (2% vs. 18%), 12 months (3% vs. 20%), and 36 months (10% vs. 22%). Compared to rATG, alemtuzumab induction in the high-risk group resulted in equivalent rates of biopsy-proven acute rejection at 6 months (6% vs. 9%), 12 months (10% vs. 13%), and 36 months (18% vs. 15%). Patient survival at 3 years was similar between alemtuzumab and basiliximab in the low-risk group (95% vs. 98%) or between alemtuzumab and ATG in the high-risk group (99% vs. 91%). The rates of late biopsy-proven acute rejection (between 12 and 36 mo) were higher in the alemtuzumab cohort when compared to participants in the conventional induction cohorts (8% vs. 3%). After censoring for deaths, graft survival at 3 years was also similar in the low-risk (97% vs. 94%) or the high-risk group (91% vs. 84%).

Muromonab—CD3 (OKT3)

Muromonab-CD3 is a mouse monoclonal immunoglobulin G2 antibody to CD3, often referred to as OKT3, which is used to treat acute cellular rejection after solid organ transplantation. Infusions of muromonab lead to depletion of T cells and decrease in T cell activity which is the major cause of acute cellular rejection. Muromonab was approved for use in treating acute rejection after renal transplantation in 1997 and its indications were later broadened to include rejection after heart and liver transplantation. Muromonab was the first monoclonal antibody approved for use in humans and is still used commonly to treat acute rejection. Muromonab is used off label to prevent cellular rejection, given as induction therapy before and/or early after transplantation. The name “muromonab” represents a shortened form of “murine monoclonal antibody” and was assigned before the official WHO nomenclature for monoclonal antibodies was introduced.

Muromonab-CD3 is available in liquid solution in 5 mL ampules of 5 mg under the brand name Orthoclone OKT3. The usual regimen in adults is 5 mg intravenously each day for 10 to 14 days. The pediatric dose (<30 kg) is 2.5 mg daily. Adverse events are common during muromonab therapy, but many are due to the underlying condition and other complications of organ transplantation. Muromonab is a mouse monoclonal antibody and hypersensitivity reactions and development of inactivating antibodies occur not infrequently. Furthermore, the initial engagement of CD3 receptors can result in a transient, acute release of proinflammatory cytokines (cytokine release syndrome) with symptoms of high fever, weakness, dyspnea, nausea, chest pain and diarrhea arising within the first two days of starting therapy. Less common, but potentially severe adverse reactions after muromonab therapy include bacterial and opportunistic infections, reactivation of viral infections (EBV, HSV, CMV, HBV, RSV, among others), acute thromboses, and malignancies, particularly EBV-associated lymphoproliferative disorders.

A randomized, controlled trial showed that OKT3 reversed 94% of acute rejection episodes in 63 kidney graft recipients compared to 75% in the 60 recipients treated with corticosteroids ⁹. Before its voluntary withdrawal from the U.S. market, OKT3 was used as an induction agent in renal transplantation and for the treatment of steroid-resistant acute rejection. OKT3-associated first-dose reaction as a result of cytokine release may be severe and includes fever, chills, respiratory symptoms, and headaches. A humanized preparation (HuM291) with lesser cytokine release reaction was investigated in a phase I study of kidney graft recipients ¹⁰ and in patients with new onset insulin-dependent diabetes mellitus ¹¹.

Cyclosporin

Cyclosporine also called cyclosporin A, is a calcineurin inhibitor and potent immunosuppressive agent used largely as a means of prophylaxis against cellular rejection after solid organ transplantation. Cyclosporine and cyclosporine (modified) are in a class of medications called immunosuppressants. They work by decreasing the activity of the immune system. Cyclosporine and cyclosporine (modified) are used with other medications to prevent transplant rejection (attack of the transplanted organ by the immune system of the person who received the organ) in people who have received kidney, liver, and heart transplants. Cyclosporine (modified) is also used alone or with methotrexate (Rheumatrex) to treat the symptoms of rheumatoid arthritis (arthritis caused by swelling of the lining of the joints) in patients whose symptoms were not relieved by methotrexate alone. Cyclosporine (modified) is also used to treat psoriasis (a skin disease in which red, scaly patches form on some areas of the body) in certain patients who have not been helped by other treatments.

Cyclosporine and cyclosporine (modified) are also sometimes used to treat Crohn’s disease (a condition in which the body attacks the lining of the digestive tract, causing pain, diarrhea, weight loss, and fever) and to prevent rejection in patients who have received pancreas or cornea transplants.

Cyclosporine is a cyclic polypeptide of 11 amino acids produced by a fungal species (Beaveria nivea) which has profound immunosuppressive properties, particularly affecting T cells and the cellular immune response. Cyclosporine acts as a inhibitor of calcineurin which is responsible for activating an important signal transduction pathway of T cell activation. The result of the inhibition is a decrease in maturation of T lymphocytes and reduction in lymphokine production, including IL-2.

Cyclosporine was introduced into use in the United States in the early 1980s and rapidly became part of the primary regimen of immunosuppression after allogenic, solid organ transplantation. Current indications are for prevention of organ rejection after transplantation and for therapy of active and recalcitrant rheumatoid arthritis and psoriasis.

Cyclosporine and cyclosporine (modified) both come as a capsule and a solution (liquid) to take by mouth. Cyclosporine is available as capsules of 25 and 100 mg in generic forms and under the brand name of Sandimmune, and as a more reliably absorbed microemulsion formulation of 25 and 100 mg in generic forms and under the brand name of Neoral (2003). Cyclosporine is also available in solution for oral and for intravenous use. Because of variable absorption, the usual maintenance dose of cyclosporine varies greatly and proper dosing requires monitoring for drug levels, which is also important because of its many dose dependent side effects and drug-drug interactions.

Cyclosporine is usually taken once a day. Cyclosporine (modified) is usually taken twice a day. It is important to take both types of cyclosporine on a regular schedule. Take cyclosporine or cyclosporine (modified) at the same time(s) each day, and allow the same amount of time between doses and meals every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take cyclosporine or cyclosporine (modified) exactly as directed. Do not take more or less of the medication or take it more often than prescribed by your doctor.

Your doctor will probably adjust your dose of cyclosporine or cyclosporine (modified) during your treatment. If you are taking either type of cyclosporine to prevent transplant rejection, your doctor will probably start you on a high dose of the medication and gradually decrease your dose. If you are taking cyclosporine (modified) to treat rheumatoid arthritis or psoriasis, your doctor will probably start you on a low dose of the medication and gradually increase your dose. Your doctor may also decrease your dose if you experience side effects of the medication. Tell your doctor how you are feeling during your treatment.

Cyclosporine (modified) helps control the symptoms of psoriasis and rheumatoid arthritis, but does not cure these conditions. If you are taking cyclosporine (modified) to treat psoriasis, it may take 2 weeks or longer for your symptoms to begin to improve, and 12 to 16 weeks for you to feel the full benefit of the medication. If you are taking cyclosporine (modified) to treat rheumatoid arthritis, it may take 4 to 8 weeks for your symptoms to improve. Continue to take cyclosporine (modified) even if you feel well. Do not stop taking cyclosporine (modified) without talking to your doctor. Your doctor may decrease your dose gradually.

You may notice an unusual smell when you open a blister card of cyclosporine capsules. This is normal and does not mean that the medication is damaged or unsafe to use.

Cyclosporine (modified) oral solution may gel or become lumpy if it is exposed to temperatures below 68 °F (20 °C). You can use the solution even if it has gelled, or you can turn the solution back to a liquid by allowing it to warm to room temperature (77 °F [25 °C]).

Cyclosporine and cyclosporine (modified) oral solution must be mixed with a liquid before use. Cyclosporine (modified) oral solution may be mixed with orange juice or apple juice but should not be mixed with milk. Cyclosporine oral solution may be mixed with milk, chocolate milk, or orange juice. You should choose one drink from the appropriate list and always mix your medication with that drink.
To take either type of oral solution, follow these steps:

1. Fill a glass (not plastic) cup with the drink you have chosen.
2. Remove the protective cover from the top of the dosing syringe that came with your medication.
3. Place the tip of the syringe into the bottle of solution and pull back on the plunger to fill the syringe with the amount of solution your doctor has prescribed.
4. Hold the syringe over the liquid in your glass and press down on the plunger to place the medication in the glass.
5. Stir the mixture well.
6. Drink all of the liquid in the glass right away.
7. Pour a little more of the drink you have chosen into the glass, swirl the glass around to rinse, and drink the liquid.
8. Dry the outside of the syringe with a clean towel and replace the protective cover. Do not wash the syringe with water. If you do need to wash the syringe, be sure that it is completely dry before you use it to measure another dose.

Common side effects of cyclosporine include headache, dizziness, paresthesias, neuropathy, tremor, hypertension, hyperlipidemia, nephropathy, acne, hirsutism and gum hyperplasia.

Cyclosporine special precautions

Before taking cyclosporine or cyclosporine (modified):

• tell your doctor and pharmacist if you are allergic to cyclosporine, cyclosporine (modified), any other medications, or any of the inactive ingredients in cyclosporine or cyclosporine (modified) capsules or solution. Ask your pharmacist for a list of the inactive ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking, or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: acyclovir (Zovirax); allopurinol (Zyloprim); amiodarone (Cordarone); angiotensin-converting enzyme (ACE) inhibitors such as benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik); angiotensin II receptor antagonists such as candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), olmesartan (Benicar), telmisartan (Micardis), and valsartan (Diovan); certain antifungal medications such as fluconazole (Diflucan), and itraconazole (Sporanox); azithromycin (Zithromax); bromocriptine (Parlodel); calcium channel blockers such as diltiazem (Cardizem), nicardipine (Cardene), and verapamil (Calan); carbamazepine (Tegretol); cholesterol-lowering medications (statins) such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol), and simvastatin (Zocor); clarithromycin (Biaxin); dalfopristin and quinupristin combination (Synercid); danazol; digoxin (Lanoxin); certain diuretics (‘water pills’) including amiloride (Midamor), spironolactone (Aldactone), and triamterene (Dyazide); erythromycin; HIV protease inhibitors such as indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir, in Kaletra), and saquinavir (Fortovase); imatinib (Gleevec); metoclopramide (Reglan); methylprednisolone (Medrol); nafcillin; octreotide (Sandostatin); oral contraceptives (birth control pills); orlistat (Xenical); phenobarbital; phenytoin (Dilantin); potassium supplements; prednisolone (Pediapred); repaglinide (Prandin); rifabutin (Mycobutin); rifampin (Rifadin, Rimactane); sulfinpyrazone (Anturane); terbinafine (Lamisil); and ticlopidine (Ticlid). Your doctor may need to change the doses of your medications or monitor you more carefully for side effects.
• if you are taking sirolimus (Rapamune), take it 4 hours after you take cyclosporine or cyclosporine (modified).
• tell your doctor what herbal products you are taking, especially St. John’s wort.
• tell your doctor if you have or have ever had any of the conditions mentioned in the IMPORTANT WARNING section or any of the following: low cholesterol, low levels of magnesium in your blood, any condition that makes it difficult for your body to absorb nutrients, or liver disease.
• tell your doctor if you are pregnant or plan to become pregnant. If you become pregnant while taking either type of cyclosporine, call your doctor. Both types of cyclosporine may increase the risk that your baby will be born too early.
• tell your doctor if you are breast-feeding or planning to breast-feed.
• do not have vaccinations without talking to your doctor.
• you should know that cyclosporine may cause growth of extra tissue in your gums. Be sure to brush your teeth carefully and see a dentist regularly during your treatment to decrease the risk that you will develop this side effect.

Special dietary instructions

Avoid drinking grapefruit juice or eating grapefruit while taking cyclosporine or cyclosporine (modified).

Your doctor may tell you to limit the amount of potassium in your diet. Follow these instructions carefully. Talk to your doctor about the amount of potassium-rich foods such as bananas, prunes, raisins, and orange juice you may have in your diet. Many salt substitutes contain potassium, so talk to your doctor about using them during your treatment.

What should I do if I forget a dose?

If you forget to take a dose, take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Cyclosporine side effects

Cyclosporine and cyclosporine (modified) may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• headache
• diarrhea
• heartburn
• gas
• increased hair growth on the face, arms, or back
• growth of extra tissue on the gums
• acne
• flushing
• uncontrollable shaking of a part of your body
• burning or tingling in the hands, arms, feet, or legs
• muscle or joint pain
• cramps
• pain or pressure in the face
• ear problems
• breast enlargement in men
• depression
• difficulty falling asleep or staying asleep

Some side effects can be serious. If you experience any of the following symptoms, or those listed in the IMPORTANT WARNING section, call your doctor immediately:

• unusual bleeding or bruising
• pale skin
• yellowing of the skin or eyes
• seizures
• loss of consciousness
• changes in behavior or mood
• difficulty controlling body movements
• changes in vision
• confusion
• rash
• purple blotches on the skin
• swelling of the hands, arms, feet, ankles, or lower legs

Cyclosporine and cyclosporine (modified) may cause other side effects. Talk to your doctor if you experience unusual problems while taking either cyclosporine.

Symptoms of cyclosporine overdose may include:

• yellowing of the skin or eyes
• swelling of the arms, hands, feet, ankles, or lower legs.

Tacrolimus

Tacrolimus (Astagraf XL, Envarsus XR, Prograf) also known as FK506, is a calcineurin inhibitor and potent immunosuppressive agent used largely to prevent rejection (attack of a transplanted organ by the immune system of a person receiving the organ) in people who have received a kidney transplant. Tacrolimus (Prograf) is also used along with other medications to prevent rejection in people who have received a liver or heart transplant. Tacrolimus is also sometimes used to treat fistulizing Crohn’s disease (a condition in which the body attacks the lining of the digestive tract, causing pain, diarrhea, weight loss, fever, and the formation of abnormal tunnels connecting the digestive tract to other organs or the skin).

Tacrolimus was approved for use in the United States in 1994 and rapidly became an important part of the primary regimen of immunosuppression after allogenic transplantation. Current indications are for prevention of organ rejection after transplantation. It is also used off label as therapy of active and recalcitrant forms of autoimmune diseases.

Tacrolimus is a macrolide antibiotic which also has profound immunosuppressive properties, particularly affecting T cells and the cellular immune response. Tacrolimus acts as a calcineurin inhibitor which is responsible for activating an important signal transduction molecule in the pathway of T cell activation. The result of the inhibition is a decrease in maturation of T lymphocytes and reduction in lymphokine production, including IL-2.

Tacrolimus comes as a capsule, granules for oral suspension (to be mixed with liquid), an extended-release (long acting) capsule, and an extended-release tablet to take by mouth. Tacrolimus is available as capsules of 0.5, 1 and 5 mg in several generic forms and under the brand name of Prograf. It is also available in extended release forms and as a solution for intravenous administration (5 mg/mL). Because of variability in individual pharmacokinetics of tacrolimus, the maintenance dose varies greatly and proper dosing requires monitoring for drug levels, which is also important because of its many dose dependent side effects and drug-drug interactions.

The immediate-release capsules (Prograf) and oral suspension (Prograf) are usually taken twice a day (12 hours apart). You may take the immediate-release capsules and oral suspension either with or without food, but be sure to take it the same way each time. The extended-release capsules (Astagraf XL) or extended-release tablets (Envarsus XR) are usually taken every morning on an empty stomach at least 1 hour before or breakfast or at least 2 hours after breakfast. Take tacrolimus at the same time(s) every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take tacrolimus exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

If you are taking the granules for oral suspension, you will need to mix it with room temperature water before use. Place 1 to 2 tablespoons (15 to 30 milliliters) of water into a cup containing the granules. Mix the contents and then immediately take the mixture by mouth from the cup or with an oral syringe; do not save the mixture for a later time. The granules will not completely dissolve. If any of the mixture remains, add 1 to 2 tablespoons (15 to 30 milliliters) of water to the mixture and immediately take it.

Swallow the extended-release capsules and extended-release tablets whole with water; do not split, chew, or crush them. Do not open the immediate-release capsules,

Your doctor will monitor you carefully and adjust your dose as needed. Talk to your doctor often about how you are feeling during your treatment. Ask your doctor if you have any questions about how much tacrolimus you should take.

Different tacrolimus products release the medication differently in your body and cannot be used interchangeably. Only take the tacrolimus product prescribed by your doctor and do not switch to a different tacrolimus product unless your doctor says that you should.

Tacrolimus can only prevent rejection of your transplant as long as you are taking the medication. Continue to take tacrolimus even if you feel well. Do not stop taking tacrolimus without talking to your doctor.

Common side effects of tacrolimus include headache, dizziness, paresthesias, neuropathy, hypertension, nephropathy, diabetes, acne, hirsuitism and opportunistic infections.

Tacrolimus special precautions

Before taking tacrolimus:

• tell your doctor and pharmacist if you are allergic to tacrolimus, any other medications, or any of the other ingredients in tacrolimus products. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Be sure to mention any of the following: amiodarone (Nexterone, Pacerone); amphotericin B (Abelcet, Ambisome); angiotensin-converting enzyme (ACE) inhibitors such as benazepril (Lotensin, in Lotrel), captopril, enalapril (Vasotec, in Vaseretic), fosinopril, lisinopril (in Prinzide, in Zestoretic), moexipril (Univasc, in Uniretic), perindopril (Aceon, in Prestalia), quinapril (Accupril, in Quinaretic), ramipril (Altace), or trandolapril (in Tarka); antacids containing magnesium and aluminum hydroxide (Maalox); certain antibiotics including aminoglycosides such as amikacin, gentamicin, neomycin (Neo-Fradin), streptomycin, and tobramycin (Tobi), and macrolides such as clarithromycin (Biaxin), erythromycin (EES, E-Mycin, Erythrocin), and troleandomycin (TAO; not available in the US); antifungal medications such as clotrimazole (Lotrimin, Mycelex), fluconazole (Diflucan), itraconazole (Onmel, Sporanox), ketoconazole, posaconazole (Noxafil), and voriconazole (Vfend); angiotensin receptor blockers (ARBs) such as azilsartan (Edarbi, in Edarbyclor), candesartan (Atacand, in Atacand HCT), eprosartan (Teveten), irbesartan (Avapro, in Avalide), losartan (Cozaar, in Hyzaar), olmesartan (Benicar, in Azor, in Benicar HCT, in Tribenzor), telmisartan (Micardis, in Micardis HCT, in Twynsta); boceprevir (Victrelis; no longer available in U.S.); calcium channel blockers such as diltiazem (Cardizem), nicardipine , nifedipine (Adalat, Procardia), and verapamil (Calan, Verelan, in Tarka); caspofungin (Cancidas); chloramphenicol; cimetidine (Tagamet); cisapride (Propulsid; not available in the U.S.); cisplatin ; danazol; certain diuretics (‘water pills’); ganciclovir (Valcyte); certain hormonal contraceptives (birth control pills, patches, rings, inserts, or injections); certain medications for HIV such as didanosine (Videx); indinavir (Crixivan), lamivudine (Epivir); nelfinavir (Viracept), ritonavir (Norvir), stavudine (Zerit), and zidovudine (Retrovir) lansoprazole (Prevacid); methylprednisolone (Medrol); metoclopramide (Reglan); mycophenolate (Cellcept); nefazodone; omeprazole (Prilosec); prednisone; rifabutin (Mycobutin); rifampin (Rifadin, Rimactane); certain medications for seizures such as carbamazepine (Tegretol, Teril), phenobarbital, and phenytoin (Dilantin, Phenytek);sirolimus (Rapamune), and telaprevir (Incivek; no longer available in U.S.). Your doctor may need to change the doses of your medications or monitor you more carefully for side effects. Many other medications may also interact with tacrolimus, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor if you are taking or have recently stopped taking cyclosporine (Gengraf, Neoral, Sandimmune). If you were taking cyclosporine, your doctor will probably tell you not to start taking tacrolimus until 24 hours after you took your last dose of cyclosporine. If you stop taking tacrolimus, your doctor will also tell you to wait 24 hours before starting to take cyclosporine.
• tell your doctor and pharmacist what herbal products you are taking, especially St. John’s wort or schisandra sphenanthera extracts. Do not take these herbal products while taking tacrolimus.
• tell your doctor if you have or have ever had QT syndrome (an inherited condition in which a person is more likely to have QT prolongation) low levels of potassium, calcium, or magnesium in your blood, an irregular heartbeat, high cholesterol levels, heart, kidney, or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you or your partner are able to become pregnant, use effective birth control before and during treatment with tacrolimus. If you become pregnant while taking tacrolimus, call your doctor. Tacrolimus may harm the fetus.
  if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking tacrolimus.
• you should know that taking tacrolimus may increase the risk that you will develop skin cancer. Protect yourself from skin cancer by avoiding unnecessary or prolonged exposure to sunlight or ultraviolet light (tanning beds) and wearing protective clothing, sunglasses, and sunscreen with a high skin protection factor (SPF).
• do not drink alcoholic beverages while you are taking tacrolimus extended-release capsules or extended-release tablets. Alcohol can make the side effects from tacrolimus worse.
• you should know that tacrolimus may cause high blood pressure. Your doctor will monitor your blood pressure carefully, and may prescribe medication to treat high blood pressure if it develops.
• you should know that there is a risk that you will develop diabetes during your treatment with tacrolimus. African American and Hispanic patients who have had kidney transplants have an especially high risk of developing diabetes during their treatment with tacrolimus. Tell your doctor if you or anyone in
• your family has or has ever had diabetes. If you experience any of the following symptoms, call your doctor immediately: excessive thirst; excessive hunger; frequent urination; blurred vision or confusion.
• do not have any vaccinations without talking to your doctor.

Special dietary instructions

Avoid eating grapefruit or drinking grapefruit juice while taking tacrolimus.

What should I do if I forget a dose?

If the immediate-release capsule or oral suspension dose is missed, take it as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

If the extended-release capsule dose is missed, take the dose if it is within 14 hours after missing the dose. However, if it is more than 14 hours, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

If the extended-release tablet dose is missed, take the dose it if it is within 15 hours after missing the dose. However, if it is more than 15 hours, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Tacrolimus side effects

Tacrolimus may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• headache
• diarrhea
• constipation
• nausea
• vomiting
• heartburn
• stomach pain
• loss of appetite
• difficulty falling asleep or staying asleep
• dizziness
• weakness
• back or joint pain
• burning, numbness, pain, or tingling in the hands or feet

Some side effects can be serious. If you experience any of the following symptoms, or those mentioned in the IMPORTANT WARNING section, call your doctor immediately:

• decreased urination
• pain or burning on urination
• shortness of breath, hives, rash, or itching
• pale skin, shortness of breath, or fast heartbeat
• tiredness; weight gain; swelling of the arms, hands, feet, ankles, or lower legs; or shortness of breath
• unusual bleeding or bruising
• seizures, vision changes, headache, confusion, or uncontrollable shaking of a part of the body
• coma (loss of consciousness for a period of time)

Tacrolimus may cause other side effects. Call your doctor if you have any unusual problems while you are taking tacrolimus.

Symptoms of tacrolimus overdose may include:

• hives
• sleepiness
• nausea, vomiting, and diarrhea
• uncontrollable shaking of a part of the body, headache, confusion, imbalance, and extreme tiredness
• swelling of arms or legs
• fever or other signs of infection

Prednisone

Prednisone is used alone or with other medications to treat the symptoms of low corticosteroid levels (lack of certain substances that are usually produced by the body and are needed for normal body functioning). Prednisone is also used to treat other conditions in patients with normal corticosteroid levels. These conditions include certain types of arthritis; severe allergic reactions; multiple sclerosis (a disease in which the nerves do not function properly); lupus (a disease in which the body attacks many of its own organs); and certain conditions that affect the lungs, skin, eyes, kidneys blood, thyroid, stomach, and intestines. Prednisone is also sometimes used to treat the symptoms of certain types of cancer. Prednisone is in a class of medications called corticosteroids. It works to treat patients with low levels of corticosteroids by replacing steroids that are normally produced naturally by the body. It works to treat other conditions by reducing swelling and redness and by changing the way the immune system works. Prednisone is also sometimes used with antibiotics to treat a certain type of pneumonia in patients with acquired immunodeficiency syndrome (AIDS).

Prednisone comes as a tablet, a solution (liquid), and a concentrated solution to take by mouth. Prednisone is usually taken with food one to four times a day or once every other day. Your doctor will probably tell you to take your dose(s) of prednisone at certain time(s) of day every day. Your personal dosing schedule will depend on your condition and on how you respond to treatment. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take prednisone exactly as directed. Do not take more or less of it or take it more often or for a longer period of time than prescribed by your doctor.

If you are taking the concentrated solution, use the specially marked dropper that comes with the medication to measure your dose. You may mix the concentrated solution with juice, other flavored liquids, or soft foods such as applesauce.

Your doctor may change your dose of prednisone often during your treatment to be sure that you are always taking the lowest dose that works for you. Your doctor may also need to change your dose if you experience unusual stress on your body such as surgery, illness, infection, or a severe asthma attack. Tell your doctor if your symptoms improve or get worse or if you get sick or have any changes in your health during your treatment.

If you are taking prednisone to treat a long-lasting disease, the medication may help control your condition but will not cure it. Continue to take prednisone even if you feel well. Do not stop taking prednisone without talking to your doctor. If you suddenly stop taking prednisone, your body may not have enough natural steroids to function normally. This may cause symptoms such as extreme tiredness, weakness, slowed movements, upset stomach, weight loss, changes in skin color, sores in the mouth, and craving for salt. Call your doctor if you experience these or other unusual symptoms while you are taking decreasing doses of prednisone or after you stop taking the medication.

Prednisone special precautions

Before taking prednisone:

• tell your doctor and pharmacist if you are allergic to prednisone, any other medications, or any of the inactive ingredients in prednisone tablets or solutions. Ask your doctor or pharmacist for a list of the inactive ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Be sure to mention any of the following: amiodarone (Cordarone, Pacerone); anticoagulants (‘blood thinners’) such as warfarin (Coumadin); certain antifungals such as fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral) and voriconazole (Vfend);aprepitant (Emend); aspirin; carbamazepine (Carbatrol, Epitol, Tegretol); cimetidine (Tagamet); clarithromycin (Biaxin, in Prevpak); cyclosporine (Neoral, Sandimmune); delavirdine (Rescriptor); diltiazem (Cardizem, Dilacor, Tiazac, others); dexamethasone (Decadron, Dexpak); diuretics (‘water pills’); efavirenz (Sustiva); fluoxetine (Prozac, Sarafem); fluvoxamine (Luvox); griseofulvin (Fulvicin, Grifulvin, Gris-PEG); HIV protease inhibitors including atazanavir (Reyataz), indinavir (Crixivan), lopinavir (in Kaletra), nelfinavir (Viracept), ritonavir (Norvir, in Kaletra), and saquinavir (Fortovase, Invirase); hormonal contraceptives (birth control pills, patches, rings, implants, and injections); lovastatin (Altocor, Mevacor); medications for diabetes; nefazodone; nevirapine (Viramune); phenobarbital; phenytoin (Dilantin, Phenytek); rifabutin (Mycobutin), rifampin (Rifadin, Rimactane, in Rifamate); sertraline (Zoloft); troleandomycin (TAO); verapamil (Calan, Covera, Isoptin, Verelan); and zafirlukast (Accolate).Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor what herbal products you are taking or plan to take, especially St. John’s wort.
• tell your doctor if you have an eye infection now or have ever had eye infections that come and go and if you have or have ever had threadworms (a type of worm that can live inside the body); diabetes; high blood pressure; emotional problems; mental illness; myasthenia gravis (a condition in which the muscles become weak); osteoporosis (condition in which the bones become weak and fragile and can break easily); seizures; tuberculosis (TB); ulcers; or liver, kidney, intestinal, heart, or thyroid disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking prednisone, call your doctor.
  if you are having surgery, including dental surgery, or need emergency medical treatment, tell the doctor, dentist, or medical staff that you are taking or have recently stopped taking prednisone. You should carry a card or wear a bracelet with this information in case you are unable to speak in a medical emergency.
• do not have any vaccinations (shots to prevent diseases) without talking to your doctor.
• you should know that prednisone may decrease your ability to fight infection and may prevent you from developing symptoms if you get an infection. Stay away from people who are sick and wash your hands often while you are taking this medication. Be sure to avoid people who have chicken pox or measles. Call your doctor immediately if you think you may have been around someone who had chicken pox or measles.

Special dietary instructions

Your doctor may instruct you to follow a low-salt, high potassium, or high calcium diet. Your doctor may also prescribe or recommend a calcium or potassium supplement. Follow these directions carefully.

Talk to your doctor about eating grapefruit and drinking grapefruit juice while you are taking this medication.

What should I do if I forget a dose?

When you start to take prednisone, ask your doctor what to do if you forget to take a dose. Write down these instructions so that you can refer to them later. Call your doctor or pharmacist if you miss a dose and do not know what to do. Do not take a double dose to make up for a missed dose.

Prednisone side effects

Prednisone may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• headache
• dizziness
• difficulty falling asleep or staying asleep
• inappropriate happiness
• extreme changes in mood
• changes in personality
• bulging eyes
• acne
• thin, fragile skin
• red or purple blotches or lines under the skin
• slowed healing of cuts and bruises
• increased hair growth
• changes in the way fat is spread around the body
• extreme tiredness
• weak muscles
• irregular or absent menstrual periods
• decreased sexual desire
• heartburn
• increased sweating

Some side effects can be serious. If you experience any of the following symptoms, call your doctor immediately:

• vision problems
• eye pain, redness, or tearing
• sore throat, fever, chills, cough, or other signs of infection
• seizures
• depression
• loss of contact with reality
• confusion
• muscle twitching or tightening
• shaking of the hands that you cannot control
• numbness, burning, or tingling in the face, arms, legs, feet, or hands
• upset stomach
• vomiting
• lightheadedness
• irregular heartbeat
• sudden weight gain
• shortness of breath, especially during the night
• dry, hacking cough
• swelling or pain in the stomach
• swelling of the eyes, face, lips, tongue, throat, arms, hands, feet, ankles, or lower legs
• difficulty breathing or swallowing
• rash
• hives
• itching

Prednisone may slow growth and development in children. Your child’s doctor will watch his or her growth carefully. Talk to your child’s doctor about the risks of giving prednisone to your child.

Prednisone may increase the risk that you will develop osteoporosis. Talk to your doctor about the risks of taking prednisone and about things that you can do to decrease the chance that you will develop osteoporosis.

Some patients who took prednisone or similar medications developed a type of cancer called Kaposi’s sarcoma. Talk to your doctor about the risks of taking prednisone.

Prednisone may cause other side effects. Call your doctor if you have any unusual problems while you are taking prednisone.

Azathioprine

Azathioprine is a purine analogue and prodrug of mercaptopurine that is used as an immunosuppressive agent in organ transplantation to prevent rejection (attack of the transplanted organ by the immune system) in people who received kidney transplants and in autoimmune diseases as a corticosteroid sparing agent. Azathioprine is also used to treat severe rheumatoid arthritis (a condition in which the body attacks its own joints, causing pain, swelling, and loss of function) when other medications and treatments have not helped. Azathioprine is also used to treat ulcerative colitis (a condition which causes swelling and sores in the lining of the colon [large intestine] and rectum) and Crohn’s disease.

Azathioprine was introduced into use in the early 1960s and represented a major breakthrough in the development of antirejection therapy, allowing for more widespread and successful use of kidney, heart and liver transplantation. Azathioprine was approved for use in the United States in 1968 and is still widely used in transplantation and in treatment of autoimmune conditions such as Crohn disease, rheumatoid arthritis and autoimmune hepatitis.

Azathioprine is an imidazolyl derivative and prodrug of mercaptopurine that inhibits lymphocyte function by antagonism of purine metabolism, thus inhibiting DNA, RNA and subsequent protein synthesis. Azathioprine inhibits the maturation of T cells and blocks delayed hypersensitivity reactions; it also has antiinflammatory activity.

Azathioprine is available generically and under the brand name of Imuran as tablets of 50, 75 and 100 mg; a parenteral formulation is also available. The usual dose is 1 to 3 mg per kilogram or 50 to 150 mg daily and it is typically given long term.

Azathioprine is usually taken once or twice a day after meals. Take azathioprine at around the same time(s) every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take azathioprine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

If you are taking azathioprine to treat rheumatoid arthritis, your doctor may start you on a low dose and gradually increase your dose after 6-8 weeks and then not more than once every 4 weeks. Your doctor may gradually decrease your dose when your condition is controlled. If you are taking azathioprine to prevent kidney transplant rejection, your doctor may start you on a high dose and decrease your dose gradually as your body adjusts to the transplant.

Azathioprine controls rheumatoid arthritis but does not cure it. It may take up to 12 weeks before you feel the full benefit of azathioprine. Azathioprine prevents transplant rejection only as long as you are taking the medication. Continue to take azathioprine even if you feel well. Do not stop taking azathioprine without talking to your doctor.

Common side effects include nausea, abdominal upset, rash, aphthous ulcers and dose related bone marrow suppression. Long term use of azathioprine is associated with an increased risk for malignancy, including lymphoma and possibly hepatocellular carcinoma.

Azathioprine special precautions

Before taking azathioprine:

• tell your doctor and pharmacist if you are allergic to azathioprine, any other medications, or any of the ingredients in azathioprine tablets. Ask your doctor or pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications mentioned in the IMPORTANT WARNING section and any of the following: allopurinol (Zyloprim); aminosalicylates such as mesalamine (Apriso, Asacol, Pentasa, others), olsalazine (Dipentum), and sulfasalazine (Azulfidine); and anticoagulants (‘blood thinners’) such as warfarin (Coumadin). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have any type of infection, or if you have or have ever had kidney disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. You should use birth control to be sure you or your partner will not become pregnant while you are taking this medication. Call your doctor if you or your partner become pregnant while you are taking azathioprine. Azathioprine may harm the fetus.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking azathioprine.
• do not have any vaccinations during or after your treatment without talking to your doctor.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Azathioprine side effects

Azathioprine may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• nausea
• vomiting
• diarrhea

Some side effects can be serious. If you experience any of the following symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately.

• rash
• fever
• weakness
• muscle pain

Azathioprine may cause other side effects. Call your doctor if you have any unusual problems while you are taking azathioprine.

Symptoms of azathioprine overdose may include the following:

• nausea
• vomiting
• diarrhea
• sore throat, fever, chills, and other signs of infection

Sirolimus

Sirolimus is macrocyclic lactone antibiotic with potent immunosuppressive activity that is used alone or in combination with calcineurin inhibitors to prevent cellular rejection after organ transplantation. Sirolimus also is used sometimes to treat psoriasis.

Sirolimus was approved for use in the United States in 1999 and current indications are for prevention of organ rejection after transplantation alone or in combination with calcineurin inhibitors or corticosteroids.

Sirolimus is a macrocyclic lactone antibiotic which also has profound immunosuppressive properties particularly affecting T cells and the cellular immune response. Sirolimus binds to the same intracellular receptor as tacrolimus and cyclosporine, but does not inhibit calcineurin, but rather blocks the “mammalian target of rapamycin” (mTOR) which interrupts signaling pathways for several cytokines and growth factors including IL2. The result of the inhibition is inactivation of T cells.

Sirolimus comes as a tablet and a solution (liquid) to take by mouth. Sirolimus is available as tablets of 1 and 2 mg and in an oral solution of 1 mg/mL under the brand name of Rapamune. After a loading dose, the usual maintenance dose in adults is 2 mg (~1 mg/m2) once daily. Sirolimus has less nephrotoxicity than the calcineurin inhibitors.

Sirolimus is usually taken once a day, either always with food or always without food. To help you remember to take sirolimus, take it around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take sirolimus exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the tablets whole; do not split, chew, or crush them.

Your doctor will probably adjust your dose of sirolimus during your treatment, usually not more than once every 7 to 14 days.

Continue to take sirolimus even if you feel well. Do not stop taking sirolimus without talking to your doctor.

Sirolimus solution may develop a haze when refrigerated. If this happens, let the bottle stand at room temperature and gently shake it until the haze goes away. The haze does not mean that the medication is damaged or unsafe to use.

To use the bottles of Sirolimus solution, follow these steps:

1. Open the solution bottle. On first use, insert the plastic tube with stopper tightly into the bottle until it is even with the top of the bottle. Do not remove from the bottle once inserted.
2. For each use, tightly insert one of the amber syringes, with the plunger fully pushed in, into the opening in the plastic tube.
3. Draw up the amount of solution your doctor has prescribed by gently pulling out the plunger of the syringe until the bottom of the black line of the plunger is even with the correct mark on the syringe. Keep the bottle upright. If bubbles form in the syringe, empty the syringe into the bottle and repeat this step.
4. Empty the syringe into a glass or plastic cup containing at least 2 ounces (60 milliliters [1/4 cup]) of water or orange juice. Do not use apple juice, grapefruit juice, or other liquids. Stir vigorously for 1 minute and drink immediately.
5. Refill the cup with at least 4 ounces (120 milliliters [1/2 cup]) of water or orange juice. Stir vigorously and drink the rinse solution.
6. Dispose of the used syringe.

If you need to carry a filled syringe with you, snap a cap onto the syringe and put the syringe in the carrying case. Use the medication in the syringe within 24 hours.

Common side effects of sirolimus include anxiety, weakness, depression, dizziness, headache, gastrointestinal upset, oral ulcers, edema, bone marrow suppression and rash.

Sirolimus special precautions

Before taking sirolimus:

• tell your doctor and pharmacist if you are allergic to sirolimus, any other medications, or any of the ingredients in sirolimus tablets or solution. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking. Be sure to mention any of the following: aminoglycoside antibiotics such as amikacin, gentamicin, kanamycin, neomycin (Neo-Fradin, Neo-Rx), streptomycin, and tobramycin (Tobi); amphotericin B (Abelcet, AmBisome, Amphocin, Fungizone); angiotensin-converting enzyme (ACE) inhibitors such as benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik); antifungals such as clotrimazole (Lotrimin), fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), and voriconazole (Vfend); bromocriptine (Cycloset, Parlodel); cimetidine (Tagamet); cisapride (Propulsid) (not available in the U.S.); clarithromycin (Biaxin); danazol (Danocrine); diltiazem (Cardizem, Dilacor, Tiazac); erythromycin (E.E.S., E-Mycin, Erythrocin); HIV protease inhibitors such as indinavir (Crixivan) and ritonavir (Norvir, in Kaletra); certain medications for cholesterol; medications for seizures such as carbamazepine (Tegretol), phenobarbital (Luminal), and phenytoin (Dilantin); metoclopramide (Reglan); nicardipine (Cardene); rifabutin (Mycobutin); rifampin (Rifadin, Rimactane); rifapentine (Priftin); telithromycin (Ketek); troleandomycin (TAO) (not available in the U.S.); and verapamil (Calan, Covera, Isoptin, Verelan). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• if you are taking cyclosporine (Neoral) soft gelatin capsules or solution, take them 4 hours before sirolimus.
• tell your doctor what herbal products you are taking, especially St. John’s wort.
• tell your doctor if you have or have ever had high cholesterol or triglycerides or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. You should use an effective method of birth control before starting to take sirolimus, while taking sirolimus, and for 12 weeks after stopping sirolimus. If you become pregnant while taking sirolimus, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking sirolimus.
• do not have any vaccinations without talking to your doctor.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Sirolimus side effects

Sirolimus may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• stomach pain
• headache
• constipation
• diarrhea
• nausea
• joint pain

Some side effects can be serious. The following symptoms are uncommon, but if you experience any of them or those listed in the IMPORTANT WARNING section, call your doctor immediately:

• unusual bleeding or bruising
• cough
• swollen, red, cracked, scaly skin
• hives
• rash
• itching
• difficulty breathing or swallowing
• swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
• hoarseness

Sirolimus may cause other side effects. Call your doctor if you have any unusual problems while taking sirolimus.

Mycophenolate mofetil

Mycophenolate mofetil is an antimetabolite and potent immunosuppressive agent that is used widely as adjunctive therapy in prevention of allograft rejection and in the treatment of serious autoimmune diseases. Mycophenolate (CellCept) is used with other medications to help prevent transplant organ rejection (attack of the transplanted organ by the immune system of the person receiving the organ) in people who have received kidney, heart, and liver transplants. Mycophenolate (Myfortic) is used with other medications to help prevent the body from rejecting kidney transplants. Mycophenolate is also used to treat Crohn’s disease (a condition in which the body attacks the lining of the digestive tract, causing pain, diarrhea, weight loss, and fever).

Mycophenolate mofetil was approved for use in the United States in 1995 and its current indications are for prevention of organ rejection after transplantation. It is also used off label in therapy of active and recalcitrant forms of autoimmune diseases.

Mycophenolate blocks de novo purine synthesis via noncompetitive inhibition of inosine monophosphate dehydrogenase (IMPDH). Lymphocytes lack the salvage pathway for purine synthesis and are particularly vulnerable to the inhibitory activity of mycophenolate. The result of the IMPDH inhibition is an inhibition of lymphocyte proliferation and function.

Mycophenolate comes as a capsule, a tablet, a delayed-release (releases the medication in the intestine) tablet, and a suspension (liquid) to take by mouth. Mycophenolate is available as capsules of 250 mg and tablets of 500 mg in several generic forms and under the brand name CellCept, and as an oral suspension (200 mg/mL) and a powder for injection (500 mg). It is also available as mycophenolic acid in 180 and 360 mg delayed release tablets under the brand name Myfortic. The typical maintenance dose is 1 to 1.5 grams twice daily.

Mycophenolate is usually taken twice a day on an empty stomach (1 hour before or 2 hours after eating or drinking, unless your doctor tells you otherwise). Take mycophenolate at about the same times every day, and try to space your doses about 12 hours apart. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take mycophenolate exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

The medication in the delayed-release tablet (Myfortic) is absorbed differently by the body than the medication in the tablet and capsule (CellCept). These products cannot be substituted for each other. Each time you have your prescription filled, make sure that you have received the right product. If you think you received the wrong medication, talk to your doctor and pharmacist right away.

Swallow the tablets, delayed-release tablets, and capsules whole; do not split, chew, or crush them. Do not open the capsules.

Do not mix mycophenolate suspension with any other medication.

Be careful not to spill the suspension or to splash it onto your skin. If you do get the suspension on your skin, wash the area well with soap and water. If you get the suspension in your eyes, rinse with plain water. Use wet paper towels to wipe up any spilled liquids.

Mycophenolate helps prevent organ transplant rejection only as long as you are taking the medication. Continue to take mycophenolate even if you feel well. Do not stop taking mycophenolate without talking to your doctor.

Common side effects include gastrointestinal upset, diarrhea, nausea, headache, fatigue and dizziness.

Mycophenolate special precautions

Before taking mycophenolate:

• tell your doctor and pharmacist if you are allergic to mycophenolate, mycophenolic acid, any other medications, or any of the ingredients in the mycophenolate or mycophenolic acid product you are taking. If you are taking mycophenolate liquid, tell your doctor and pharmacist if you are allergic to aspartame or sorbitol. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: activated charcoal; acyclovir (Zovirax); certain antibiotics such as amoxicillin and clavulanic acid (Augmentin), ciprofloxacin (Cipro),, and sulfamethoxazole/trimethoprim (Bactrim); azathioprine (Azasan, Imuran); cholestyramine (Prevalite); colestipol (Colestid); ganciclovir (Cytovene, Valcyte); other medications that suppress the immune system; probenecid (Probalan); rifampin (Rifadin, Rimactane); salicylate pain relievers such as aspirin, choline magnesium trisalicylate (Trisalate), choline salicylate (Arthropan), diflunisal, magnesium salicylate (Doan’s, others) and salsalate (Argesic, Disalcid, Salgesic); sevelamer (Renagel, Renvela); valacyclovir (Valtrex); and valganciclovir (Valcyte). Also
• tell your doctor if you are taking a combination of both norfloxacin (Noroxin) and metronidazole (Flagyl). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• if you are taking antacids, take them 2 hours before or 4 hours after you take mycophenolate.
• tell your doctor if you have or have ever had Lesch-Nyhan syndrome or Kelley-Seegmiller syndrome (inherited diseases that cause high levels of a certain substance in the blood, joint pain, and problems with motion and behavior); anemia (a lower than normal number of red blood cells); neutropenia (less than normal number of white blood cells); ulcers or any disease that affects your stomach, intestines, or digestive system; any type of cancer; or kidney or liver disease.
• tell your doctor if you are breast-feeding.
• do not have any vaccinations without talking to your doctor. Ask your doctor if you should get a flu vaccine before or during your treatment because taking mycophenolate may increase your risk of infection.
• if you have phenylketonuria (PKU, an inherited condition in which a special diet must be followed to prevent mental retardation), you should know that mycophenolate suspension contains aspartame, a source of phenylalanine.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Mycophenolate side effects

Mycophenolate may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• constipation
• stomach pain or swelling
• nausea
• vomiting
• difficulty falling asleep or staying asleep
• pain, especially in the back, muscles, or joints
• uncontrollable shaking of a part of the body
• headache
• gas

Some side effects can be serious. If you experience any of the following symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately:

• diarrhea
• swelling of the hands, arms, feet, ankles, or lower legs
• difficulty breathing
• chest pain
• rash
• itching
• fast heartbeat
• dizziness
• fainting
• lack of energy
• pale skin
• black and tarry stools
• red blood in stools
• bloody vomit
• vomit that looks like coffee grounds
• yellowing of the skin or eyes

Mycophenolate may cause other side effects. Call your doctor if you have any unusual problems while taking mycophenolate.

Symptoms of mycophenolate overdose may include:

• stomach pain
• nausea
• vomiting
• heartburn
• diarrhea
• fever, sore throat, chills, cough and other signs of infection

Belatacept

Belatacept injection is used in combination with other medications to prevent rejection (attack of a transplanted organ by the immune system of a person receiving the organ) of kidney transplants. Belatacept injection is in a class of medications called immunosuppressants. It works by decreasing the activity of the immune system to prevent it from attacking the transplanted kidney.

Belatacept injection comes as a solution (liquid) to be injected over 30 minutes into a vein, usually by a doctor or nurse in a hospital or medical facility. It is usually given on the day of transplant, 5 days after transplant, at the end of weeks 2 and 4, then once every 4 weeks.

Your doctor will monitor you carefully. Talk to your doctor about how you are feeling during your treatment.

Belatacept special precautions

Before receiving belatacept injection:

• tell your doctor and pharmacist if you are allergic to belatacept or any other medications, or any of the ingredients in belatacept injection. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have any medical conditions.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking belatacept injection, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are receiving belatacept injection.
• plan to avoid unnecessary or prolonged exposure to sunlight, tanning beds, and sun lamps. Belatacept may make your skin sensitive to sunlight. Wear protective clothing, sunglasses, and sunscreen with a high protection factor (SPF) when you have to be in the sun during your treatment.
• do not have any vaccinations without talking to your doctor.

What should I do if I forget a dose?

If you miss an appointment to receive belatacept injection, call your doctor as soon as possible.

Belatacept side effects

Belatacept injection may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• headache
• excessive tiredness
• pale skin
• fast heart beat
• weakness
• swelling of the hands, feet, ankles, or lower legs
• constipation

Some side effects can be serious. If you experience any of these symptoms, or those listed in the IMPORTANT WARNING section, call your doctor immediately:

• shortness of breath

Belatacept injection may cause other side effects. Call your doctor if you have any unusual problems while receiving this medication.

Symptoms of belatacept overdose may include the following:

• confusion
• difficulty remembering
• change in mood, personality, or behavior
• clumsiness
• change in walking or talking
• decreased strength or weakness on one side of body
• change in vision or speech

Leflunomide

Leflunomide is used alone or in combination with other medications to treat rheumatoid arthritis (a condition in which the body attacks its own joints, causing pain, swelling, and loss of function). Leflunomide is in a class of medications called disease-modifying antirheumatic drugs (DMARDs). It works by decreasing inflammation and slowing the progress of the condition, which can help improve the physical activity of people with rheumatoid arthritis.

Leflunomide comes as a tablet to take by mouth. It is usually taken once a day. Your doctor may tell you to take a larger dose of leflunomide for the first 3 days of treatment. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take leflunomide exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor may need to decrease your dose or stop treatment if you experience certain severe side effects. Be sure to tell your doctor how you are feeling during your treatment.

Leflunomide may help control the symptoms of your rheumatoid arthritis but does not cure it. Continue to take leflunomide even if you feel well. Do not stop taking leflunomide without talking to your doctor.

Leflunomide special precautions

Before taking leflunomide:

• tell your doctor and pharmacist if you are allergic to leflunomide, teriflunomide (Aubagio), any other medications, or any of the ingredients in leflunomide tablets. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: anticoagulants (‘blood thinners’) such as warfarin (Coumadin Jantoven); cholestyramine (Prevalite); gold compounds such as auranofin (Ridaura); medications to treat cancer; other medications that suppress the immune system such as azathioprine (Azasan, Imuran), cyclosporine (Gengraf, Neoral, Sandimmune), sirolimus (Rapamune), and tacrolimus (Astagraf, Prograf); penicillamine (Cuprimine, Depen), and tolbutamide. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had serious infections or if you frequently get infections, cancer or other conditions affecting the bone marrow or the immune system (including human immunodeficiency virus [HIV] and acquired immunodeficiency syndrome [AIDS]), diabetes, or kidney disease.
• tell your doctor if you are breastfeeding. Do not breastfeed while you are taking leflunomide.
• if you are planning to father a child, you should talk to your doctor about stopping leflunomide and receiving a treatment to help to remove this medication from your body more quickly.
• ask your doctor about the safe use of alcoholic beverages while you are taking leflunomide.
• Taking leflunomide may decrease your ability to fight infection. Tell your doctor if you have an infection now or if you have any signs of infection such as fever, cough, or flu-like symptoms. If you experience any of the following symptoms during your treatment with leflunomide, call your doctor: fever; sore throat; cough; flu-like symptoms; area of warm, red, swollen, or painful skin; painful, difficult, or frequent urination; or other signs of infection. Your treatment with leflunomide may need to be interrupted if you have an infection.
• You may already be infected with tuberculosis (TB; a serious lung infection) but not have any symptoms of the disease. In this case, leflunomide may make your infection more serious and cause you to develop symptoms. Tell your doctor if you have or have ever had TB, if you have lived in or visited a country where TB is common, or if you have been around someone who has or has ever had TB. Before you begin your treatment with leflunomide, your doctor will perform a skin test to see if you have TB. If you do have TB, your doctor will treat this infection with antibiotics before you begin taking leflunomide.
• do not have any vaccinations without talking to your doctor.
• you should know that leflunomide may cause high blood pressure. You should have your blood pressure checked before starting treatment and regularly while you are taking this medication.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for your next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Leflunomide side effects

Leflunomide may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• diarrhea
• vomiting
• heartburn
• headache
• dizziness
• weight loss
• back pain
• muscle pain or weakness
• pain, burning, numbness, or tingling in the hands or feet
• hair loss
• leg cramps
• dry skin

Some side effects can be serious. If you experience any of the following symptoms or those listed in the IMPORTANT WARNING or SPECIAL PRECAUTIONS section, call your doctor immediately or get emergency medical treatment:

• rash with or without a fever
• hives
• blisters or peeling of skin
• mouth sores
• itching
• difficulty breathing
• new or worsening cough
• chest pain
• pale skin

Receiving medications which suppress the immune system may increase the risk of developing certain types of cancer. An increase in cancers was not reported in clinical studies with leflunomide to date. Talk to your doctor about the risks of receiving leflunomide.

Leflunomide may cause other side effects. Call your doctor if you have any unusual problems while taking leflunomide.

Symptoms of leflunomide overdose may include the following:

• diarrhea
• stomach pain
• extreme tiredness
• weakness
• pale skin
• fast heartbeat
• shortness of breath

Immunosuppressant side effects

Major side effects of immunosuppressants include:

• Increased risk of serious infections, including cytomegalovirus (CMV)
• Increased cancer risk
• Kidney damage
• Increased risk of developing diabetes
• Osteoporosis
• Increased cholesterol, increasing the risk of heart disease

Less-serious immunosuppressant side effects include:

• Acne
• Weight gain
• Sleeplessness
• Hair loss
• Bruising
• Diarrhea
• Headaches
• Nausea

One of the major side effects of corticosteroids is osteoporosis. Osteoporosis is when the density of your bones is decreased, increasing the risk for fractures. Any bone in your body can be affected; however, fractures are most commonly seen at the hip, spine, or wrist. The effects of osteoporosis can be lessened through exercise, supplemental Vitamin D and calcium, and medications such as Fosomax and Boneva, which you can ask your doctor about. It is important to engage in an exercise program that includes weight bearing activities and resistance training to maintain your bone density, and hopefully make your bones stronger and lessen the risk for fractures.

Several immunosuppressant medications have been linked to a decrease in muscle function. Tacrolimus and cyclosporine derived medications have been linked to a delay in muscle contraction, decrease in coordination between the different types of muscle fibers to efficiently contract and relax, and a decrease in the adaptability of muscle fibers to change to meet the demands we place upon our muscles.

Corticosteroids also adversely affect muscle fibers, particularly the type two muscle fibers that contract rapidly to produce immediate force or power so we can respond quickly. Corticosteroids decrease muscle protein production and decrease the ability of the muscle to produce muscle energy in an effective manner. Participating in a general exercise program that includes aerobic and resistive training appears to improve muscle function and decreases the adverse effects on the muscles.

Another side effect of immunosuppressant medications is hyperglycemia (high blood sugar) and secondary diabetes because they may alter the way your body manages glucose (sugar). It is important to routinely check your blood sugar and work closely with an endocrinologist to establish an effective medication regimen to maintain stable blood sugar level that is close to normal, 80 to 120. Exercise can help lower your blood sugar and possibly decrease medications requirements. Aerobic exercise such as walking, biking and swimming for 30 minutes four-five days a week is very helpful and can lead to an improvement in your health, along with resistive training to increase your muscle mass, which will improve your body’s ability to utilize glucose.

Another way to decrease the adverse effects of hyperglycemia or diabetes is to improve your diet. Most of us need to increase the amount of lean protein (chicken, fish and lean beef), vegetables, and whole grains that we eat. It is also important to limit your consumption of sweets.

Immunosuppressant drugs for kidney transplant

When you get a kidney transplant, your body knows that the new kidney is foreign (that is, not originally part of your body). Your body will attack the new kidney and try to damage or destroy it. The immunosuppressant drugs suppress your body’s ability to do this. The goal is to adjust these drugs to prevent rejection and to minimize any side effects of the drugs.

Immunosuppressants are drugs used to suppress your immune system commonly used in the treatment of autoimmune diseases, immune-mediated diseases and in transplantation to prevent rejection of transplanted organs. Another term for immunosuppressant drugs is anti-rejection drugs. There are 2 types of immunosuppressants:

1. Induction drugs: Powerful antirejection medicine used at the time of transplant
2. Maintenance drugs: Antirejection medications used for the long term.

There are usually 4 classes of maintenance drugs:

• Calcineurin Inhibitors: Tacrolimus and Cyclosporine
• Antiproliferative agents: Mycophenolate Mofetil, Mycophenolate Sodium and Azathioprine
• mTOR inhibitor: Sirolimus
• Steroids: Prednisone

Almost everyone who has a kidney transplant must take these drugs every day as directed. If your new kidney came from an identical twin, however, you may not have to take them. Even missing a single dose may make it more likely for you to have a rejection. The only time you should skip a dose is if your doctor or other health care team member tells you to do so. If you are not sure, call your doctor. Also, when you have a clinic visit, you should not take your immunosuppressant medicines until your blood is drawn for lab work.

Because of the large number of pills you may need to take each day, forgetting a dose is easy to do. You can do three things to help you remember your medicine:

1. Know the name of each drug you take and what it does. If you have a good understanding of your drugs, you will be less likely to forget one.
2. Use a pill box or organizer. This allows you to set up an entire week of pills. Once the week is set up, all you have to do is take the pills in each on the right day and time.
3. Try to take your medicine at the same time every day.

What should I do if I miss a dose?

Take it as soon as you remember and call your doctor. If it is time for the next dose, do not take a double dose.

Are there any signs or symptoms I should watch for?

Yes. Even though you are taking your medicines every day, you may still develop rejection of the kidney transplant. You need to know your body very well. If you have any of the following, you should call your transplant center right away:

• a drop in your urine output
• a fever above 100 degrees
• tenderness of your new kidney
• bloody urine
• flu-like feelings
• weight gain (more than 3 pounds in two days)

The transplant center will probably ask you to have some blood tests and maybe other tests. The long-term success of your kidney transplant depends largely on careful follow-up and a good working relationship between you and your transplant team.

Are there any side effects from taking these drugs?

Yes. One of the side effects of these drugs is an increased chance of infections. This is more of a problem in the early period after a transplant or following treatment of a rejection because the dosage of these drugs is higher at these times. You should call the transplant center if you have:

• a fever above 100 degrees F (37.8 °C)
• drainage from your surgical scar
• burning when you pass your urine
• a cold or cough that will not go away

The most common side effects of the immunosuppressant drugs are “stomach upset”. If this happens, ask your doctor if you can space your medicine at different times to help with this problem.

About 6 months to a year after transplant, the immunosuppression is usually lowered and the chance of side effects should be low. If you still have side effects, speak to your transplant team to either change the dose or switch to a different medicine. Changes to immunosuppressant medicine should only be made after checking with your transplant center.

Are there other medicines and food that can act against immunosuppressants?

Yes. There are many other medicines, food, and supplements that can change the levels (up or down) of immunosuppressants in the blood. Some of the common ones are grapefruit juice, St. John’s Wort, erythromycin, anti-TB (tuberculosis) medicines, anti-seizure medicines and common blood pressure medicines (cardizem or diltiazem, and Verapamil).

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