Tacrolimus

About Tacrolimus
Tacrolimus is a potent immunosuppressive drug approved for prophylaxis of rejection in patients receiving allogenic liver or kidney transplants. Unlabeled or investigational use includes prophylaxis of rejection in small bowel, heart, lung and peripheral stem cell/bone marrow transplant.

How Tacrolimus Works
Tacrolimus binds to a T-cell binding protein and prevents synthesis of interleukin-2 and other lymphokines essential to T- and B-lymphocyte function.

PTLD in Liver Graft

Common Side Effects

• diarrhea
• insomnia
• loss of appetite
• stomach pain

• vomiting

Serious Side Effects

• nephrotoxicity
• infection
• PTLD
• hypertension
• hyperkalemia PTLD in liver graft
• neurotoxicity (i.e., headache, tremor,
  decreased motor function, mental status changes)

• glucose intolerance (diabetes)

Tacrolimus in Pregnancy
Some women have become pregnant and given birth while receiving tacrolimus after organ transplantation. Some of the newborn infants had temporary kidney problems after birth; some were born prematurely.

Tacrolimus passes into breast milk and may cause the same side effects in the infant that are observed in people taking the medication. It may be necessary to stop breast-feeding while you are taking tacrolimus.

Drug-Drug Interactions
Increased tacrolimus levels: calcium channel blockers, macrolide antibiotics, cimetidine, azole antifungals, metoclopramide.

Decreased tacrolimus levels: carbamazepine, phenobarbital, phenytoin, rifampin; Synergistic Nephrotoxicity: amphotericin B, aminoglycosides, and vancomycin.

Drug-Food Interactions
Grapefruit/grapefruit juice – Flavonoids in grapefruit juice inhibit cytochrome P4503A hepatic enzymes, which are responsible for metabolizing tacrolimus. Consumption of grapefruit/grapefruit juice may cause an INCREASE in tacrolimus blood trough concentrations.

Dosage Forms

• capsules, 0.5 mg, 1 mg and 5 mg
• injection, 5 mg ampule

Dosage and Administration

• usual dose is 2 - 4 mg twice daily by mouth
• intravenous infusion 0.5 - 1 mg twice daily

Compatibilities/Special Administration Techniques

• capsules may be opened and given on or under the patients tongue (use gloves, and be sure all of the powder gets to the patient)

• **NG TUBE MUST BE CLAMPED DURING ADMINISTRATION OF PO PROGRAF**

Patient Education
Instruct patients to take medication on the same schedule every day, on empty stomach, drink plenty of fluids, avoid dehydration, and check with transplant physician before taking any medications prescribed by other physicians.

Additional Precautions

• If possible, avoid contact with people with colds, flu or other infections.
• Keep cuts and scratches clean; use good oral and personal hygiene.
• Tacrolimus may increase your risk of certain types of cancer; you may wish to discuss this with your doctor.
• Do not eat raw oysters or other raw shellfish while taking tacrolimus; ensure that all shellfish and fish are well cooked before consuming.
• Avoid persons who have recently received oral poliovirus vaccine; do not stay in close contact with them for very long.
• Tacrolimus is not available in all countries; if you are travelling to another country, be sure to have an adequate supply for your trip.
• Grapefruit and grapefruit juice may increase the effects of tacrolimus by increasing the amount of this medicine in your body; do not consume grapefruit or grapefruit juice while you are taking this medicine.

Brand Names
Prograf, manufactured by Astellas Pharma US Inc

Cyclosporine

About Cyclosporine
Cyclosporine is a potent immunosuppressant drug approved for prophylaxis of organ rejection in kidney, heart and liver transplantation. Unlabeled or investigational use includes prophylaxis of organ rejection in lung and pancreas transplant.

How Cyclosporine Works
Cyclosporine preferentially inhibits T-lymphocytes and suppresses activation of T-lymphocytes by inhibiting production and release of lymphokines, specifically interleukin-2.

Gingival Hyperplasia

Serious Side Effects

• nephrotoxicity
• hyperkalemia
• hypertension
• tremors
• headache
• paresthesia
• hirsutism
• gingival hyperplasia

Drug-Drug Interactions
Increased cyclosporine levels: calcium channel blockers, macrolide antibiotics, cimetidine, azole antifungals, metoclopramide; Decreased cyclosporine levels: carbamazepine, phenobarbital, phenytoin, rifampin; Synergistic Nephrotoxicity: amphotericin B, aminoglycosides, vancomycin.

Drug-Food Interactions
Grapefruit/grapefruit juice – Flavonoids in grapefruit juice inhibit cytochrome P450-3A hepatic enzymes, which are responsible for metabolizing cyclosporine. Consumption of grapefruit/grapefruit juice may cause an INCREASE in cyclosporine blood trough concentrations.

Dosage Forms

• Neoral®, Sandimmune® and Gengraf® capsules, 25 mg and 100 mg
• Neoral®, Sandimmune® oral solution, 50 mL bottle (100 mg/mL)

• injection, 5 mL ampule (50 mg/mL)

Dosage and Administration

• usual starting dose is 100 - 150 mg PO BID
• capsules to be swallowed whole; oral solution measured with pipette provided, and transferred to a glass or plastic container and mixed with milk or juice (do not use foam cups – they may adsorb drug)

• intravenous dose is one-third of the oral dose and is infused for two to six hours (do not filter)

**NEORAL® AND GENGRAF® ARE NOT INTERCHANGEABLE WITH SANDIMMUNE. CHECK WRITTEN ORDERS AND CLARIFY IF NECESSARY**

**IF A PHYSICIAN WRITES AN ORDER FOR ”Cyclosporine,” THE ORDER MUST BE CLARIFIED. IF A PHYSICIAN WRITES AN ORDER FOR “Generic Cyclosporine,” GENGRAF® WILL BE DISPENSED**

Compatibilities/Special Administration Techniques
IV solution needs to be given alone! Monitor patient for anaphylactic reactions (due to the cremaphor EL used as the vehicle in the IV formulation).

Patient Education
Instruct patients to take medication on the same schedule every day; oral solution may be diluted with milk, chocolate milk, or orange juice, preferably at room temperature; keep gel capsules stored in blister packs until ready to use.

Brand Names
Neoral® Sandimmune®, manufactured by Novartis, Gengraf®

Sirolimus (Rapamune®)

Immunosuppressant Agent

Mechanism of Action: Forms a complex with FK binding proteins, inhibiting lymphocyte effects driven by certain cytokine receptors, particularly interleukin-2.

Therapeutic Uses
FDA approved: Prophylaxis of organ rejection in patients receiving renal transplants.

Non-FDA
Prophylaxis of organ rejection in all other solid organ transplants.

Adverse Drug Events
Hyperlipidemia, additive nephrotoxicity, constipation, nausea, diarrhea, vomiting, thrombocytopenia, anemia, leukopenia, arthralgias, rash and acne.

Patient Monitoring
Baseline lipid profile; sirolimus levels in patients with altered
Metabolism or hepatic impairment, in patients <13 years weighing less than 40 kg, and during administration of CYP3A4 inducers and inhibitors.

Drug-Drug Interactions
Important: Increased sirolimus levels may occur with cyclosporine (give sirolimus 4 hours after cyclosporine dose). Drugs which may increase sirolimus levels include: diltiazem, ketoconazole, rifampin, nicardipine, verapamil, clotrimazole, fluconazole, itraconazole, clarithromycin, erythromycin, cisapride, metoclopramide. Drugs which may decrease sirolimus levels include: carbamazepine, phenobarbital, and phenytoin.

Dosage Forms
Rapamune® 1 mg tablet; Rapamune® oral solution, 60 mL or 150 mL bottle (1mg/mL) supplied with oral syringe adapter for bottle and oral syringes and caps for daily dosing. This is a refrigerated solution.

Dosage and Administration
Usual dose of Rapamune® is 2 mg once daily; a loading dose of three times the maintenance dose (6 mg) is recommended. Certain patient populations may require a higher of lower dose.

Compatibilities/Special Administration Techniques
Ordered dose of Rapamune® should be emptied into a glass or plastic container with at least two ounces of water or orange juice. No other liquids should be used for dilution. Stir vigorously and administer at once; refill container with additional 4 ounces of water or orange juice, stir vigorously and administer at once.

Rapamune® is not absorbed through the skin so there are no special handling precautions. However, if direct contact with skin or mucous membranes occurs, wash thoroughly with soap and water; rinse eyes with plain water.

Patient Education
It is recommended that patients take Rapamune® 4 hours after their cyclosporine (Neoral® Sandimmune®, Gengraf®) or Prograf® dose. Rapamune® should be stored in the refrigerator but not frozen; it may be kept at room temperature for up to 30 days.

Mycophenolate Mofetil (Cellcept®); Mycophenolate Sodium EC (Myfortic®)

Immunosuppressant Agent

Mechanism of Action: Inhibits guanosine monophosphate synthesis in T- and B-lymphocytes, thereby interfering with their differentiation and proliferation, blocking antibody formation, and down-regulating generation of cytotoxic T cells.

Therapeutic Uses
FDA approved: Adjuvant therapy for prevention of kidney rejection.

Non-FDA
Adjuvant therapy for prevention of rejection in all other solid organ transplants.

Adverse Drug Events
Neutropenia, PTLD, nausea, vomiting, diarrhea, general bone marrow toxicity.

Patient Monitoring
CBC

Drug-Drug Interactions
Antacids, cholestyramine (both agents bind Cellcept®).

Dosage Forms
CellCept® 250 mg capsules, 500 mg tablets, oral suspension, 200 mg/mL, injection 500 mg/vial Myfortic® 180 mg and 360 mg enteric coated tablets

Dosage and Administration
Usual dose is 1000 mg PO BID (same dose for suspension and IV form) do not crush; precautions with drug handling.

Compatibilities/Special Administration Techniques
None.

Patient Education
May take with food to reduce incidence of nausea.

Azathioprine (Imuran®)

Immunosuppressant Agent

Mechanism of Action
Interferes with DNA and RNA synthesis, thereby inhibiting differentiation and proliferation of both T- and B-lymphocytes.

Therapeutic Uses
FDA approved: Adjuvant therapy for prevention of kidney rejection.

Non-FDA
Adjuvant therapy for prevention of rejection in all other solid organ transplants.

Adverse Drug Events
Hepatotoxicity, bone marrow toxicity (neutropenia, thrombocytopenia, etc.), nausea and vomiting, infection.

Patient Monitoring
CBC, bleeding, fever, chills, rash, liver function tests

Drug-Drug Interactions
Allopurinol; concurrent administration may result in severe pancytopenia.

Dosage Forms
Tablets, 50 mg; injection 5mg/5ml (20 ml ampule)

Dosage and Administration
Usual dose is 50 mg PO BID, or 3 - 5 mg/kg/day IV.

Use precaution with drug handling.

Prednisone (Deltasone®), Methylprednisolone (Solumedrol®)

Adrenal Corticosteroid; Anti-inflammatory Agent; Corticosteroid, systemic

Mechanism of Action
Causes emigration of circulating T cells from intravascular tissue compartment to lymphoid tissue; inhibits production of T cell lymphokines that are needed to amplify macrophage and lymphocyte response.

Therapeutic Uses
FDA approved: Immunosuppressive adjunct for the prevention and treatment of solid organ rejection.

Adverse Drug Events
Fluid retention, edema, hypernatremia, hypokalemia, hyperglycemia, headaches, insomnia, GI mucosal damage, mood swings, hypocalcemia, weight gain, thrombosis, muscle wasting, delayed wound healing, fat mobilization (moon facies, buffalo hump).

Patient Monitoring
Blood chemistry, blood sugar, blood pressure

Drug-Drug Interactions
Antacids, potassium depleting agents (loop diuretics such as furosemide, amphotericin B), rifampin, phenytoin, salicylates, vaccines, toxoids.

Dosage Forms
Tablet (5, 10, 20 & 50 mg); oral solution, 5 mg/ml; injection (Solumedrol®).

Dosage and Administration
Solu-Medrol® taper = 200 mg, 180 mg, 120 mg, 80 mg, and 40 mg IV divided doses, followed by Prednisone 20 mg PO QD with food.

Compatibilities/Special Administration Techniques
Slow IV push.

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