Реферат: Такролимус

*Note: two divided doses, q12h

Liver Transplantation

It is recommended that patients initiate oral therapy with Prograf capsules if possible. If IV therapy is necessary, conversion from IV to oral Prograf is recommended as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. The initial dose of Prograf should be administered no sooner than 6 hours after transplantation. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion. The recommended starting oral dose of Prograf capsules is 0.10-0.15 mg/kg/day administered in two divided daily doses every 12 hours. Co-administered grapefruit juice has been reported to increase tacrolimus blood trough concentrations in liver transplant patients. (See Drugs That May Alter Tacrolimus Concentrations.)

Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Prograf dosages may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post transplant.

Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring: Liver Transplantation below.

Kidney Transplantation

The recommended starting oral dose of Prograf is 0.2 mg/kg/day administered every 12 hours in two divided doses. The initial dose of Prograf may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered (as indicated for example by a serum creatinine<4 mg/dL). Black patients may require higher doses to achieve comparable blood concentrations. Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring: Kidney Transplantation below.

The data in kidney transplant patients indicate that the Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients.

Pediatric Patients

Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations. Therefore, it is recommended that therapy be initiated in pediatric patients at a starting IV dose of 0.03-0.05 mg/kg/day and a starting oral dose of 0.15-0.20 mg/kg/day. Dose adjustments may be required. Experience in pediatric kidney transplantation patients is limited.

Patients with Hepatic or Renal Dysfunction

Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Pugh > 10) may require lower doses of Prograf. Close monitoring of blood concentrations is warranted.

Due to the potential for nephrotoxicity, patients with renal or hepatic impairment should receive doses at the lowest value of the recommended IV and oral dosing ranges. Further reductions in dose below these ranges may be required. Prograf therapy usually should be delayed up to 48 hours or longer in patients with post-operative oliguria.

Conversion from One Immunosuppressive Regimen to Another

Prograf should not be used simultaneously with cyclosporine. Prograf or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated Prograf or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

Blood Concentration Monitoring

Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments and compliance. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the posttransplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies.

Two methods have been used for the assay of tacrolimus, a microparticle enzyme immunoassay (MEIA) and an ELISA. Both methods have the same monoclonal antibody for tacrolimus. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anti-coagulant. Heparin anti-coagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; if samples are to be kept longer they should be deep frozen at -20° C for up to 12 months.

Liver Transplantation

Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from Phase II and III studies of liver transplant patients have shown an increasing incidence of adverse events with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between 5 to 20 ng/mL. Long term posttransplant patients often are maintained at the low end of this target range.

Data from the U.S. clinical trial show that tacrolimus whole blood concentrations, as measured by ELISA, were most variable during the first week post-transplantation. After this early period, the median trough blood concentrations, measured at intervals from the second week to one year post-transplantation, ranged from 9.8 ng/mL to 19.4 ng/mL.

Therapeutic Drug Monitoring, 1995, Volume 17, Number 6 contains a consensus document and several position papers regarding the therapeutic monitoring of tacrolimus from the 1995 International Consensus Conference on Immunosuppressive Drugs. Refer to these manuscripts for further discussions of tacrolimus monitoring.

Kidney Transplantation

Data from the Phase III study indicates that trough concentrations of tacrolimus in whole blood, as measured by IMx®, were most variable during the first week of dosing. During the first three months, 80% of the patients maintained trough concentrations between 7-20 ng/mL, and then between 5-15 ng/mL, through one-year.

The relative risk of toxicity is increased with higher trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity.

HOW SUPPLIED:

Manufactured for:
Fujisawa Healthcare, Inc.
Deerfield, IL 60015-2548

Rx only

ZL40305/06

REFERENCE

1. CDC: Recommendations of the Advisory Committee on Immunization Practices: Use of vaccines and immune globulins in persons with altered immunocompetence. MMWR 1993;42(RR-4):1-18.

http://www.fujisawa.com/medinfo/pi/pi_main_pg.htm

GENERIC NAME: tacrolimus

BRAND NAME: Prograf

DRUG CLASS AND MECHANISM: Tacrolimus is a drug that suppresses the immune system and is used to prevent rejection of transplanted organs. Tacrolimus accomplishes its immune-suppressing effecting by inhibiting an enzyme (calcineurin) crucial for the multiplication of T-cells, cells that are vital to the immune process. The use of oral tacrolimus allows transplantation specialists to reduce the dose of steroids which are also used to prevent rejection. This "steroid-sparing effect" is important because of the many side effects that can occur when larger doses of steroids are used for a long period of time. Tacrolimus was approved by the FDA in April, 1994 for liver transplantation and also has been used in patients for heart, kidney, small bowel, and bone marrow transplantation.

GENERIC AVAILABLE: No

PRESCRIPTION: Yes

PREPARATIONS: Tacrolimus is available as 1mg and 5mg capsules. It also is available for intravenous use.

STORAGE: Tacrolimus should be stored at room temperature between 15° and 30°C (59° and 86°F).

PRESCRIBED FOR: Tacrolimus is used for the prevention of rejection of transplanted organs.

DOSING: Oral tacrolimus is taken twice daily. Doses vary widely and are based on blood tests that measure the amount of tacrolimus in the body. Taking tacrolimus with food can reduce some of the abdominal pain that can occur with this medicine; however, food can reduce the amount of tacrolimus that is absorbed. This is especially true with fatty foods. Thus, tacrolimus is best taken without food. If it must be taken with food, it should be taken with non-fatty food.

DRUG INTERACTIONS: The destruction of tacrolimus by the body may be inhibited by a large number of drugs, resulting in higher blood levels of tacrolimus, and possibly increasing its side effects. Such drugs include bromocriptine (Parlodel), cimetidine (Tagamet), cisapride (Propulsid), clarithromycin (Biaxin), cyclosporine (Sandimmune; Neoral), danazol (Danacrine), diltiazem (Cardizem; Tiazac), erythromycin, fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), metoclopramide (Reglan), methylprednisolone (Medrol), nicardipine (Cardene), troleandomycin (Tao), and verapamil (Calan; Isoptin; Verelan; Covera-HS). Grapefruit juice also may have a similar effect on tacrolimus and should be avoided.

Other drugs can stimulate the break-down of tacrolimus, decreasing its blood concentration and possibly reducing its effectiveness. Such drugs include carbamazepine (Tegretol), nifedipine (Procardia; Adalat); phenobarbital, phenytoin (Dilantin), rifabutin, and rifampin,

tacrolimus

Live virus vaccines should be avoided while receiving tacrolimus or any other medicine that suppresses the immune system since the vaccines may be less effective.

Since tacrolimus can cause hyperkalemia (high potassium in the blood), the use of tacrolimus with diuretics that also cause retention of potassium is not recommended. Such diuretics include triamterene (found in Dyazide and Maxzide), amiloride (found in Moduretic), and spironolactone (Aldactone).

Aluminum hydroxide, which is found in many antacids, binds tacrolimus in the stomach. Aluminum-containing antacids should not be taken with tacrolimus.

PREGNANCY: Tacrolimus crosses the placenta, but there have been no adequate studies in pregnant women to assess the effects on the fetus. Among women who have received tacrolimus while pregnant, high potassium levels and kidney injury in newborns have been reported. Therefore, tacrolimus should be used during pregnancy only when it is clearly needed.

NURSING MOTHERS: Tacrolimus passes into breast milk. It is recommended that breast-feeding be discontinued while women are receiving oral tacrolimus.

SIDE EFFECTS: Tacrolimus is associated with many and various side effects. These include baldness (which can occur in 1 in 5 patients who take it), anemia (1 in 2), loss of appetite (1 in 3), diarrhea (3 of 4), high concentrations of potassium in the blood (1 in 2), high blood presure (1 in 2), nausea (1 in 2), vomiting (1 in 4), tingling sensation in the extremities (2 in 5), itching (1 in 3), tremor (1 in 2), fever (1 in 2), headache (2 in 3), rash (1 in 4), high blood sugar concentrations (between 1 in 3 and 1 in 2), and abdominal pain (1in 4).

Other side effects may include confusion, painful joints, increased sensitivity to light, blurred vision, insomnia, infection, jaundice (yellowing of the skin due to effects on the liver), kidney injury, swollen ankles, and seizures.

PROGRAF (tacrolimus) Capsules and Injection

July 25, 2001: Fujisawa

Revisions to the PRECAUTIONS and ADVERSE REACTIONS sections. A new Patient’s Information leaflet is added to the PROGRAF Capsules labeling

PRECAUTIONS

*Drugs That May Decrease Tacrolimus Blood Concentrations:

Anticonvulsants Antibiotics

carbamazepine rifabutin

phenobarbital rifampin

phenytoin

Herbal Preparations

St. John’s Wort

*This table is not all inclusive.

St. John’s Wort (hypericum perforatum) induces CYP3A4 and P-glycoprotein. Since tacrolimus is a substrate for CYP3A4, there is the potential that the use of St. John’s Wort in patients receiving Prograf could result in reduced tacrolimus levels.

ADVERSE REACTIONS

Post Marketing

The following have been reported: increased amylase including pancreatitis, hearing loss including deafness, leukoencephalopathy, thrombocytopenic purpura, hemolytic-uremic syndrome, acute renal failure, Stevens-Johnson syndrome, stomach ulcer, glycosuria, and cardiac arrhythmia and gastroenteritis.

Patient Information

PROGRAF

(tacrolimus capsules)

Read this important information before you start using PROGRAF [PRO-graf] and each time you refill your prescription. This summary does not take the place of talking with your transplant team.

Talk with your transplant team if you have any questions or want more information about PROGRAF. You can also visit the Fujisawa Internet site at www.fujisawa.com.

What Is PROGRAF?

PROGRAF is a medicine that slows down the body’s immune system. For this reason, it works as an anti-rejection medicine.

PROGRAF helps patients who have had a liver or kidney transplant protect their new organ and prevent it from being rejected by the body.

How Does PROGRAF Protect My New Organ?

The body’s immune system protects the body against anything that it does not recognize as part of the body. For example, when the immune system detects a virus or bacteria it tries to get rid of it to prevent infection. When a person has a liver or kidney transplant, the immune system does not recognize the new organ as a part of the body and tries to get rid of it, too. This is called "rejection." PROGRAF protects your new organ by slowing down the body’s immune system.

Who Should Not Take PROGRAF?

Do not take PROGRAF if you are allergic to any of the ingredients in PROGRAF. The active ingredient is tacrolimus. Ask your doctor or pharmacist about the inactive ingredients.

Tell your transplant team about all your health conditions, including kidney and/or liver problems. Discuss with your transplant team the use of any other prescription and non- prescription medications, including any herbal or over-the-counter remedies that you may take while on Prograf. In very rare cases you may not be able to take Prograf.

Tell your transplant team if you are pregnant, planning to have a baby or are breastfeeding. Talk with your transplant doctor about possible effects PROGRAF could have on your child. Do not nurse a baby while taking PROGRAF since the medicine will be in the breast milk.

How Should I Take PROGRAF?

PROGRAF can protect your new kidney or liver only if you take the medicine correctly.

Your new organ needs around-the-clock protection so your body does not reject it. The success of your transplant depends a great deal upon how well you help PROGRAF do its job. Here is what you can do to help.

Take PROGRAF exactly as prescribed

It is important to take PROGRAF capsules exactly as your transplant team tells you to.

PROGRAF comes in several different strength capsules--0.5 mg, 1 mg and 5 mg. Your transplant team will tell you what dose to take and how often to take it. Your transplant team may adjust your dose until they find what works best for you.

Never change your dose on your own. Never stop taking PROGRAF even if you are feeling well. However, if you feel poorly on Prograf, discuss this with your transplant team.

Take PROGRAF two times a day, 12 hours apart

Try to pick times that will be easy for you. For example, if you take your first dose at 7:00 a.m. you should take your second dose at 7:00 p.m. Do not vary the times. You must take PROGRAF at the same times every day. If you decide to take PROGRAF at 7:00 a.m. and 7:00 p.m., take it at these same times every day. This will make sure you always have enough medicine in your body to give your new organ the around-the-clock protection it needs.

Take PROGRAF the same way each day

Some people prefer to take PROGRAF with food to help reduce possible stomach upset. Whether you take PROGRAF with or without food, it is important to take PROGRAF the same way every day. For example, if you take PROGRAF with food, you should always take it with food. Do not eat grapefruit or drink grapefruit juice in combination with your medicine unless your transplant teams approves. Do not change the way you take this medicine without telling

your transplant team, since this could change the amount of protection you get from PROGRAF.

Take all your doses

It is important to take your doses twice a day exactly as prescribed by your doctor. If you miss even two doses, your new liver or kidney could lose the protection it needs to defend itself against rejection by your body.

If you miss one dose, do not try to catch up on your own. Call your transplant team right away for instructions on what to do.

If you travel and change time zones, be sure to ask your transplant team how to adjust your dosage schedule so your new organ does not lose its protection.

Plan ahead so that you do not run out of PROGRAF

Make sure you have your prescription for PROGRAF refilled and at home before you need it. Circle the date on a calendar when you need to order your refill. Allow extra time if you receive your medicines through the mail.

Your transplant team will follow your progress and watch for early signs of side effects. This is why you will have blood tests done often after your transplant. On the days you are going to have a blood test to measure the amount of PROGRAF in your body, your transplant team may ask you not to take your morning dose until after the blood sample is taken. Check with your transplant team before skipping this dose.

Can Other Medicines Affect How PROGRAF Works?

Some medicines and alcohol can affect how well PROGRAF works. After you start taking PROGRAF:

·     Be sure to tell your transplant team, family doctor, dentist, pharmacist and any other health care professional treating you the names of all the medicines you are taking. This includes PROGRAF as well as all other prescription medicines and non- prescription medicines, natural or herbal remedies, nutritional supplements, and vitamins. This is the only way that your health care team can help prevent drug interactions that could be serious.

·     Always check with your transplant team before you start taking any new medicine.

·     While you are taking PROGRAF, do not get any vaccinations without your transplant team’s approval. The vaccination may not work as well as it should.

·     Liver transplant patients, including those taking PROGRAF, should not drink alcohol.

What Are the Possible Side Effects of PROGRAF?

Tell your transplant team right away if you think you might be having a side effect. Your transplant team will decide if it is a medicine side effect or a sign that has nothing to do with the medicine but needs to be treated. Infection or reduced urine can be signs of serious problems that you should discuss with your transplant team.

Your transplant team will also follow your progress and watch for the early signs of any side effects. This is why you will have blood tests done often during the first few months after your transplant. On the days you are going to have a blood test to measure the amount of PROGRAF in your body, your transplant team may ask you not to take your morning dose until after the blood sample is taken. Check skipping this dose.

For Kidney Transplant Patients:

The most common side effects of PROGRAF for kidney transplant patients are infection, headache, tremors (shaking of the body), diarrhea, constipation, nausea, high blood pressure, changes in the amount of urine, and trouble sleeping.

Less common side effects are abdominal pain (stomach pain), numbness or tingling in your hands or feet; loss of appetite; indigestion or "upset stomach"; vomiting; urinary tract infections; fever; pain; swelling of the hands, ankles or legs; shortness of breath or trouble breathing; cough; leg cramps; heart "fluttering", palpitations or chest pain; unusual weakness or tiredness; dizziness; confusion; changes in mood or emotions; itchy skin, skin rash, and diabetes.

For Liver Transplant Patients:

The most common side effects of PROGRAF for liver transplant patients are headache, tremors (shaking of the body), diarrhea, high blood pressure, nausea and changes in the amount of urine.

Less common side effects are numbness or tingling in your hands or feet; trouble sleeping; constipation; loss of appetite; vomiting; urinary tract infections; fever; pain (especially in the back or abdomen [stomach area]); swelling of the hands, ankles, legs or abdomen; shortness of breath or trouble breathing; cough; unusual bruising; leg cramps; heart "fluttering" or palpitations; unusual weakness or tiredness; confusion; changes in mood or emotions; itchy skin, and skin rash.