Такролимус

Категория реферата: Рефераты по медицине
Теги реферата: реферат вещество, реферат туризм
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|*use of insulin for 30 or more consecutive days, with < 5 day gap, |
|without a prior history of insulin dependent diabetes mellitus or |
|non insulin dependent diabetes mellitus. |

Development of Post Transplant Diabetes Mellitus by Race

and by Treatment Group during First Year Post Kidney Transplantation in the

Phase III Study

|Patient |Prograf | |CBIR | |
|Race | | | | |
| |No. of |Patients Who |No. of |Patients Who |
| |Patients |Developed |Patients |Developed |
| |at Risk |PTDM* |at Risk |PTDM* |
|Black |41 |15 (37%) |36 |3 (8%) |
|Hispanic |17 |5 (29%) |18 |1 (6%) |
|Caucasian |82 |10 (12%) |87 |1 (1%) |
|Other |11 |0 (0%) |10 |1 (10%) |
|Total |151 |30 (20%) |151 |6 (4%) |

|* use of insulin for 30 or more consecutive days, with < 5 day gap, |
|without a prior history of insulin dependent diabetes mellitus or |
|non insulin dependent diabetes mellitus. |

Insulin-dependent post-transplant diabetes mellitus was reported in 18% and
11% of Prograf-treated liver transplant patients and was reversible in 45% and 31% of these patients at one year post transplant, in the U.S. and
European randomized studies, respectively (See Table below). Hyperglycemia was associated with the use of Prograf in 47% and 33% of liver transplant recipients in the U.S. and European randomized studies, respectively, and may require treatment (see ADVERSE REACTIONS).

Incidence of Post Transplant Diabetes Mellitus and Insulin Use

at One Year in Liver Transplant Recipients
|Status of PTDM* |US Study| |European| |
| | | |Study | |
| |Prograf |CBIR |Prograf |CBIR |
|Patients at risk ** |239 |236 |239 |249 |
|New Onset PTDM* |42 (18%)|30 (13%)|26 (11%)|12(5%)|
|Patients still on insulin at 1 year |23 (10%)|19 (8%) |18 (8%) |6 (2%)|

* use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus.

**Patients without pretransplant history of diabetes mellitus.
Prograf can cause neurotoxicity and nephrotoxicity, particularly when used in high doses. Nephrotoxicity was reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving Prograf in the U.S. and European randomized trials, respectively (see ADVERSE REACTIONS). More overt nephrotoxicity is seen early after transplantation, characterized by increasing serum creatinine and a decrease in urine output. Patients with impaired renal function should be monitored closely as the dosage of Prograf may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to another immunosuppressive therapy. Care should be taken in using tacrolimus with other nephrotoxic drugs. In particular, to avoid excess nephrotoxicity, Prograf should not be used simultaneously with cyclosporine. Prograf or cyclosporine should be discontinued at least 24 hours prior to initiating the other. In the presence of elevated Prograf or cyclosporine concentrations, dosing with the other drug usually should be further delayed.
Mild to severe hyperkalemia was reported in 31% of kidney transplant recipients and in 45% and 13% of liver transplant recipients treated with
Prograf in the U.S. and European randomized trials, respectively, and may require treatment (see ADVERSE REACTIONS). Serum potassium levels should be monitored and potassium-sparing diuretics should not be used during Prograf therapy (see PRECAUTIONS).
Neurotoxicity, including tremor, headache, and other changes in motor function, mental status, and sensory function were reported in approximately 55% of liver transplant recipients in the two randomized studies. Tremor occurred more often in Prograf-treated kidney transplant patients (54%) compared to cyclosporine-treated patients. The incidence of other neurological events in kidney transplant patients was similar in the two treatment groups (see ADVERSE REACTIONS). Tremor and headache have been associated with high whole-blood concentrations of tacrolimus and may respond to dosage adjustment. Seizures have occurred in adult and pediatric patients receiving Prograf (see ADVERSE REACTIONS). Coma and delirium also have been associated with high plasma concentrations of tacrolimus.
As in patients receiving other immunosuppressants, patients receiving
Prograf are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. A lymphoproliferative disorder (LPD) related to Epstein-
Barr Virus (EBV) infection has been reported in immunosuppressed organ transplant recipients. The risk of LPD appears greatest in young children who are at risk for primary EBV infection while immunosuppressed or who are switched to Prograf following long-term immunosuppression therapy. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution.
A few patients receiving Prograf injection have experienced anaphylactic reactions. Although the exact cause of these reactions is not known, other drugs with castor oil derivatives in the formulation have been associated with anaphylaxis in a small percentage of patients. Because of this potential risk of anaphylaxis, Prograf injection should be reserved for patients who are unable to take Prograf capsules.
Patients receiving Prograf injection should be under continuous observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter. If signs or symptoms of anaphylaxis occur, the infusion should be stopped. An aqueous solution of epinephrine should be available at the bedside as well as a source of oxygen.
PRECAUTIONS:
General
Hypertension is a common adverse effect of Prograf therapy (see ADVERSE
REACTIONS). Mild or moderate hypertension is more frequently reported than severe hypertension. Antihypertensive therapy may be required; the control of blood pressure can be accomplished with any of the common antihypertensive agents. Since tacrolimus may cause hyperkalemia, potassium- sparing diuretics should be avoided. While calcium-channel blocking agents can be effective in treating Prograf-associated hypertension, care should be taken since interference with tacrolimus metabolism may require a dosage reduction (see Drug Interactions).
Renally and Hepatically Impaired Patients
For patients with renal insufficiency some evidence suggests that lower doses should be used (see CLINICAL PHARMACOLOGY and DOSAGE AND
ADMINISTRATION).
The use of Prograf in liver transplant recipients experiencing post- transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood levels of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients (see DOSAGE AND ADMINISTRATION).
Myocardial Hypertrophy
Myocardial hypertrophy has been reported in association with the administration of Prograf, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. Hypertrophy has been observed in infants, children and adults. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In a group of 20 patients with pre- and post-treatment echocardiograms who showed evidence of myocardial hypertrophy, mean tacrolimus whole blood concentrations during the period prior to diagnosis of myocardial hypertrophy ranged from 11 to 53 ng/mL in infants (N=10, age 0.4 to 2 years), 4 to 46 ng/mL in children (N=7, age 2 to 15 years) and 11 to 24 ng/mL in adults (N=3, age 37 to 53 years).
In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving Prograf therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of Prograf should be considered.
Information for Patients
Patients should be informed of the need for repeated appropriate laboratory tests while they are receiving Prograf. They should be given complete dosage instructions, advised of the potential risks during pregnancy, and informed of the increased risk of neoplasia. Patients should be informed that changes in dosage should not be undertaken without first consulting their physician.
Patients should be informed that Prograf can cause diabetes mellitus and should be advised of the need to see their physician if they develop frequent urination, increased thirst or hunger.
Laboratory Tests
Serum creatinine, potassium, and fasting glucose should be assessed regularly. Routine monitoring of metabolic and hematologic systems should be performed as clinically warranted.
Drug Interactions
Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering Prograf with drugs that may be associated with renal dysfunction. These include, but are not limited to, aminoglycosides, amphotericin B, and cisplatin. Initial clinical experience with the co-administration of Prograf and cyclosporine resulted in additive/synergistic nephrotoxicity. Patients switched from cyclosporine to Prograf should receive the first Prograf dose no sooner than 24 hours after the last cyclosporine dose. Dosing may be further delayed in the presence of elevated cyclosporine levels.
Drugs That May Alter Tacrolimus Concentrations
Since tacrolimus is metabolized mainly by the CYP3A enzyme systems, substances known to inhibit these enzymes may decrease the metabolism or increase bioavailability of tacrolimus as indicated by increased whole blood or plasma concentrations. Drugs known to induce these enzyme systems may result in an increased metabolism of tacrolimus or decreased bioavailability as indicated by decreased whole blood or plasma concentrations. Monitoring of blood concentrations and appropriate dosage adjustments are essential when such drugs are used concomitantly.
|*Drugs That | | | | |
|May Increase | | | | |
|Tacrolimus | | | | |
|Blood | | | | |
|Concentration| | | | |
|s: | | | | |
|Calcium | |Antifungal | |Macrolide |
|Channel | |Agents | |Antibiotics |
|Blockers | | | | |
|diltiazem | |clotrimazole | |clarithromyci|
| | | | |n |
|nicardipine | |fluconazole | |erythromycin |
|nifedipine | |itraconazole | |troleandomyci|
| | | | |n |
|verapamil | |ketoconazole | | |
| | | | | |
|Gastrointesti| |Other | | |
|nal | |Drugs | | |
|Prokinetic | | | | |
|Agents | | | | |
|cisapride | |bromocriptine| | |
|metoclopramid| |cimetidine | | |
|e | | | | |
| | |cyclosporine | | |
| | |danazol | | |
| | |ethinyl | | |
| | |estradiol | | |
| | |methylprednis| | |
| | |olone | | |
| | |omeprazole | | |
| | |protease | | |
| | |inhibitors | | |
| | |nefazodone | | |
| | | | | |
|In a study of| | | | |
|6 normal | | | | |
|volunteers, a| | | | |
|significant | | | | |
|increase in | | | | |
|tacrolimus | | | | |
|oral | | | | |
|bioavailabili| | | | |
|ty (14±5% vs.| | | | |
|30±8%) was | | | | |
|observed with| | | | |
|concomitant | | | | |
|ketoconazole | | | | |
|administratio| | | | |
|n (200 mg). | | | | |
|The apparent | | | | |
|oral | | | | |
|clearance of | | | | |
|tacrolimus | | | | |
|during | | | | |
|ketoconazole | | | | |
|administratio| | | | |
|n was | | | | |
|significantly| | | | |
|decreased | | | | |
|compared to | | | | |
|tacrolimus | | | | |
|alone | | | | |
|(0.430±0.129L| | | | |
|/hr/kg vs. | | | | |
|0.148±0.043L/| | | | |
|hr/kg). | | | | |
|Overall, IV | | | | |
|clearance of | | | | |
|tacrolimus | | | | |
|was not | | | | |
|significantly| | | | |
|changed by | | | | |
|ketoconazole | | | | |
|co-administra| | | | |
|tion, | | | | |
|although it | | | | |
|was highly | | | | |
|variable | | | | |
|between | | | | |
|patients. | | | | |
|*Drugs That | | | | |
|May Decrease | | | | |
|Tacrolimus | | | | |
|Blood | | | | |
|Concentration| | | | |
|s: | | | | |
|Anticonvulsan| |Antibiotics | |Herbal |
|ts | | | |Preparations |
|carbamazepine| |rifabutin | |St. John's |
| | | | |Wort |
|phenobarbital| |rifampin | | |
|phenytoin | | | | |

*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.
In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14±6% vs. 7±3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance (0.036±0.008L/hr/kg vs.
0.053±0.010L/hr/kg) with concomitant rifampin administration.
Interaction studies with drugs used in HIV therapy have not been conducted.
However, care should be exercised when drugs that are nephrotoxic (e.g., ganciclovir) or that are metabolized by CYP3A (e.g., ritonavir) are administered concomitantly with tacrolimus. Tacrolimus may effect the pharmacokinetics of other drugs (e.g. phenytoin) and increase their concentration. Grapefruit juice affects CYP3A-mediated metabolism and should be avoided (see DOSAGE AND ADMINISTRATION).
Other Drug Interactions
Immunosuppressants may affect vaccination. Therefore, during treatment with
Prograf, vaccination may be less effective. The use of live vaccines should be avoided; live vaccines may include, but are not limited to measles, mumps, rubella, oral polio, BCG, yellow fever, and TY 21a typhoid.1
Carcinogenesis, Mutagenesis and Impairment of Fertility
An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin's lymphomas and carcinomas of the skin. As with other immunosuppressive therapies, the risk of malignancies in Prograf recipients may be higher than in the normal, healthy population.
Lymphoproliferative disorders associated with Epstein-Barr Virus infection have been seen. It has been reported that reduction or discontinuation of immunosuppression may cause the lesions to regress.
No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.
Carcinogenicity studies were carried out in male and female rats and mice.
In the 80-week mouse study and in the 104-week rat study no relationship of tumor incidence to tacrolimus dosage was found. The highest doses used in the mouse and rat studies were 0.8 - 2.5 times (mice) and 3.5 - 7.1 times
(rats) the recommended clinical dose range of 0.1 - 0.2 mg/kg/day when corrected for body surface area.
No impairment of fertility was demonstrated in studies of male and female rats. Tacrolimus, given orally at 1.0 mg/kg (0.7 - 1.4X the recommended clinical dose range of 0.1 - 0.2 mg/kg/day based on body surface area corrections) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and with adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (2.3 - 4.6X the recommended clinical dose range based on body surface area correction), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.
Pregnancy: Category C
In reproduction studies in rats and rabbits, adverse effects on the fetus were observed mainly at dose levels that were toxic to dams. Tacrolimus at oral doses of 0.32 and 1.0 mg/kg during organogenesis in rabbits was associated with maternal toxicity as well as an increase in incidence of abortions; these doses are equivalent to 0.5 - 1X and 1.6 - 3.3X the recommended clinical dose range (0.1 - 0.2 mg/kg) based on body surface area corrections. At the higher dose only, an increased incidence of malformations and developmental variations was also seen. Tacrolimus, at oral doses of 3.2 mg/kg during organogenesis in rats, was associated with maternal toxicity and caused an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally at 1.0 and 3.2 mg/kg (equivalent to 0.7 - 1.4X and 2.3 - 4.6X the recommended clinical dose range based on body surface area corrections) to pregnant rats after organogenesis and during lactation, was associated with reduced pup weights.
No reduction in male or female fertility was evident.
There are no adequate and well-controlled studies in pregnant women.
Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. Prograf should be used during pregnancy only if the potential benefit to the mother justifies potential risk to the fetus.
Nursing Mothers
Since tacrolimus is excreted in human milk, nursing should be avoided.
Pediatric Patients
Experience with Prograf in pediatric kidney transplant patients is limited.
Successful liver transplants have been performed in pediatric patients
(ages up to 16 years) using Prograf. The two randomized active-controlled trials of Prograf in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to Prograf-based and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of Prograf to maintain blood trough concentrations of tacrolimus similar to adult patients (see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS:
Liver Transplantation
The principal adverse reactions of Prograf are tremor, headache, diarrhea, hypertension, nausea, and renal dysfunction. These occur with oral and IV administration of Prograf and may respond to a reduction in dosing.
Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting.
Hyperkalemia and hypomagnesemia have occurred in patients receiving Prograf therapy. Hyperglycemia has been noted in many patients; some may require insulin therapy (see WARNINGS).
The incidence of adverse events was determined in two randomized comparative liver transplant trials among 514 patients receiving tacrolimus and steroids and 515 patients receiving a cyclosporine-based regimen
(CBIR). The proportion of patients reporting more than one adverse event was 99.8% in the tacrolimus group and 99.6% in the CBIR group. Precautions must be taken when comparing the incidence of adverse events in the U.S. study to that in the European study. The 12-month posttransplant information from the U.S. study and from the European study is presented below. The two studies also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse events reported in > 15% in tacrolimus patients
(combined study results) are presented below for the two controlled trials in liver transplantation:
LIVER TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN > 15% OF PROGRAF-TREATED

PATIENTS
| |U.S. | |EUROPEAN| |
| |STUDY | |STUDY | |
| |(%) | |(%) | |
| |Progra|CBIR |Prograf |CBIR |
| |f |(N=250|(N=264) |(N=265) |
| |(N=250|) | | |
| |) | | | |
|Nervous System | | | | |
|Headache (see WARNINGS) |64 |60 |37 |26 |
|Tremor (see WARNINGS) |56 |46 |48 |32 |
|Insomnia |64 |68 |32 |23 |
|Paresthesia |40 |30 |17 |17 |
|Gastrointestinal | | | | |
|Diarrhea |72 |47 |37 |27 |
|Nausea |46 |37 |32 |27 |
|Constipation |24 |27 |23 |21 |
|LFT Abnormal |36 |30 |6 |5 |
|Anorexia |34 |24 |7 |5 |
|Vomiting |27 |15 |14 |11 |
|Cardiovascular | | | | |
|Hypertension (see PRECAUTIONS) |47 |56 |38 |43 |
|Urogenital | | | | |
|Kidney Function Abnormal (see WARNINGS)|40 |27 |36 |23 |
|Creatinine Increased (see WARNINGS) |39 |25 |24 |19 |
|BUN Increased (see WARNINGS) |30 |22 |12 |9 |
|Urinary Tract Infection |16 |18 |21 |19 |
|Oliguria |18 |15 |19 |12 |
|Metabolic and Nutritional | | | | |
|Hyperkalemia (see WARNINGS) |45 |26 |13 |9 |
|Hypokalemia |29 |34 |13 |16 |
|Hyperglycemia (see WARNINGS) |47 |38 |33 |22 |
|Hypomagnesemia |48 |45 |16 |9 |
|Hemic and Lymphatic | | | | |
|Anemia |47 |38 |5 |1 |
|Leukocytosis |32 |26 |8 |8 |
|Thrombocytopenia |24 |20 |14 |19 |
|Miscellaneous | | | | |
|Abdominal Pain |59 |54 |29 |22 |
|Pain |63 |57 |24 |22 |
|Fever |48 |56 |19 |22 |
|Asthenia |52 |48 |11 |7 |
|Back Pain |30 |29 |17 |17 |
|Ascites |27 |22 |7 |8 |
|Peripheral Edema |26 |26 |12 |14 |
|Respiratory System | | | | |
|Pleural Effusion |30 |32 |36 |35 |
|Atelectasis |28 |30 |5 |4 |
|Dyspnea |29 |23 |5 |4 |
|Skin and Appendages | | | | |
|Pruritus |36 |20 |15 |7 |
|Rash |24 |19 |10 |4 |

Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less

Frequently Reported Adverse Reactions below.
Kidney Transplantation
The most common adverse reactions reported were infection, tremor, hypertension, decreased renal function, constipation, diarrhea, headache, abdominal pain and insomnia.
Adverse events that occurred in > 15 % of Prograf-treated kidney transplant patients are presented below:

KIDNEY TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN > 15% OF PROGRAF-

TREATED PATIENTS
| |Prograf |CBIR |
| |(N=205) |(N=207) |
|Nervous System | | |
|Tremor (see WARNINGS) |54 |34 |
|Headache (see WARNINGS) |44 |38 |
|Insomnia |32 |30 |
|Paresthesia |23 |16 |
|Dizziness |19 |16 |
|Gastrointestinal | | |
|Diarrhea |44 |41 |
|Nausea |38 |36 |
|Constipation |35 |43 |
|Vomiting |29 |23 |
|Dyspepsia |28 |20 |
|Cardiovascular | | |
|Hypertension (see PRECAUTIONS) |50 |52 |
|Chest Pain |19 |13 |
|Urogenital | | |
|Creatinine Increased (see WARNINGS) |45 |42 |
|Urinary Tract Infection |34 |35 |
|Metabolic and Nutritional | | |
|Hypophosphatemia |49 |53 |
|Hypomagnesemia |34 |17 |
|Hyperlipemia |31 |38 |
|Hyperkalemia (see WARNINGS) |31 |32 |
|Diabetes Mellitus (see WARNINGS) |24 |9 |
|Hypokalemia |22 |25 |
|Hyperglycemia (see WARNINGS) |22 |16 |
|Edema |18 |19 |
|Hemic and Lymphatic | | |
|Anemia |30 |24 |
|Leukopenia |15 |17 |
|Miscellaneous | | |
|Infection |45 |49 |
|Peripheral Edema |36 |48 |
|Asthenia |34 |30 |
|Abdominal Pain |33 |31 |
|Pain |32 |30 |
|Fever |29 |29 |
|Back Pain |24 |20 |
|Respiratory System | | |
|Dyspnea |22 |18 |
|Cough Increased |18 |15 |
|Musculoskeletal | | |
|Arthralgia |25 |24 |
|Skin | | |
|Rash |17 |12 |
|Pruritis |15 |7 |

Less frequently observed adverse reactions in both liver transplantion and kidney transplantation patients are described under the subsection Less

Frequently Reported Adverse Reactions shown below.
Less Frequently Reported Adverse Reactions
The following adverse events were reported in the range of 3% to less than
15% incidence in either liver or kidney transplant recipients who were treated with tacrolimus in the Phase 3 comparative trials.
NERVOUS SYSTEM: (see WARNINGS) abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, depression, dizziness, emotional lability, encephalopathy, hallucinations, hypertonia, incoordination, myoclonus, nervousness, neuropathy, psychosis, somnolence, thinking abnormal; SPECIAL
SENSES: abnormal vision, amblyopia, ear pain, otitis media, tinnitus;
GASTROINTESTINAL: anorexia, cholangitis, cholestatic jaundice, dyspepsia, dysphagia, esophagitis, flatulence, gastritis, gastrointestinal hemorrhage,
GGT increase, GI perforation, hepatitis, ileus, increased appetite, jaundice, liver damage, liver function test abnormal, oral moniliasis, rectal disorder, stomatitis; CARDIOVASCULAR: angina pectoris, chest pain, deep thrombophlebitis, abnormal ECG, hemorrhage, hypotension, postural hypotension, peripheral vascular disorder, phlebitis, tachycardia, thrombosis, vasodilatation; UROGENITAL: (see WARNINGS) albuminuria, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy, oliguria, urinary frequency, urinary incontinence, vaginitis; METABOLIC/NUTRITIONAL: acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased,
AST (SGOT) increased, bicarbonate decreased, bilirubinemia, BUN increased, dehydration, GGT increased, healing abnormal, hypercalcemia, hypercholesterolemia, hyperlipemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactic dehydrogenase increase, weight gain; ENDOCRINE:
(see PRECAUTIONS) Cushing's syndrome, diabetes mellitus; HEMIC/LYMPHATIC: coagulation disorder, ecchymosis, hypochromic anemia, leukocytosis, leukopenia, polycythemia, prothrombin decreased, serum iron decreased, thrombocytopenia; MISCELLANEOUS: abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, flu syndrome, generalized edema, hernia, peritonitis, photosensitivity reaction, sepsis;
MUSCULOSKELETAL: arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis; RESPIRATORY: asthma, bronchitis, cough increased, lung disorder, pneumothorax, pulmonary edema, pharyngitis, pneumonia, respiratory disorder, rhinitis, sinusitis, voice alteration;
SKIN: acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, hirsutism, skin discoloration, skin disorder, skin ulcer, sweating.
There have been rare spontaneous reports of myocardial hypertrophy associated with clinically manifested ventricular dysfunction in patients receiving Prograf therapy (see PRECAUTIONS-Myocardial Hypertrophy).
Post Marketing
The following have been reported: increased amylase including pancreatitis, hearing loss including deafness, leukoencephalopathy, thrombocytopenic purpura, hemolytic-uremia syndrome, acute renal failure, Stevens-Johnson syndrome, stomach ulcer, glycosuria, cardiac arrhythmia and gastroenteritis.
OVERDOSAGE:
Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Occasionally, acute overdosage has been followed by adverse reactions consistent with those listed in the ADVERSE REACTIONS section except in one case where transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.
In acute oral and IV toxicity studies, mortalities were seen at or above the following doses: in adult rats, 52X the recommended human oral dose; in immature rats, 16X the recommended oral dose; and in adult rats, 16X the recommended human IV dose (all based on body surface area corrections).
DOSAGE AND ADMINISTRATION:
Prograf injection (tacrolimus injection)
For IV Infusion Only
NOTE: Anaphylactic reactions have occurred with injectables containing castor oil derivatives. See WARNINGS.
In patients unable to take oral Prograf capsules, therapy may be initiated with Prograf injection. The initial dose of Prograf should be administered no sooner than 6 hours after transplantation. The recommended starting dose of Prograf injection is 0.03-0.05 mg/kg/day as a continuous IV infusion.
Adult patients should receive doses at the lower end of the dosing range.
Concomitant adrenal corticosteroid therapy is recommended early post- transplantation. Continuous IV infusion of Prograf injection should be continued only until the patient can tolerate oral administration of
Prograf capsules.
Preparation for Administration/Stability
Prograf injection must be diluted with 0.9% Sodium Chloride Injection or 5%
Dextrose Injection to a concentration between 0.004 mg/mL and 0.02 mg/mL prior to use. Diluted infusion solution should be stored in glass or polyethylene containers and should be discarded after 24 hours. The diluted infusion solution should not be stored in a PVC container due to decreased stability and the potential for extraction of phthalates. In situations where more dilute solutions are utilized (e.g., pediatric dosing, etc.),
PVC-free tubing should likewise be used to minimize the potential for significant drug adsorption onto the tubing. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Due to the chemical instability of tacrolimus in alkaline media, Prograf injection should not be mixed or co-infused with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir).
Prograf capsules (tacrolimus capsules)

Summary of Initial Oral Dosage Recommendations and Typical Whole Blood

Trough Concentrations
|Patient Population |Recommended |Typical Whole Blood Trough |
| |Initial |Concentrations |
| |Oral Dose* | |
|Adult kidney transplant |0.2 mg/kg/day |month 1-3 : 7-20 ng/mL |
|patients | |month 4-12 : 5-15 ng/mL |
|Adult liver transplant |0.10-0.15 |month 1-12 : 5-20 ng/mL |
|patients |mg/kg/day | |
|Pediatric liver |0.15-0.20 |month 1-12 : 5-20 ng/mL |
|transplant patients |mg/kg/day | |

*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 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:
|Prograf capsules (tacrolimus capsules) 0.5 mg |
|Oblong, light yellow, branded with red "0.5 mg" on the capsule cap and "|
|607" on the capsule body, supplied in 60-count bottles (NDC |
|0469-0607-67), containing the equivalent of 0.5 mg anhydrous tacrolimus.|
| |
|Prograf capsules (tacrolimus capsules) 1 mg |
|Oblong, white, branded with red "1 mg" on the capsule cap and " 617" on |
|the capsule body, supplied in 100-count bottles (NDC 0469-0617-71) and |
|10 blister cards of 10 capsules (NDC 0469-0617-10), containing the |
|equivalent of 1 mg anhydrous tacrolimus. |
|Prograf capsules (tacrolimus capsules) 5mg |
|Oblong, grayish/red, branded with white "5 mg" on the capsule cap and " |
|657" on the capsule body, supplied in 100-count bottles (NDC |
|0469-0657-71) and 10 blister cards of 10 capsules (NDC 0469-0657-10), |
|containing the equivalent of 5 mg anhydrous tacrolimus. |
|Store and Dispense |
|Store at 25° C (77° F); excursions permitted to15° C-30° C (59° F-86° |
|F). |
|Prograf injection (tacrolimus injection) 5mg (for IV infusion only) |
|Supplied as a sterile solution in 1 mL ampules containing the equivalent|
|of 5 mg of anhydrous tacrolimus per mL, in boxes of 10 ampules (NDC |
|0469-3016-01). |
|Store and Dispense |
|Store between 5° C and 25° C (41° F and 77° F). |
|Made in Ireland |
|Prograf capsules (tacrolimus capsules) 0.5 mg |
|Oblong, light yellow, branded with red "0.5 mg" on the capsule cap and "|
|607" on the capsule body, supplied in 100-count plastic bottles (NDC |
|0469-0607-73) containing the equivalent of 0.5 mg anhydrous tacrolimus. |
|Prograf capsules (tacrolimus capsules) 1 mg |
|Oblong, white, branded with red "1 mg" on the capsule cap and " 617" on |
|the capsule body, supplied in 100-count plastic bottles (NDC |
|0469-0617-73) and 10 blister cards of 10 capsules (NDC 0469-0617-11), |
|containing the equivalent of 1 mg anhydrous tacrolimus. |
|Prograf capsules (tacrolimus capsules) 5mg |
|Oblong, grayish/red, branded with white "5 mg" on the capsule cap and " |
|657" on the capsule body, supplied in 100-count plastic bottles (NDC |
|0469-0657-73) and 10 blister cards of 10 capsules (NDC 0469-0657-11), |
|containing the equivalent of 5 mg anhydrous tacrolimus |
|Store and Dispense |
|Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). |
|Made in Japan |

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

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