Реферат: Такролимус
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 Concentrations: | ||||||||
| Calcium Channel Blockers | Antifungal Agents | Macrolide Antibiotics | ||||||
| diltiazem | clotrimazole | clarithromycin | ||||||
| nicardipine | fluconazole | erythromycin | ||||||
| nifedipine | itraconazole | troleandomycin | ||||||
| verapamil | ketoconazole | |||||||
| Gastrointestinal Prokinetic Agents | Other Drugs | |||||||
| cisapride | bromocriptine | |||||||
| metoclopramide | cimetidine | |||||||
| cyclosporine | ||||||||
| danazol | ||||||||
| ethinyl estradiol | ||||||||
| methylprednisolone | ||||||||
| omeprazole | ||||||||
| protease inhibitors | ||||||||
| nefazodone | ||||||||
| In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration 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-administration, although it was highly variable between patients. | ||||||||
| *Drugs That May Decrease Tacrolimus Blood Concentrations: | ||||||||
| Anticonvulsants | Antibiotics | Herbal 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. STUDY (%) | EUROPEAN STUDY (%) | |||||
| Prograf (N=250) | CBIR (N=250) | Prograf (N=264) | CBIR (N=265) | |||
| 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.