Рефераты. Такролимус

|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 |

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