|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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