referat Tacrolimus (677976), страница 2

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Special Populations

Pediatric

Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5±3.8 hours, 2.6±2.1 L/kg and 0.138±0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC and C_max were 337±167 ng•hr/mL and 43.4±27.9 ng/mL, respectively. The absolute bioavailability was 31± 21%.

Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations. (See DOSAGE AND ADMINISTRATION).

Renal and Hepatic Insufficiency

The mean pharmacokinetic parameters for tacrolimus following single administrations to patients with renal and hepatic impairment are given in the following table.

Population (No. of Patients)	Dose	AUC 0-t (ng·hr/mL)	t½ (hr)	V (L/kg)	Cl (L/hr/kg)
Renal Impairment (n=12)	0.02 mg/kg/4hr IV	393±123 (t = 60hr)	26.3±9.2	1.07 ±0.20	0.038 ±0.014
Mild Hepatic Impairment (n=6)	0.02 mg/kg/4hr IV	367±107 (t=72hr)	60.6±43.8 Range: 27.8 - 141	3.1 ±1.6	0.042 ±0.02
	7.7 mg PO	488±320 (t = 72hr)	66.1±44.8 Range: 29.5 - 138	3.7 ±4.7*	0.034 ±0.019*
Severe Hepatic Impairment (n=6, IV)	0.02 mg/kg/4hr IV (n=2)	762±204 (t=120hr)	198±158 Range: 81-436	3.9 ±1.0	0.017 ±0.013
	0.01 mg/kg/8hr IV (n=4)	289±117 (t=144hr)
Severe Hepatic Impairment (n=5, PO)†	8 mg PO (n=1)	658 (t=120hr)	119±35 Range: 85-178	3.1 ±3.4*	0.016 ±0.011*
	5mg PO (n=4)	533±156 (t=144hr)
	4 mg PO (n=1)

* corrected for bioavailability † 1 patient did not receive the PO dose

Renal Insufficiency:

Tacrolimus pharmacokinetics following a single IV administration were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9±1.6 and 12.0±2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups.

The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (see previous table).

Hepatic Insufficiency:

Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with sever hepatic dysfunction (mean Pugh score: >10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration.

Race

A formal study to evaluate the pharmacokinetic disposition of tacrolimus in Black transplant patients has not been conducted. However, a retrospective comparison of Black and Caucasian kidney transplant patients indicated that Black patients required higher tacrolimus doses to attain similar trough concentrations. (See DOSAGE AND ADMINISTRATION).

Gender

A formal study to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney and liver transplant patients indicated no gender-based differences.

Clinical Studies

Liver Transplantation

The safety and efficacy of Prograf-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter studies. The active control groups were treated with a cyclosporine-based immunosuppressive regimen. Both studies used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These studies were designed to evaluate whether the two regimens were therapeutically equivalent, with patient and graft survival at 12 months following transplantation as the primary endpoints. The Prograf-based immunosuppressive regimen was found to be equivalent to the cyclosporine-based immunosuppressive regimens.

In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the Prograf-based immunosuppressive regimen and 266 to a cyclosporine-based immunosuppressive regimen (CBIR). In 10 of the 12 sites, the same CBIR protocol was used, while 2 sites used different control protocols. This trial excluded patients with renal dysfunction, fulminant hepatic failure with Stage IV encephalopathy, and cancers; pediatric patients (< 12 years old) were allowed.

In the second trial, 545 patients were enrolled at 8 clinical sites in Europe; prior to surgery, 270 were randomized to the Prograf-based immunosuppressive regimen and 275 to CBIR. In this study, each center used its local standard CBIR protocol in the active-control arm. This trial excluded pediatric patients, but did allow enrollment of subjects with renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy, and cancers other than primary hepatic with metastases.

One-year patient survival and graft survival in the Prograf-based treatment groups were equivalent to those in the CBIR treatment groups in both studies. The overall one-year patient survival (CBIR and Prograf-based treatment groups combined) was 88% in the U.S. study and 78% in the European study. The overall one-year graft survival (CBIR and Prograf-based treatment groups combined) was 81% in the U.S. study and 73% in the European study. In both studies, the median time to convert from IV to oral Prograf dosing was 2 days.

Because of the nature of the study design, comparisons of differences in secondary endpoints, such as incidence of acute rejection, refractory rejection or use of OKT3 for steroid-resistant rejection, could not be reliably made.

Kidney Transplantation

Prograf-based immunosuppression following kidney transplantation was assessed in a Phase III randomized, multicenter, non-blinded, prospective study. There were 412 kidney transplant patients enrolled at 19 clinical sites in the United States. Study therapy was initiated when renal function was stable as indicated by a serum creatinine < 4 mg/dL (median of 4 days after transplantation, range 1 to 14 days). Patients less than 6 years of age were excluded.

There were 205 patients randomized to Prograf-based immunosuppression and 207 patients were randomized to cyclosporine-based immunosuppression. All patients received prophylactic induction therapy consisting of an antilymphocyte antibody preparation, corticosteroids and azathioprine. Overall one year patient and graft survival was 96.1% and 89.6%, respectively and was equivalent between treatment arms.

Because of the nature of the study design, comparisons of differences in secondary endpoints, such as incidence of acute rejection, refractory rejection or use of OKT3 for steroid-resistant rejection, could not be reliably made.

INDICATIONS AND USAGE:

Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver or kidney transplants. It is recommended that Prograf be used concomitantly with adrenal corticosteroids. Because of the risk of anaphylaxis, Prograf injection should be reserved for patients unable to take Prograf capsules orally.

CONTRAINDICATIONS:

Prograf is contraindicated in patients with a hypersensitivity to tacrolimus. Prograf injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil).

WARNINGS:

(See boxed WARNING.)

Insulin-dependent post-transplant diabetes mellitus (PTDM) was reported in 20% of Prograf-treated kidney transplant patients without pretransplant history of diabetes millitus in the Phase III study below (See Tables Below). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at two years post transplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM.

Incidence of Post Transplant Diabetes Mellitus
and Insulin Use at 2 years in Kidney Transplant Recipients in the Phase III Study

Status of PTDM*	Prograf	CBIR
Patients without pretransplant history of diabetes mellitus.	151	151
New onset PTDM*, 1st Year	30/151 (20%)	6/151 (4%)
Still insulin dependent at one year in those without prior history of diabetes.	25/151(17%)	5/151 (3%)
New onset PTDM* post 1 year	1	0
Patients with PTDM* at 2 years	16/151 (11%)	5/151 (3%)

*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 Race	Prograf		CBIR
	No. of Patients at Risk	Patients Who Developed PTDM*	No. of Patients at Risk	Patients Who Developed 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.

*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.

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