Такролимус

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| |

| |(%) | |(%) | |

| |f |(N=250|(N=264) |(N=265) |

| |(N=250|) | | |

| |) | | | |

|Headache (see WARNINGS) |64 |60 |37 |26 |

|Tremor (see WARNINGS) |56 |46 |48 |32 |

|Insomnia |64 |68 |32 |23 |

|Paresthesia |40 |30 |17 |17 |

|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 |

|Hypertension (see PRECAUTIONS) |47 |56 |38 |43 |

|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 |

|Hyperkalemia (see WARNINGS) |45 |26 |13 |9 |

|Hypokalemia |29 |34 |13 |16 |

|Hyperglycemia (see WARNINGS) |47 |38 |33 |22 |

|Hypomagnesemia |48 |45 |16 |9 |

|Anemia |47 |38 |5 |1 |

|Leukocytosis |32 |26 |8 |8 |

|Thrombocytopenia |24 |20 |14 |19 |

|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 |

|Pleural Effusion |30 |32 |36 |35 |

|Atelectasis |28 |30 |5 |4 |

|Dyspnea |29 |23 |5 |4 |

|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

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