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 tacrolimus 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 to 2.5 times (mice) and 3.5 to 7.1 times (rats) the recommended clinical dose range of 0.1 to 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 to 1.4X the recommended clinical dose range of 0.1 to 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 to 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.
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 to 1X and 1.6 to 3.3X the recommended clinical dose range (0.1 to 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 to 1.4X and 2.3 to 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. Tacrolimus should be used during pregnancy only if the potential benefit to the mother justifies potential risk to the fetus.
Since tacrolimus is excreted in human milk, nursing should be avoided.
Experience with tacrolimus in pediatric kidney transplant patients is limited. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using tacrolimus. Two randomized active-controlled trials of tacrolimus in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to tacrolimus-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 tacrolimus to maintain blood trough concentrations of tacrolimus similar to adult patients (see DOSAGE AND ADMINISTRATION).
The principal adverse reactions of tacrolimus are tremor, headache, diarrhea, hypertension, nausea, and abnormal renal function. These occur with oral and IV administration of tacrolimus 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 tacrolimus 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 post-transplant 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:
|U.S. STUDY||EUROPEAN STUDY|
|Headache (see WARNINGS)||64%||60%||37%||26%|
|Tremor (see WARNINGS)||56%||46%||48%||32%|
|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%|
|Metabolic and Nutritional|
|Hyperkalemia (see WARNINGS)||45%||26%||13%||9%|
|Hyperglycemia (see WARNINGS)||47%||38%||33%||22%|
|Hemic and Lymphatic|
|Skin and Appendages|
Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions below.
The most common adverse reactions reported were infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain and insomnia.
Adverse events that occurred in ≥15% of kidney transplant patients treated with tacrolimus in conjunction with azathioprine are presented below:
|Tremor (see WARNINGS)||54%||34%|
|Headache (see WARNINGS)||44%||38%|
|Hypertension (see PRECAUTIONS)||50%||52%|
|Creatinine Increased (see WARNINGS)||45%||42%|
|Urinary Tract Infection||34%||35%|
|Metabolic and Nutritional|
|Hyperkalemia (see WARNINGS)||31%||32%|
|Diabetes Mellitus (see WARNINGS)||24%||9%|
|Hyperglycemia (see WARNINGS)||22%||16%|
|Hemic and Lymphatic|
Adverse events that occurred in ≥ 10% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 1* are presented below:
|Tacrolimus (Group C) (N=403)||Cyclosporine (Group A) (N=384)||Cyclosporine (Group B) (N=408)|
|*Study 1 was conducted entirely outside of the United States. Such studies often report a lower incidence of adverse events in comparison to US studies.|
|Urinary tract infection||24%||28%||24%|
|Hypertension (see PRECAUTIONS)||13%||14%||12%|
Adverse events that occurred in ≥15% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 2 are presented below:
|Tacrolimus (N=212)||Cyclosporine (N=212)|
|Injury, Poisoning, and Procedural Complications|
|Post Procedural Pain||29%||27%|
|Incision Site Complication||28%||23%|
|Metabolism and Nutrition Disorders|
|Hyperkalemia (see WARNINGS)||26%||19%|
|Hyperglycemia (see WARNINGS)||21%||15%|
|Nervous System Disorders|
|Blood and Lymphatic System Disorders|
|Hypertension (see PRECAUTIONS)||32%||35%|
|Urinary Tract Infection||26%||22%|
|Blood creatinine increased||23%||23%|
Less frequently observed adverse reactions in both liver transplantation 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 either liver and/or kidney transplant recipients who were treated with tacrolimus in clinical trials.
Nervous System (see WARNINGS)
Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, dizziness, elevated mood, emotional lability, encephalopathy, hemorrhagic stroke, hallucinations, headache, hypertonia, incoordination, insomnia, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paresthesia, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired
Abnormal vision, amblyopia, ear pain, otitis media, tinnitus
Anorexia, cholangitis, cholestatic jaundice, diarrhea, duodenitis, dyspepsia, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, liver function test abnormal, nausea, nausea and vomiting, esophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis, vomiting
Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, cardiovascular disorder, chest pain, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, peripheral vascular disorder, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation
Urogenital (see WARNINGS)
Acute kidney failure, albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, oliguria, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis
Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, BUN increased, dehydration, edema, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperkalemia, hyperlipemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactic dehydrogenase increase, peripheral edema, weight gain
Endocrine (see PRECAUTIONS)
Cushing’s syndrome, diabetes mellitus
Coagulation disorder, ecchymosis, hematocrit increased, hemoglobin abnormal, hypochromic anemia, leukocytosis, leukopenia, polycythemia, prothrombin decreased, serum iron decreased, thrombocytopenia
Abdomen enlarged, abdominal pain, abscess, accidental injury, allergic reaction, asthenia, back pain, cellulitis, chills, fall, feeling abnormal, fever, flu syndrome, generalized edema, hernia, mobility decreased, pain, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer
Arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis
Asthma, bronchitis, cough increased, dyspnea, emphysema, hiccups, lung disorder, lung function decreased, pharyngitis, pleural effusion, pneumonia, pneumothorax, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration
Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin disorder, skin ulcer, sweating.
Post Marketing Adverse Events
The following adverse events have been reported from worldwide marketing experience with tacrolimus. Because these events are reported voluntarily from a population of uncertain size, are associated with concomitant diseases and multiple drug therapies and surgical procedures, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these events in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) frequency of the reporting, or (3) strength of causal connection to the drug.
There have been rare spontaneous reports of myocardial hypertrophy associated with clinically manifested ventricular dysfunction in patients receiving tacrolimus therapy (see PRECAUTIONS-Myocardial Hypertrophy).
Other events include:
Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischemia, pericardial effusion, QT prolongation, Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation
Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastrooesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis hemorrhagic, pancreatitis necrotizing, stomach ulcer, venoocclusive liver disease
Disseminated intravascular coagulation, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura
Glycosuria, increased amylase including pancreatitis, weight decreased
Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction
Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope
Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure
Stevens-Johnson syndrome, toxic epidermal necrolysis
Blindness, blindness cortical, hearing loss including deafness, photophobia
Acute renal failure, cystitis hemorrhagic, hemolytic-uremic syndrome, micturition disorder.
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