Tacrolimus
Generic: TACROLIMUS
Basic Information
Manufacturer
Amneal Pharmaceuticals NY LLC
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
4eb1b6bd-beec-4dd5-9a48-c93a9fe918b3
Indications & Usage
1 INDICATIONS AND USAGE Tacrolimus extended-release capsules is indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants in adult and pediatric patients who can swallow capsules intact [see Use in Specific Populations (8.4) and Clinical Studies (14.1), (14.2)] .
Tacrolimus extended-release capsules is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants in adult and pediatric patients who can swallow capsules intact.
( 1 , 8.4 , 14.1 , 14.2 )
Tacrolimus extended-release capsules is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants in adult and pediatric patients who can swallow capsules intact.
( 1 , 8.4 , 14.1 , 14.2 )
Adverse Reactions
6 ADVERSE REACTIONS The following clinically significant adverse drug reactions are discussed in greater detail in other sections of labeling: Lymphoma and Other Malignancies [see Warnings and Precautions (5.1) ] Serious Infections [see Warnings and Precautions (5.2) ] Increased Mortality in Female Liver Transplant Patients [see Warnings and Precautions (5.3) ] New Onset Diabetes after Transplant [see Warnings and Precautions (5.5) ] Nephrotoxicity due to Tacrolimus Extended-Release Capsules and Drug Interactions [see Warnings and Precautions (5.6) ] Neurotoxicity [see Warnings and Precautions (5.7) ] Hyperkalemia [see Warnings and Precautions (5.8) ] Hypertension [see Warnings and Precautions (5.9) ] QT Prolongation [see Warnings and Precautions (5.11) ] Pure Red Cell Aplasia [see Warnings and Precautions (5.13) ] Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura [see Warnings and Precautions (5.14) ] The most common adverse reactions (≥ 30%) are: diarrhea, constipation, nausea, peripheral edema, tremor and anemia.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.
Kidney transplant patients were treated with tacrolimus extended-release capsules (N=214) or tacrolimus immediate- release product (N=212) and concomitant immunosuppressants (median duration of exposure of 12 months) in a randomized, open-label, active-controlled trial of mostly U.S.
patients (Study 1) [see Clinical Studies (14.1) ] .
The types of adverse reactions seen in Study 1 were similar to the adverse reactions seen in Study 2 [non-U.S.
trial in kidney transplant patients treated with tacrolimus extended-release capsules (N=331) or tacrolimus immediate-release product (N=336) and concomitant immunosuppressants] [see Clinical Studies (14.2) ] .
In Study 1, the proportion of patients who discontinued treatment due to adverse reactions was 9% and 11% in the tacrolimus extended-release capsules and tacrolimus immediate-release treatment groups, respectively, through 12 months of treatment.
The most common adverse reactions leading to discontinuation in tacrolimus extended-release capsules-treated patients were related to infections or renal/urinary disorders.
Infections The overall incidence of infections, serious infections, and infections with identified etiology reported in patients treated with the tacrolimus extended-release capsules or tacrolimus immediate-release product in Study 1 are shown in Table 2 .
Table 2: Percentage of Patients with Infections in Study 1 a Through One Year Post-Kidney Transplant Tacrolimus extended-release capsules, MMF, steroids, basiliximab induction N=214 Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=212 All Infections 69% 69% Respiratory Infections 34% 31% Urinary Tract Infections 16% 25% Cytomegalovirus Infections 10% 11% Bacterial Infections 8% 12% Gastroenteritis 7% 3% Polyomavirus Infections 3% 5% Serious Infections 22% 23% a Study 1 was not designed to support comparative claims of tacrolimus extended-release capsules compared to tacrolimus immediate-release product for the adverse reactions reported in this table.
New Onset Diabetes After Transplant (NODAT) The incidence of new onset diabetes after transplantation (defined by the composite occurrence of ≥ 2 fasting plasma glucose values that were more than 126 mg/dL at ≥ 30 days apart, insulin use for≥ 30 consecutive days, oral hypoglycemic use for ≥ 30 consecutive days, and/or HbA 1C ≥ 6.5%) is summarized in Table 3 below for Study 1 through one year post-transplant [see Warnings and Precautions (5.5) ].
Table 3: Percentage of Patients with NODAT Through One Year Post-Kidney Transplant in Study 1 a Tacrolimus extended-release capsules, MMF, steroids, basiliximab induction N=162 Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=151 Composite NODAT 36% 35% ≥ 2 Fasting Plasma Glucose Values ≥ 126 mg/dL ≥ 30 days apart 26% 23% HbA 1C ≥ 6.5% 19% 22% Oral hypoglycemic use ≥ 30 consecutive days 14% 9% Insulin use ≥ 30 consecutive days 6% 8% a Study 1 was not designed to support comparative claims of tacrolimus extended-release capsules compared to tacrolimus immediate-release product for the adverse reactions reported in this table.
Hyperkalemia In Study 1 [see Clinical Studies (14.1) ] , 73 of 214 (34.1%) patients on tacrolimus extended-release capsules had a serum potassium level greater than 5.4 up to 6.4 mEq/L, and 8 out of 214 (3.7%) patients had a serum potassium level greater than 6.4 mEq/L [see Warnings and Precautions (5.8) ] .
Common Adverse Reactions The most common (≥ 30%) adverse reactions observed with tacrolimus extended-release capsules in Study 1 were: diarrhea, constipation, nausea, peripheral edema, tremor, and anemia.
The incidence of adverse reactions that occurred in ≥ 15% of tacrolimus extended-release capsules-treated patients compared to tacrolimus immediate-release product through one year of treatment in Study 1 is shown by treatment groups in Table 4 .
Table 4: Adverse Reactions (≥ 15%) in Kidney Transplant Patients Through One Year Post-Transplant in Study 1 a Tacrolimus extended-release capsules, MMF, steroids, basiliximab induction N=214 Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=212 Diarrhea 45% 44% Constipation 40% 32% Nausea 36% 35% Peripheral Edema 36% 34% Tremor 35% 34% Anemia 33% 29% Hypertension 28% 30% Vomiting 25% 25% Hypomagnesemia 24% 27% Insomnia 24% 28% Hypophosphatemia 23% 28% Headache 22% 24% Hyperkalemia 20% 23% Increased Blood Creatinine 19% 23% Fatigue 16% 10% Leukopenia 16% 16% Hyperlipidemia 16% 17% Hyperglycemia 16% 18% a Study 1 was not designed to support comparative claims of tacrolimus extended-release capsules compared to tacrolimus immediate-release for the adverse reactions reported in this table.
Less Frequently Reported Adverse Reactions (less than 15% in tacrolimus extended-release capsules-treated patients) by System Organ Class The following adverse reactions were reported in clinical studies of kidney transplant patients who were treated with tacrolimus extended-release capsules, MMF, and steroids (Studies 1 and 2): Blood and Lymphatic System Disorders: Hemolytic anemia, leukocytosis, neutropenia, thrombocytopenia, thrombotic microangiopathy Cardiac Disorders: Atrial fibrillation, atrial flutter, tachycardia Ear Disorders: Tinnitus Eye Disorders: Vision blurred, conjunctivitis Gastrointestinal Disorders: Abdominal distension, abdominal pain, aphthous stomatitis, dyspepsia, esophagitis, flatulence, gastritis, gastroesophageal reflux disease General Disorders and Administration Site Conditions: Anasarca, asthenia, edema, pyrexia Hepatobiliary Disorders: Abnormal hepatic function, cholestasis, hepatitis (acute and chronic), hepatotoxicity Infections and Infestations: Condyloma acuminatum, tinea versicolor Injury: Fall Investigations: Increased blood lactate dehydrogenase, increased blood urea, increased hepatic enzyme Metabolism and Nutrition Disorders: Anorexia, hyperphosphatemia, hyperuricemia, hypokalemia, hyponatremia, metabolic acidosis Musculoskeletal and Connective Tissue Disorders: Arthralgia, osteopenia, osteoporosis Neoplasms: Kaposi’s sarcoma Nervous System Disorders: Convulsion, dizziness, hypoesthesia, neurotoxicity, paresthesia, peripheral neuropathy Psychiatric Disorders: Agitation, anxiety, confusional state, depression, hallucination, mood swings, nightmare Renal and Urinary Disorders: Anuria, oliguria, proteinuria, renal failure, renal tubular necrosis, toxic nephropathy Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, dyspnea, pulmonary edema, productive cough Skin and Subcutaneous Tissue Disorders: Acne, alopecia, dermatitis, hyperhidrosis, hypotrichosis, pruritus, rash Vascular Disorders: Deep vein thrombosis, flushing Pediatrics De Novo Pediatric Transplant Patients A study was conducted in 44 de novo pediatric transplant patients (including 25 kidney transplant patients; 13 randomized to tacrolimus extended-release capsules and 12 randomized to Prograf), who were started on 0.3 mg/kg daily of tacrolimus product, given once daily for tacrolimus extended-release capsules and divided into two doses for Prograf.
Two kidney transplant patients on Prograf discontinued the study (withdrawn consent, sapovirus enteritis).
Thirteen (13) pediatric kidney transplant patients completed 52 weeks on tacrolimus extended-release capsules.
The most common adverse reactions were diarrhea [7/13 (54%)], increased blood creatinine [6/13 (46%)], hypertension [3/13 (23%)], cough [4/13 (31%)], and upper respiratory tract infection [4/13 (31%)].
Stable Pediatric Transplant Patients Another study was conducted in 81 stable pediatric allograft recipients (including 48 kidney transplant patients) 5 to 16 years of age converted 1:1 (mg:mg) from Prograf to tacrolimus extended-release capsules.
Seventy-six (76) pediatric patients completed at least one year of tacrolimus extended-release capsules-based treatment.
Treatment-related adverse reactions were reported in 35%, including 13% serious adverse reactions.
The most frequent adverse reactions by system organ class were infections (55.7%), followed by gastrointestinal disorders (27.8%), skin and subcutaneous tissue disorders (21.5%), respiratory, thoracic and mediastinal disorders (20.3% each).
The most common adverse reactions were diarrhea (13.9%), headache (13.9%) and cough (11.4%).
6.2 Postmarketing Experience The following adverse reactions have been reported from marketing experience with tacrolimus in the U.S.
and outside the U.S.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to tacrolimus extended-release capsules: Blood and Lymphatic System Disorders: Agranulocytosis, disseminated intravascular coagulation, hemolytic uremic syndrome, febrile neutropenia, pancytopenia, pure red cell aplasia [see Warnings and Precautions (5.13) ] , coagulopathy, thrombotic thrombocytopenic purpura, prolonged activated partial thromboplastin time, decreased blood fibrinogen Cardiac Disorders: Cardiac arrest, myocardial infarction, ventricular fibrillation, congestive cardiac failure, hypertrophic cardiomyopathy, pericardial effusion, angina pectoris, supraventricular extrasystoles, supraventricular tachycardia, bradycardia, Torsades de pointes , QT prolongation Ear Disorders: Hearing loss Eye Disorders: Blindness, optic neuropathy, optic atrophy, photophobia Gastrointestinal Disorders: Gastrointestinal hemorrhage, gastrointestinal perforation, pancreatitis, peritonitis, stomach ulcer, intestinal obstruction, ascites, colitis, ileus, impaired gastric emptying, dysphagia Hepatobiliary Disorders: Hepatic failure, hepatic necrosis, cirrhosis, cholangitis, venoocclusive liver disease, bile duct stenosis, hepatic steatosis, jaundice Hypersensitivity Reactions: Hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria Immune System Disorders: Graft versus host disease (acute and chronic) Investigations: Increased international normalized ratio Metabolism and Nutrition Disorders: Hypoproteinemia Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, myalgia, polyarthritis, pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) Neoplasms: Lymphoma including EBV-associated lymphoproliferative disorder, hepatosplenic T-cell lymphoma, PTLD [see Warnings and Precautions (5.1) ] , leukemia, melanoma Nervous System Disorders: Cerebral infarction, progressive multifocal leukoencephalopathy (PML) sometimes fatal [see Warnings and Precautions (5.2) ] , posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions (5.7) ], coma, status epilepticus, quadriplegia, flaccid paralysis, hemiparesis, aphasia, syncope, carpal tunnel syndrome, nerve compression, mutism, dysarthria, somnolence Psychiatric Disorders: Mental status changes Renal and Urinary Disorders: Hemorrhagic cystitis, hematuria, urinary retention, urinary incontinence Respiratory, Thoracic and Mediastinal Disorders: Interstitial lung disease, pulmonary hypertension, lung infiltration, rhinitis allergic, hiccups Skin and Subcutaneous Tissue Disorders: Hyperpigmentation, photosensitivity Vascular Disorders: Hemorrhage
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.
Kidney transplant patients were treated with tacrolimus extended-release capsules (N=214) or tacrolimus immediate- release product (N=212) and concomitant immunosuppressants (median duration of exposure of 12 months) in a randomized, open-label, active-controlled trial of mostly U.S.
patients (Study 1) [see Clinical Studies (14.1) ] .
The types of adverse reactions seen in Study 1 were similar to the adverse reactions seen in Study 2 [non-U.S.
trial in kidney transplant patients treated with tacrolimus extended-release capsules (N=331) or tacrolimus immediate-release product (N=336) and concomitant immunosuppressants] [see Clinical Studies (14.2) ] .
In Study 1, the proportion of patients who discontinued treatment due to adverse reactions was 9% and 11% in the tacrolimus extended-release capsules and tacrolimus immediate-release treatment groups, respectively, through 12 months of treatment.
The most common adverse reactions leading to discontinuation in tacrolimus extended-release capsules-treated patients were related to infections or renal/urinary disorders.
Infections The overall incidence of infections, serious infections, and infections with identified etiology reported in patients treated with the tacrolimus extended-release capsules or tacrolimus immediate-release product in Study 1 are shown in Table 2 .
Table 2: Percentage of Patients with Infections in Study 1 a Through One Year Post-Kidney Transplant Tacrolimus extended-release capsules, MMF, steroids, basiliximab induction N=214 Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=212 All Infections 69% 69% Respiratory Infections 34% 31% Urinary Tract Infections 16% 25% Cytomegalovirus Infections 10% 11% Bacterial Infections 8% 12% Gastroenteritis 7% 3% Polyomavirus Infections 3% 5% Serious Infections 22% 23% a Study 1 was not designed to support comparative claims of tacrolimus extended-release capsules compared to tacrolimus immediate-release product for the adverse reactions reported in this table.
New Onset Diabetes After Transplant (NODAT) The incidence of new onset diabetes after transplantation (defined by the composite occurrence of ≥ 2 fasting plasma glucose values that were more than 126 mg/dL at ≥ 30 days apart, insulin use for≥ 30 consecutive days, oral hypoglycemic use for ≥ 30 consecutive days, and/or HbA 1C ≥ 6.5%) is summarized in Table 3 below for Study 1 through one year post-transplant [see Warnings and Precautions (5.5) ].
Table 3: Percentage of Patients with NODAT Through One Year Post-Kidney Transplant in Study 1 a Tacrolimus extended-release capsules, MMF, steroids, basiliximab induction N=162 Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=151 Composite NODAT 36% 35% ≥ 2 Fasting Plasma Glucose Values ≥ 126 mg/dL ≥ 30 days apart 26% 23% HbA 1C ≥ 6.5% 19% 22% Oral hypoglycemic use ≥ 30 consecutive days 14% 9% Insulin use ≥ 30 consecutive days 6% 8% a Study 1 was not designed to support comparative claims of tacrolimus extended-release capsules compared to tacrolimus immediate-release product for the adverse reactions reported in this table.
Hyperkalemia In Study 1 [see Clinical Studies (14.1) ] , 73 of 214 (34.1%) patients on tacrolimus extended-release capsules had a serum potassium level greater than 5.4 up to 6.4 mEq/L, and 8 out of 214 (3.7%) patients had a serum potassium level greater than 6.4 mEq/L [see Warnings and Precautions (5.8) ] .
Common Adverse Reactions The most common (≥ 30%) adverse reactions observed with tacrolimus extended-release capsules in Study 1 were: diarrhea, constipation, nausea, peripheral edema, tremor, and anemia.
The incidence of adverse reactions that occurred in ≥ 15% of tacrolimus extended-release capsules-treated patients compared to tacrolimus immediate-release product through one year of treatment in Study 1 is shown by treatment groups in Table 4 .
Table 4: Adverse Reactions (≥ 15%) in Kidney Transplant Patients Through One Year Post-Transplant in Study 1 a Tacrolimus extended-release capsules, MMF, steroids, basiliximab induction N=214 Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=212 Diarrhea 45% 44% Constipation 40% 32% Nausea 36% 35% Peripheral Edema 36% 34% Tremor 35% 34% Anemia 33% 29% Hypertension 28% 30% Vomiting 25% 25% Hypomagnesemia 24% 27% Insomnia 24% 28% Hypophosphatemia 23% 28% Headache 22% 24% Hyperkalemia 20% 23% Increased Blood Creatinine 19% 23% Fatigue 16% 10% Leukopenia 16% 16% Hyperlipidemia 16% 17% Hyperglycemia 16% 18% a Study 1 was not designed to support comparative claims of tacrolimus extended-release capsules compared to tacrolimus immediate-release for the adverse reactions reported in this table.
Less Frequently Reported Adverse Reactions (less than 15% in tacrolimus extended-release capsules-treated patients) by System Organ Class The following adverse reactions were reported in clinical studies of kidney transplant patients who were treated with tacrolimus extended-release capsules, MMF, and steroids (Studies 1 and 2): Blood and Lymphatic System Disorders: Hemolytic anemia, leukocytosis, neutropenia, thrombocytopenia, thrombotic microangiopathy Cardiac Disorders: Atrial fibrillation, atrial flutter, tachycardia Ear Disorders: Tinnitus Eye Disorders: Vision blurred, conjunctivitis Gastrointestinal Disorders: Abdominal distension, abdominal pain, aphthous stomatitis, dyspepsia, esophagitis, flatulence, gastritis, gastroesophageal reflux disease General Disorders and Administration Site Conditions: Anasarca, asthenia, edema, pyrexia Hepatobiliary Disorders: Abnormal hepatic function, cholestasis, hepatitis (acute and chronic), hepatotoxicity Infections and Infestations: Condyloma acuminatum, tinea versicolor Injury: Fall Investigations: Increased blood lactate dehydrogenase, increased blood urea, increased hepatic enzyme Metabolism and Nutrition Disorders: Anorexia, hyperphosphatemia, hyperuricemia, hypokalemia, hyponatremia, metabolic acidosis Musculoskeletal and Connective Tissue Disorders: Arthralgia, osteopenia, osteoporosis Neoplasms: Kaposi’s sarcoma Nervous System Disorders: Convulsion, dizziness, hypoesthesia, neurotoxicity, paresthesia, peripheral neuropathy Psychiatric Disorders: Agitation, anxiety, confusional state, depression, hallucination, mood swings, nightmare Renal and Urinary Disorders: Anuria, oliguria, proteinuria, renal failure, renal tubular necrosis, toxic nephropathy Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, dyspnea, pulmonary edema, productive cough Skin and Subcutaneous Tissue Disorders: Acne, alopecia, dermatitis, hyperhidrosis, hypotrichosis, pruritus, rash Vascular Disorders: Deep vein thrombosis, flushing Pediatrics De Novo Pediatric Transplant Patients A study was conducted in 44 de novo pediatric transplant patients (including 25 kidney transplant patients; 13 randomized to tacrolimus extended-release capsules and 12 randomized to Prograf), who were started on 0.3 mg/kg daily of tacrolimus product, given once daily for tacrolimus extended-release capsules and divided into two doses for Prograf.
Two kidney transplant patients on Prograf discontinued the study (withdrawn consent, sapovirus enteritis).
Thirteen (13) pediatric kidney transplant patients completed 52 weeks on tacrolimus extended-release capsules.
The most common adverse reactions were diarrhea [7/13 (54%)], increased blood creatinine [6/13 (46%)], hypertension [3/13 (23%)], cough [4/13 (31%)], and upper respiratory tract infection [4/13 (31%)].
Stable Pediatric Transplant Patients Another study was conducted in 81 stable pediatric allograft recipients (including 48 kidney transplant patients) 5 to 16 years of age converted 1:1 (mg:mg) from Prograf to tacrolimus extended-release capsules.
Seventy-six (76) pediatric patients completed at least one year of tacrolimus extended-release capsules-based treatment.
Treatment-related adverse reactions were reported in 35%, including 13% serious adverse reactions.
The most frequent adverse reactions by system organ class were infections (55.7%), followed by gastrointestinal disorders (27.8%), skin and subcutaneous tissue disorders (21.5%), respiratory, thoracic and mediastinal disorders (20.3% each).
The most common adverse reactions were diarrhea (13.9%), headache (13.9%) and cough (11.4%).
6.2 Postmarketing Experience The following adverse reactions have been reported from marketing experience with tacrolimus in the U.S.
and outside the U.S.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to tacrolimus extended-release capsules: Blood and Lymphatic System Disorders: Agranulocytosis, disseminated intravascular coagulation, hemolytic uremic syndrome, febrile neutropenia, pancytopenia, pure red cell aplasia [see Warnings and Precautions (5.13) ] , coagulopathy, thrombotic thrombocytopenic purpura, prolonged activated partial thromboplastin time, decreased blood fibrinogen Cardiac Disorders: Cardiac arrest, myocardial infarction, ventricular fibrillation, congestive cardiac failure, hypertrophic cardiomyopathy, pericardial effusion, angina pectoris, supraventricular extrasystoles, supraventricular tachycardia, bradycardia, Torsades de pointes , QT prolongation Ear Disorders: Hearing loss Eye Disorders: Blindness, optic neuropathy, optic atrophy, photophobia Gastrointestinal Disorders: Gastrointestinal hemorrhage, gastrointestinal perforation, pancreatitis, peritonitis, stomach ulcer, intestinal obstruction, ascites, colitis, ileus, impaired gastric emptying, dysphagia Hepatobiliary Disorders: Hepatic failure, hepatic necrosis, cirrhosis, cholangitis, venoocclusive liver disease, bile duct stenosis, hepatic steatosis, jaundice Hypersensitivity Reactions: Hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria Immune System Disorders: Graft versus host disease (acute and chronic) Investigations: Increased international normalized ratio Metabolism and Nutrition Disorders: Hypoproteinemia Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, myalgia, polyarthritis, pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) Neoplasms: Lymphoma including EBV-associated lymphoproliferative disorder, hepatosplenic T-cell lymphoma, PTLD [see Warnings and Precautions (5.1) ] , leukemia, melanoma Nervous System Disorders: Cerebral infarction, progressive multifocal leukoencephalopathy (PML) sometimes fatal [see Warnings and Precautions (5.2) ] , posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions (5.7) ], coma, status epilepticus, quadriplegia, flaccid paralysis, hemiparesis, aphasia, syncope, carpal tunnel syndrome, nerve compression, mutism, dysarthria, somnolence Psychiatric Disorders: Mental status changes Renal and Urinary Disorders: Hemorrhagic cystitis, hematuria, urinary retention, urinary incontinence Respiratory, Thoracic and Mediastinal Disorders: Interstitial lung disease, pulmonary hypertension, lung infiltration, rhinitis allergic, hiccups Skin and Subcutaneous Tissue Disorders: Hyperpigmentation, photosensitivity Vascular Disorders: Hemorrhage