The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
- Lymphoma and Other Malignancies [see WARNINGS AND PRECAUTIONS]
- Serious Infections [see WARNINGS AND PRECAUTIONS]
- Polyoma Virus Infections [see WARNINGS AND PRECAUTIONS]
- Cytomegalovirus (CMV) Infections [see WARNINGS AND PRECAUTIONS]
- New Onset Diabetes after Transplant [see WARNINGS AND PRECAUTIONS]
- Nephrotoxicity [see WARNINGS AND PRECAUTIONS]
- Neurotoxicity [see WARNINGS AND PRECAUTIONS]
- Hyperkalemia [see WARNINGS AND PRECAUTIONS]
- Hypertension [see WARNINGS AND PRECAUTIONS]
- Pure Red Cell Aplasia [see WARNINGS AND PRECAUTIONS]
- Gastrointestinal Perforation [see WARNINGS AND PRECAUTIONS]
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.
The data described below reflect exposure to ASTAGRAF XL in 545 renal transplant recipients exposed to ASTAGRAF XL for periods up to two years [see Clinical Studies].
The most frequent diseases leading to transplantation were glomerulonephritis, polycystic kidney disease, nephrosclerosis/hypertensive nephropathy, and diabetic nephropathy in both studies.
Study 1: With Basiliximab Induction
The proportion of patients who discontinued treatment due to adverse reactions was 9% in the ASTAGRAF XL arm and 11% in the Prograf control arm through 12 months of treatment. The most common adverse reactions leading to discontinuation in ASTAGRAF XL-treated patients were related to infections or renal/urinary disorders. The most common ( ≥ 30%) adverse reactions observed in the ASTAGRAF XL group were: diarrhea, constipation, nausea, peripheral edema, tremor and anemia.
Study 2: Without Induction
The proportion of patients who discontinued treatment due to adverse reactions was 13% in the ASTAGRAF XL arm and 11% in the Prograf control arm through 12 months of treatment. The most common adverse reactions leading to discontinuation in ASTAGRAF XL-treated patients were related to infections, graft dysfunction, renal vascular/ischemic conditions and diabetes. The most common ( ≥ 30%) adverse reaction observed in the ASTAGRAF XL group was anemia.
Information on selected significant adverse reactions observed during Studies 1 and 2 are summarized below.
New Onset Diabetes After Transplant (NODAT)
New onset diabetes after transplantation (defined by the composite occurrence of ≥ 2 fasting plasma glucose values that were > 126 mg/dL at ≥ 30 days apart, insulin use for ≥ 30 consecutive days, oral hypoglycemic use for ≥ 30 consecutive days, and/or HbA1C ≥ 6.5%) is summarized in Table 2 below for Study 1 and Study 2 through one year post-transplant.
Table 2: Composite NODAT Through 1 Year Post-Transplant in Studies 1 and 2
| Study 1 | Study 2 | |||
| ASTAGRAF XL n (%) (N=162) |
Prograf n (%) (N=151) |
ASTAGRAF XL n (%) (N=288) |
Prograf n (%) (N=299) |
|
| Composite NODAT | 58 (36) | 53 (35) | 105 (37) | 90 (30) |
| ≥ 2 Fasting Plasma Glucose Values ≥ 126 mg/dL ≥ 30 days apart | 42 (26) | 35 (23) | 51 (18) | 47 (16) |
| Insulin use ≥ 30 consecutive days | 10 (6) | 12 (8) | 29 (10) | 29 (10) |
| Oral hypoglycemic use ≥ 30 consecutive days | 22 (14) | 13 (9) | 20 (7) | 23 (8) |
| HbA1C ≥ 6.5% | 31 (19) | 33 (22) | 48 (17) | 39 (13) |
Infections
Adverse reactions of infectious etiology were reported based on clinical assessment by physicians. The causative organisms for these reactions are identified when provided by the physician. The overall number of infections, serious infections, and select infections with identified etiology reported in patients treated with ASTAGRAF XL or the control in Studies 1 and 2 are shown in Table 3.
Table 3: Overall Infections and Select Infections by Treatment Group in Studies 1 and 2 Through One Year Post-Transplant
| Study 1 | Study 2 | |||
| ASTAGRAF XL n (%) (N=214) |
Prograf n (%) (N=212) |
ASTAGRAF XL n (%) (N=331) |
Prograf n (%) (N=336) |
|
| All Infections | 148 (69) | 146 (69) | 228 (69) | 216 (64) |
| Serious Infections | 48 (22) | 49 (23) | 79 (24) | 64 (19) |
| Bacterial Infections | 18 (8) | 25 (12) | 125 (38) | 137 (41) |
| Respiratory Infections | 73 (34) | 65 (31) | 75 (23) | 74 (22) |
| Cytomegalovirus Infections | 21 (10) | 24 (11) | 38 (12) | 21 (6) |
| Polyomavirus Infections | 6 (3) | 10 (5) | 7 (2) | 1 (0) |
| Gastroenteritis | 16 (7) | 6 (3) | 16 (5) | 8 (2) |
| Studies 1 and 2 were not designed to support comparative claims for ASTAGRAF XL for the adverse reactions reported in this table. | ||||
Glomerular Filtration Rate
The estimated mean glomerular filtration rates, using the Modification of Diet in Renal Disease (MDRD) formula, by treatment group at Month 12 in the ITT population in Studies 1 and 2 are shown in Table 4.
Table 4: Estimated Glomerular Filtration Rate (mL/min/1.73m²) by MDRD Formula at 12 Months Post-Transplant
| Study 1 | Study 2 | |||
| ASTAGRAF XL (n=201) |
Prograf (n=202) |
ASTAGRAF XL (n=287) |
Prograf (n=300) |
|
| Month 1 Baseline Mean (SD) | 56 (20) | 56 (21) | 51 (19) | 52 (20) |
| Month 12 LOCFa | ||||
| Mean (Standard deviation) | 58 (21) | 56 (23) | 52 (20) | 55 (19) |
| Median (Min-Max) | 56 (0, 177) | 57 (0, 120) | 54 (0, 116) | 54 (0, 134) |
| Mean Difference XL-Prografb | +2.3 (-1.2, +5.8) | -1.8 (-4.6, +0.8) | ||
| a Subject's last observation carried forward (LOCF) for missing data at Month 1; patients who died, lost the graft or were lost to follow-up are imputed as zeroes b Tacrolimus XL-Prograf treatment mean difference results of analysis of covariance model with Month 1 Baseline as a covariate. |
||||
The incidence of adverse reactions that occurred in ≥ 15% of ASTAGRAF XL-treated patients compared to control through one year of treatment in Studies 1 and 2 are shown in Table 5.
Table 5: Adverse Events Occurring in ≥ 15% of ASTAGRAF XL-Treated Kidney Transplant Patients Through One year Post Transplant in Studies 1 or 2a
| Study 1 | Study 2 | |||
| ASTAGRAF XL n (%) (N=214) |
Prograf n (%) (N=212) |
ASTAGRAF XL n (%) (N=331) |
Prograf n (%) (N=336) |
|
| Anemia | 70 (33) | 61 (29) | 103 (31) | 87 (26) |
| Constipation | 85 (40) | 68 (32) | 45 (14) | 60 (18) |
| Diarrhea | 96 (45) | 94 (44) | 88 (27) | 103 (31) |
| Fatigue | 34 (16) | 22 (10) | 7 (2) | 6 (2) |
| Graft Dysfunction | 29 (14) | 45 (21) | 57 (17) | 56 (17) |
| Headache | 46 (22) | 50 (24) | 39 (12) | 33 (10) |
| Hyperglycemia | 34 (16) | 39 (18) | 61 (18) | 65 (19) |
| Hyperkalemia | 43 (20) | 49 (23) | 50 (15) | 49 (15) |
| Hyperlipidemia | 35 (16) | 36 (17) | 23 (7) | 28 (8) |
| Hypertension | 59 (28) | 63 (30) | 80 (24) | 76 (23) |
| Hypomagnesemia | 52 (24) | 57 (27) | 9 (3) | 12 (4) |
| Hypophosphatemia | 50 (23) | 59 (28) | 15 (5) | 22 (7) |
| Increased Blood Creatinine | 40 (19) | 49 (23) | 54 (16) | 63 (19) |
| Insomnia | 52 (24) | 60 (28) | 29 (9) | 34 (10) |
| Leukopenia | 35 (16) | 33 (16) | 51 (15) | 37 (11) |
| Nausea | 76 (36) | 75 (35) | 51 (15) | 42 (13) |
| Peripheral Edema | 76 (36) | 73 (34) | 38 (12) | 49 (15) |
| Tremor | 75 (35) | 73 (34) | 58 (18) | 58 (17) |
| Urinary Tract Infection | 34 (16) | 53 (25) | 7 (2) | 10 (3) |
| Urinary Tract Infection (bacterial) | 1 (1) | 6 (3) | 86 (26) | 102 (30) |
| Vomiting | 53 (25) | 53 (25) | 42 (13) | 43 (13) |
| aStudies 1 and 2 were not designed to support comparative claims for ASTAGRAF XL for the adverse reactions reported in this table. | ||||
Less Frequently Reported Adverse Reactions ( < 15%) by System Organ Class
The following adverse reactions were also reported in clinical studies of kidney transplant recipients who were treated with ASTAGRAF XL.
Blood and Lymphatic System Disorders
Coagulopathy, hemolytic anemia, leukocytosis, neutropenia, pancytopenia, thrombocytopenia, thrombotic microangiopathy
Cardiac Disorders
Angina pectoris, atrial fibrillation, atrial flutter, bradycardia, cardiac arrest, congestive cardiac failure, hypertrophic cardiomyopathy, myocardial ischemia, myocardial infarction, pericardial effusion, tachycardia, ventricular extrasystoles
Ear Disorders
Hearing loss, otitis (media and externa), tinnitus
Eye Disorders
Vision blurred, conjunctivitis
Gastrointestinal Disorders
Abdominal distension, abdominal pain, aphthous stomatitis, ascites, colitis, dyspepsia, esophagitis, flatulence, gastritis, gastroesophageal reflux disease, gastrointestinal hemorrhage, ileus, impaired gastric emptying, pancreatitis, stomach ulcer
General Disorders and Administration Site Conditions
Anasarca, asthenia, edema
Hepatobiliary Disorders
Abnormal hepatic function, cholestasis, hepatitis (acute and chronic), hepatotoxicity
Infections and Infestations
Condyloma acuminatum, Epstein-Barr virus infection, tinea versicolor
Injury, Poisoning and Procedural Complications
Fall
Investigations
Abnormal electrocardiogram T wave, increased blood lactate dehydrogenase, increased blood urea, increased hematocrit, increased hepatic enzyme, increased international normalized ratio, weight fluctuation
Metabolism and Nutrition Disorders
Anorexia, dehydration, fluid overload, hypercalcemia, hyperphosphatemia, hyperuricemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, hypoproteinemia, metabolic acidosis
Musculoskeletal and Connective Tissue Disorders
Arthralgia, osteopenia, osteoporosis
Neoplasms
Bladder cancer, Kaposi's sarcoma, non-melanoma skin cancer, papillary thyroid cancer
Nervous System Disorders
Aphasia, carpal tunnel syndrome, cerebral infarction, cerebral ischemia, convulsion, dizziness, hypoesthesia, neurotoxicity, paresthesia, peripheral neuropathy, somnolence, syncope
Psychiatric Disorders
Agitation, anxiety, confusional state, depression, hallucination, mental status changes, mood swings, nightmare
Renal and Urinary Disorders
Anuria, hematuria, oliguria, proteinuria, renal failure, renal graft dysfunction, renal tubular necrosis, toxic nephropathy, urinary incontinence, urinary retention
Respiratory, Thoracic and Mediastinal Disorders
Acute respiratory distress syndrome, allergic rhinitis, dyspnea, emphysema, hiccups, lung infiltration, pulmonary edema, productive cough, respiratory failure
Skin and Subcutaneous Tissue Disorders
Acne, alopecia, dermatitis, hyperhidrosis, hypotrichosis, pruritus, rash
Vascular Disorders
Deep vein thrombosis, flushing, hemorrhage, hypotension, orthostatic hypotension
Postmarketing Experience
The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. 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.
Blood and Lymphatic System Disorders
Agranulocytosis, decreased blood fibrinogen, disseminated intravascular coagulation, hemolytic uremic syndrome, prolonged activated partial thromboplastin time, pure red cell aplasia [see WARNINGS AND PRECAUTIONS], thrombotic thrombocytopenic purpura
Cardiac Disorders
QT prolongation, supraventricular extrasystoles, supraventricular tachycardia, Torsade de Pointes, ventricular fibrillation
Eye Disorders
Blindness, photophobia, optic atrophy
Gastrointestinal Disorders
Dysphagia, gastrointestinal perforation [see WARNINGS AND PRECAUTIONS], intestinal obstruction, peritonitis
General Disorders
Multi-organ failure
Hepatobiliary Disorders
Bile duct stenosis, cholangitis, cirrhosis, hepatic failure, hepatic necrosis, hepatic steatosis, jaundice, venoocclusive liver disease
Immune disorders
Graft versus host disease (acute and chronic)
Musculoskeletal and Connective Tissue Disorders
Myalgia, polyarthritis, rhabdomyolysis
Neoplasms
Lymphoma including EBV-associated lymphoproliferative disorder, hepatosplenic T-cell lymphoma, PTLD [see WARNINGS AND PRECAUTIONS]; leukemia, melanoma
Nervous System Disorders
Coma, dysarthria, flaccid paralysis, hemiparesis, mutism, nerve compression, posterior reversible encephalopathy syndrome (PRES) [see WARNINGS AND PRECAUTIONS], progressive multifocal leukoencephalopathy (PML) sometimes fatal [see WARNINGS AND PRECAUTIONS], quadriplegia, status epilepticus
Renal and Urinary Disorders
Hemorrhagic cystitis
Respiratory, Thoracic and Mediastinal Disorders
Interstitial lung disease, pulmonary hypertension
Skin and Subcutaneous Tissue Disorders
Hyperpigmentation, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria