ADVERSE REACTIONS
Liver Transplantation
The principal adverse reactions of Prograf are tremor, headache, diarrhea, hypertension, nausea, and abnormal renal function. 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)
Tremor (see WARNINGS)
Insomnia
Paresthesia
|
64%
56%
64%
40%
|
60%
46%
68%
30%
|
37%
48%
32%
17%
|
26%
32%
23%
17%
|
|
Gastrointestinal
| | | | |
|
Diarrhea
Nausea
Constipation
LFT Abnormal
Anorexia
Vomiting
|
72%
46%
24%
36%
34%
27%
|
47%
37%
27%
30%
24%
15%
|
37%
32%
23%
6%
7%
14%
|
27%
27%
21%
5%
5%
11%
|
|
Cardiovascular
| | | | |
|
Hypertension (see PRECAUTIONS)
|
47%
|
56%
|
38%
|
43%
|
|
Urogenital
| | | | |
|
Kidney Function Abnormal (see WARNINGS)
Creatinine Increased (see WARNINGS)
BUN Increased (see WARNINGS)
Urinary Tract Infection
Oliguria
|
40%
39%
30%
16%
18%
|
27%
25%
22%
18%
15%
|
36%
24%
12%
21%
19%
|
23%
19%
9%
19%
12%
|
|
Metabolic and Nutritional
| | | | |
|
Hyperkalemia (see WARNINGS)
Hypokalemia
Hyperglycemia (see WARNINGS)
Hypomagnesemia
|
45%
29%
47%
48%
|
26%
34%
38%
45%
|
13%
13%
33%
16%
|
9%
16%
22%
9%
|
|
Hemic and Lymphatic
| | | | |
|
Anemia
Leukocytosis
Thrombocytopenia
|
47%
32%
24%
|
38%
26%
20%
|
5%
8%
14%
|
1%
8%
19%
|
|
Miscellaneous
| | | | |
|
Abdominal Pain
Pain
Fever
Asthenia
Back Pain
Ascites
Peripheral Edema
|
59%
63%
48%
52%
30%
27%
26%
|
54%
57%
56%
48%
29%
22%
26%
|
29%
24%
19%
11%
17%
7%
12%
|
22%
22%
22%
7%
17%
8%
14%
|
|
Respiratory System
| | | | |
|
Pleural Effusion
Atelectasis
Dyspnea
|
30%
28%
29%
|
32%
30%
23%
|
36%
5%
5%
|
35%
4%
4%
|
|
Skin and Appendages
| | | | |
|
Pruritus
Rash |
36%
24% |
20%
19% |
15%
10% |
7%
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, abnormal 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
(N=205) |
CBIR
(N=207) |
|
Nervous System
| | |
|
Tremor (see WARNINGS)
Headache (see WARNINGS)
Insomnia
Paresthesia
Dizziness
|
54%
44%
32%
23%
19%
|
34%
38%
30%
16%
16%
|
|
Gastrointestinal
| | |
|
Diarrhea
Nausea
Constipation
Vomiting
Dyspepsia
|
44%
38%
35%
29%
28%
|
41%
36%
43%
23%
20%
|
|
Cardiovascular
| | |
|
Hypertension (see PRECAUTIONS)
Chest pain
|
50%
19%
|
52%
13%
|
|
Urogenital
| | |
|
Creatinine Increased (see WARNINGS)
Urinary Tract Infection
|
45%
34%
|
42%
35%
|
|
Metabolic and Nutritional
| | |
|
Hypophosphatemia
Hypomagnesemia
Hyperlipemia
Hyperkalemia (see WARNINGS)
Diabetes Mellitus (see WARNINGS)
Hypokalemia
Hyperglycemia (see WARNINGS)
Edema
|
49%
34%
31%
31%
24%
22%
22%
18%
|
53%
17%
38%
32%
9%
25%
16%
19%
|
|
Hemic and Lymphatic
| | |
|
Anemia
Leukopenia
|
30%
15%
|
24%
17%
|
|
Miscellaneous
| | |
|
Infection
Peripheral Edema
Asthenia
Abdominal Pain
Pain
Fever
Back Pain
|
45%
36%
34%
33%
32%
29%
24%
|
49%
48%
30%
31%
30%
29%
20%
|
|
Respiratory System
| | |
|
Dyspnea
Cough Increased
|
22%
18%
|
18%
15%
|
|
Musculoskeletal
| | |
|
Arthralgia
|
25%
|
24%
|
|
Skin
| | |
|
Rash
Pruritus |
17%
15% |
12%
7% |
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.
Heart Transplantation
The more common adverse reactions in Prograf-treated heart transplant recipients were abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, and hyperlipemia.
Adverse events in heart transplant patients in the European trial are presented below:
HEART TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN ≥15% OF PROGRAF-TREATED PATIENTS |
COSTART Body System
COSTART Term |
Prograf+
Azathioprine
(n=157) |
CsA + Azathioprine
(n=157) |
| Cardiovascular System |
| Hypertension (See PRECAUTIONS) | 62% | 69% |
| Pericardial effusion | 15% | 14% |
| Body as a Whole |
| CMV infection | 32% | 30% |
| Infection | 24% | 21% |
| Metabolic and Nutritional Disorders |
| Hyperlipemia | 18% | 27% |
| Diabetes Mellitus (See WARNINGS) | 26% | 16% |
| Hyperglycemia (See WARNINGS) | 23% | 17% |
| Hemic and Lymphatic System |
| Leukopenia | 48% | 39% |
| Anemia | 50% | 36% |
| Urogenital System |
| Kidney function abnormal (See WARNINGS) | 56% | 57% |
| Urinary tract infection | 16% | 12% |
| Respiratory System |
| Bronchitis | 17% | 18% |
| Nervous System |
| Tremor (See WARNINGS) | 15% | 6% |
In the European study, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100-200 ng/mL) at Day 122 and beyond in 32-68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5-15 ng/mL) in 74-86% of the patients in the tacrolimus treatment arm.
Only selected targeted treatment-emergent adverse events were collected in the US heart transplantation study. Those events that were reported at a rate of 15% or greater in patients treated with Prograf and mycophenolate mofetil include the following: any target adverse events (99.1%), hypertension (88.8%), hyperglycemia requiring antihyperglycemic therapy (70.1%) (see WARNINGS), hypertriglyceridemia (65.4%), anemia (hemoglobin <10.0 g/dL) (65.4%), fasting blood glucose >140 mg/dL (on two separate occasions) (60.7%) (see WARNINGS), hypercholesterolemia (57.0%), hyperlipidemia (33.6%), WBCs <3000 cells/mcL (33.6%), serious bacterial infections (29.9%), magnesium <1.2 mEq/L (24.3%), platelet count <75,000 cells/mcL (18.7%), and other opportunistic infections (15.0%).
Other targeted treatment-emergent adverse events in Prograf-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome.
Less Frequently Reported Adverse Reactions
The following adverse events were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials.
Nerv o us System (see WARNINGS)
Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, dizziness, elevated mood, emotional lability, encephalopathy, haemorrhagic 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
Special Senses
Abnormal vision, amblyopia, ear pain, otitis media, tinnitus
Gastrointestinal
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, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis, vomiting
Cardiovascular
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, 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
Metabolic/Nutritional
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
Hemic/Lymphatic
Coagulation disorder, ecchymosis, haematocrit increased, haemoglobin abnormal, hypochromic anemia, leukocytosis, leukopenia, polycythemia, prothrombin decreased, serum iron decreased, thrombocytopenia
Miscellaneous
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
Musculoskeletal
Arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis
Respiratory
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
Skin
Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin disorder, skin ulcer, sweating.
Post Marketing
Post Marketing Adverse Events
The following adverse events have been reported from worldwide marketing experience with Prograf. 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 Prograf therapy (see PRECAUTIONS- Myocardial Hypertrophy).
Other events include:
Cardiovascular
Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation
Gastrointestinal
Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastrooesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis haemorrhagic, pancreatitis necrotizing, stomach ulcer, venoocclusive liver disease
Hemic/Lymphatic
Disseminated intravascular coagulation, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura
Metabolic/Nutritional
Glycosuria, increased amylase including pancreatitis, weight decreased
Miscellaneous
Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction
Nervous System
Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, quadriplegia, speech disorder, syncope
Respiratory
Acute respiratory distress syndrome, lung infiltration, respiratory distress, respiratory failure
Skin
Stevens-Johnson syndrome, toxic epidermal necrolysis
Special Senses
Blindness, blindness cortical, hearing loss including deafness, photophobia
Urogenital
Acute renal failure, cystitis haemorrhagic, hemolytic-uremic syndrome, micturition disorder.
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