Side Effects of Prograf (tacrolimus)

Prograf (tacrolimus), previously known as FK506, is a macrolide immunosuppressant used to prevent rejection of transplanted kidneys, liver, or heart. It can be combined with steroids, azathioprine (Imuran, Azasan) or mycophenolate mofetil (CellCept).

Common side effects of Prograf include:

• baldness,
• anemia,
• loss of appetite,
• diarrhea,
• high levels of potassium in the blood,
• high blood pressure (hypertension),
• nausea,
• vomiting,
• tingling in the extremities,
• itching,
• tremor,
• fever,
• headache,
• rash,
• high blood sugar, and
• abdominal pain.

Other side effects of Prograf include:

• confusion,
• painful joints,
• increased sensitivity to light,
• blurred vision,
• insomnia,
• infection,
• yellowing of the skin and eyes due to effects on the liver (jaundice),
• kidney injury,
• swollen ankles, and
• seizures.

Drug interactions of Prograf include "live" vaccines for measles, mumps, rubella (MMR), rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine because you could develop a serious infection.

Grapefruit may interact with Prograf and lead to unwanted side effects. Avoid drinking alcohol which may increase the risk of side effects.

Prograf can harm the kidneys, especially if you also use certain medicines for infections, cancer, osteoporosis, bowel disorders, or pain or arthritis (including aspirin, Tylenol, Advil, and Aleve). Many drugs can affect Prograf, especially amiodarone, cyclosporine, sirolimus, antibiotics, antifungals, antivirals, blood pressure medications, and diuretics (water pills).

Prograf crosses the placenta, but there have been no adequate studies in pregnant women to assess the effects on the fetus. Among women who have received Prograf while pregnant, high potassium levels and kidney injury in newborns have been reported. Prograf should be used during pregnancy only when it is clearly needed.

Prograf passes into breast milk. It is recommended that breastfeeding be discontinued while women are receiving oral Prograf.

Tacrolimus is associated with many and various side effects. These include:

• baldness,
• anemia,
• loss of appetite,
• diarrhea,
• high concentrations of potassium in the blood,
• high blood pressure,
• nausea,
• vomiting,
• tingling sensation in the extremities,
• itching,
• tremor,
• fever,
• headache,
• rash,
• high blood sugar concentrations, and
• abdominal pain.

Other side effects include

• confusion,
• painful joints,
• increased sensitivity to light,
• blurred vision,
• insomnia,
• infection,
• jaundice (yellowing of the skin due to effects on the liver),
• kidney injury,
• swollen ankles, and
• seizures.

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

• Lymphoma and Other Malignancies
• Serious Infections
• New Onset Diabetes After Transplant
• Nephrotoxicity
• Neurotoxicity
• Hyperkalemia
• Hypertension
• Anaphylactic Reactions with Prograf Injection
• Myocardial Hypertrophy
• Pure Red Cell Aplasia

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 Transplantation

The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression.

Prograf-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a trial where 205 patients received Prograf-based immunosuppression and 207 patients received cyclosporine-based immunosuppression. The trial population had a mean age of 43 years (mean ± SD was 43 ± 13 years on Prograf and 44 ± 12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), African-American (25%), Hispanic (12%), and Other (5%). The 12-month post-transplant information from this trial is presented below.

The most common adverse reactions (≥ 30%) observed in Prograf-treated kidney transplant patients are:

• infection,
• tremor,
• hypertension,
• abnormal renal function,
• constipation,
• diarrhea,
• headache,
• abdominal pain,
• insomnia,
• nausea,
• hypomagnesemia,
• urinary tract infection,
• hypophosphatemia,
• peripheral edema,
• asthenia,
• pain,
• hyperlipidemia,
• hyperkalemia, and
• anemia.

Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients.

Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with Prograf in conjunction with azathioprine are presented below:

Table 4: Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Prograf in Conjunction with Azathioprine (AZA)

Two trials were conducted for Prograf-based immunosuppression in conjunction with MMF and corticosteroids. In the non-US trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received Prograf (Group C, n = 403), or one of two cyclosporine (CsA) regimens (Group A, n = 384 and Group B, n = 408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76); the distribution was 65% male, and the composition was 93% Caucasian. The 12-month post-transplant information from this trial is presented below.

Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with Prograf in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below:

Table 5: Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with Prograf in Conjunction with MMF (Study 1)

In the U.S. trial (Study 2) with Prograf-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received Prograf (n = 212) or cyclosporine (n = 212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77); the distribution was 63% male, and the composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12-month post-transplant information from this trial is presented below.

Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with Prograf in conjunction with MMF in Study 2 are presented below:

Table 6: Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Prograf in Conjunction with MMF (Study 2)

Less frequently observed adverse reactions in kidney transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.”

Liver Transplantation

There were two randomized comparative liver transplant trials. In the U.S. trial, 263 adult and pediatric patients received tacrolimus and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). The trial population had a mean age of 44 years (range 0.4 to 70); the distribution was 52% male, and the composition was:

• White (78%),
• African-American (5%),
• Asian (2%),
• Hispanic (13%), and
• Other (2%).

In the European trial, 270 patients received tacrolimus and steroids and 275 patients received CsA/AZA. The trial population had a mean age of 46 years (range 15 to 68); the distribution was 59% male, and the composition was:

• White (95.4%),
• Black (1%),
• Asian (2%), and
• Other (2%).

The proportion of patients reporting more than one adverse event was > 99% in both the tacrolimus group and the CsA/AZA group. Precautions must be taken when comparing the incidence of adverse reactions in the U.S. trial to that in the European trial. The 12-month post-transplant information from the U.S. trial and from the European trial is presented below. The two trials also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse reactions reported in ≥ 15% in tacrolimus patients (combined trial results) are presented below for the two controlled trials in liver transplantation.

The most common adverse reactions (≥ 40%) observed in Prograf-treated liver transplant patients are:

• tremor,
• headache,
• diarrhea,
• hypertension,
• nausea,
• abnormal renal function,
• abdominal pain,
• insomnia,
• paresthesia,
• anemia,
• pain,
• fever,
• asthenia,
• hyperkalemia,
• hypomagnesemia, and
• hyperglycemia.

These all occur with oral and IV administration of Prograf and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving Prograf in the U.S. and European randomized trials.

Table 7: Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Prograf

Table 8: Pediatric Liver Transplantation: Adverse Reactions Occurring in > 10% of Patients Treated with Prograf Granules (STUDY 01-13)

Less frequently observed adverse reactions in liver transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.”

Heart Transplantation

The incidence of adverse reactions was determined based on two trials in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine (AZA) in combination with Prograf (n = 157) or cyclosporine (n = 157) for 18 months. The trial population had a mean age of 51 years (range 18 to 65); the distribution was 82% male, and the composition was White (96%), Black (3%), and Other (1%).

The most common adverse reactions (≥ 15%) observed in Prograf-treated heart transplant patients are:

• abnormal renal function,
• hypertension,
• diabetes mellitus,
• CMV infection,
• tremor,
• hyperglycemia,
• leukopenia,
• infection,
• anemia,
• bronchitis,
• pericardial effusion,
• urinary tract infection, and
• hyperlipemia.

Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial.

Adverse reactions in heart transplant patients in the European trial are presented below:

Table 9: Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Prograf in Conjunction with Azathioprine (AZA)

In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm.

In a U.S. trial, the incidence of adverse reactions was based on 331 heart transplant patients that received corticosteroids and Prograf in combination with sirolimus (n=109), Prograf in combination with MMF (n=107) or cyclosporine modified in combination with MMF (n=115) for 1 year. The trial population had a mean age of 53 years (range 18 to 75); the distribution was 78% male, and the composition was White (83%), African-American (13%) and Other (4%).

Only selected targeted treatment-emergent adverse reactions were collected in the U.S. heart transplantation trial. Those reactions that were reported at a rate of 15% or greater in patients treated with Prograf and MMF include the following:

• any target adverse reactions (99%),
• hypertension (89%),
• hyperglycemia requiring antihyperglycemic therapy (70%),
• hypertriglyceridemia (65%),
• anemia (hemoglobin < 10.0 g/dL) (65%),
• fasting blood glucose > 140 mg/dL (on two separate occasions) (61%),
• hypercholesterolemia (57%),
• hyperlipidemia (34%),
• WBCs < 3000 cells/mcL (34%),
• serious bacterial infections (30%),
• magnesium < 1.2 mEq/L (24%),
• platelet count < 75,000 cells/mcL (19%), and
• other opportunistic infections (15%).

Other targeted treatment-emergent adverse reactions 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. Other less frequently observed adverse reactions in heart transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney and Heart Transplant Studies.”

New Onset Diabetes After Transplant

Kidney Transplantation

New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose = 126 mg/dL, HbA1C = 6%, insulin use = 30 days, or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the Prograf-treated and 61% in the NEORAL-treated patients without pre-transplant history of diabetes mellitus (Table 10).

Table 10: Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2)

In early trials of Prograf, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criterion of “use of insulin for 30 or more consecutive days with < 5-day gap” in patients without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Data are presented in Tables 11 to 14. PTDM was reported in 20% of Prograf/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial (Table 11). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post-transplant. African-American and Hispanic kidney transplant patients were at an increased risk of development of PTDM (Table 12).

Table 11: Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA)

Table 12: Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial

Liver Transplantation

Insulin-dependent PTDM was reported in 18% and 11% of Prograf-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post-transplant, in the U.S. and European randomized trials, respectively (Table 13). Hyperglycemia was associated with the use of Prograf in 47% and 33% of liver transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment.

Table 13: Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients

Heart Transplantation

Insulin-dependent PTDM was reported in 13% and 22% of Prograf-treated heart transplant patients receiving mycophenolate mofetil (MMF) or azathioprine (AZA) and was reversible in 30% and 17% of these patients at one year post-transplant, in the U.S. and European randomized trials, respectively (Table 14). Hyperglycemia, defined as two fasting plasma glucose levels = 126 mg/dL, was reported with the use of Prograf plus MMF or AZA in 32% and 35% of heart transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment.

Table 14: Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients

Less Frequently Reported Adverse Reactions (> 3% and < 15%) In Liver, Kidney, And Heart Transplant Studies

The following adverse reactions were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials.

Nervous System: Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, hemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired

Special Senses: Abnormal vision, amblyopia, ear pain, otitis media, tinnitus

Gastrointestinal: Cholangitis, cholestatic jaundice, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, esophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, stomatitis

Cardiovascular: Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation

Urogenital: Acute kidney failure, albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, 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, dehydration, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increased, weight gain

Endocrine: Cushing's syndrome

Hemic/Lymphatic: Coagulation disorder, ecchymosis, hematocrit increased, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased

Miscellaneous: Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer

Musculoskeletal: Arthralgia, cramps, generalized spasm, leg cramps, myalgia, myasthenia, osteoporosis

Respiratory: Asthma, emphysema, hiccups, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, rhinitis, sinusitis, voice alteration

Skin: Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin ulcer, sweating

Postmarketing Adverse Reactions

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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to the drug.

Other Reactions Include

Cardiovascular: 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, myocardial hypertrophy

Gastrointestinal: Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastroesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis hemorrhagic, pancreatitis necrotizing, stomach ulcer, veno-occlusive liver disease

Hemic/Lymphatic: Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, febrile neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia

Infections: Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal; polyoma virus-associated nephropathy (PVAN) including graft loss

Metabolic/Nutritional: Glycosuria, increased amylase including pancreatitis, weight decreased

Miscellaneous: Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction

Musculoskeletal and Connective Tissue Disorders: Pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS)

Nervous System: Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope

Respiratory: Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure

Skin: Stevens-Johnson syndrome, toxic epidermal necrolysis

Special Senses: Blindness, optic neuropathy, blindness cortical, hearing loss including deafness, photophobia

Urogenital: Acute renal failure, cystitis hemorrhagic, hemolytic-uremic syndrome

Mycophenolic Acid

When Prograf is prescribed with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher with Prograf co-administration than with cyclosporine co-administration with MPA, because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Monitor for MPA-associated adverse reactions and reduce the dose of concomitantly administered mycophenolic acid products as needed.

Effects Of Other Drugs On Prograf

Table 15  displays the effects of other drugs on Prograf.

Table 15: Effects of Other Drugs/Substances on Prograf*