Side effects of tacrolimus

PMC

Discussion

Tacrolimus allograft nephrotoxicity is widely recognized, but to our knowledge, only one study has attempted to estimate its incidence in kidney transplant recipients (6). That investigation based the diagnosis of nephrotoxicity on the clinical course of the patient and graft biopsy, but the actual criteria used were not explicitly stated. It was found that renal toxicity was dependent on the dosing regimen and prior clinical experience with the drug. Thus, this study recorded a 44% incidence of nephrotoxicity when tacrolimus was administered at a dose of 0.3 mg/kg/d. Subsequently, with additional experience in the use of the tacrolimus a reduction in incidence to 20.5% was observed (6).

In the present study, we have observed a 17% incidence of nephrotoxicity in renal transplant biosies. The actual incidence of nephrotoxicity is probably higher, since tacrolimus dosage reduction is at times performed without a biopsy. The initial maintainence dose of tacrolimus in our patients was 0.15 mg/kg twice daily. The ultimate maintainence dose, which was fine tuned by serial determinations of plasma or whole-blood levels of tacrolimus, varied in different patients. It is important to stress that the incidence of nephrotoxicity reported here refers to the use of tacrolimus as a primary immunosuppressant after renal transplantation. In patients receiving intravenous tacrolimus as “rescue” therapy for refractory renal or hepatic allograft rejection, initial nephrotoxicity is seen in nearly all patients (19–21). The definition of nephrotoxicity used in this study required a fall in creatinine in response to reduction in the maintainence dose of tacrolimus. Hence, only reversible episodes of tacrolimus nephrotoxicity were identified. Other investigators have described patients with apparently persistent nephrotoxicity (6, 10). However, it is not always clear whether the clinically non-responsive cases sustained additional adverse effects such as dehydration, acute tubular necrosis, drug reactions or transplant glomerulopathy to explain the persistent graft dysfunction. Progressive drug induced renal dysfunction may occur in patients receiving continuous tacrolimus immunosuppression, since the nephrotoxic and antirejection actions of this drug are mechanistically related (22). However, recognition and distinction of such insidiously developing toxicity from chronic rejection is difficult on clinical grounds. Chronic tacrolimus nephrotoxicity could be better studied in liver transplant recipients without the confounding influence of chronic rejection. However, these patients are predisposed to renal dysfunction caused by sepsis, hypotension, hepato-renal syndrome, and glomerulopathy associated with liver disease, all of which would need to be distinguished from tacrolimus nephrotoxicity. Studies of chronic tacrolimus toxicity in heart and lung transplant recipients should likewise control for elevations in serum creatinine due to nephrotoxic antibiotics and congestive heart failure existing at the time of transplantation or developing subsequently.

Nephrotoxicity episodes were associated with elevated plasma or whole-blood in tacrolimus levels in 18/22 patients. In other investigations, good correlation between blood tacrolimus levels and graft dysfunction have been observed by some authors (23, 24), but not by others (11, 25). The percent dose reduction necessary to restore allograft function varied, reflecting the known variability of tacrolimus pharmacokinetics in individual patients (26). Drug interactions appeared to modify further the disposition of tacrolimus in three cases. Thus, case 8, which required the greatest dose reduction (89%), was receiving itraconazole, a drug known to compete with tacrolimus for metabolism by the hepatic microsmal cytochrome P450 system (27). Inhibition of tacrolimus detoxification by itraconazole would explain why this patient required such a drastic reduction in dose, and showed a lag period of 14 d before reversal of nephrotoxicity could be observed clinically. Diltiazem, another drug biotransformed by the liver microsomes (28), was used in patient # 10, who required a 66% dose reduction in tacrolimus. An extremely high level of whole-blood tacrolimus (50.5 ng/ml) was recorded in case 5, who received clarithromycin, a macrolide antibiotic structurally related to both erythromycin and tacrolimus. Interactions between clarithromycin and tacrolimus have not been previously observed to the best of our knowledge, but erythromycin is known to inhibit competitively the metabolism of tacrolimus by the cytochrome P-450 system. We have previously reported a kidney transplant recipient in whom the plasma Tacrolimus level increased from 1.3 to 8.5 ng/ml within 4 d of starting erythromycin (29).

The reported incidence of hyperkalemia in Tacrolimus treated kidney transplant patients varies from 27 to 67% (6, 10, 19, 30–32). Its specific incidence in patients with nephrotoxicity is not mentioned in these studies. In the current study, one or more values of elevated serum potassium occurred in 9/22 (41 %) cases with renal dysfunction. Hyperkalemia as an isolated finding without other evidence of impaired kidney function has been described in 9% of patients (31). The mechanisms responsible for hyperkalemia are not well understood, but an effect of tacrolimus on mineralocorticoid secretion and altered mineralocorticoid activity at the renal tubules have been proposed. Clinically, hyperkalemia induced by Tacrolimus usually responds readily to dietary restriction, potassium binding resins and fludrocortisone.

Altered glucose metabolism is another recognized toxicity of Tacrolimus. Changes in the peripheral sensitivity to insulin and/or response of islet cells to blood glucose lead to hyperglycemia in 25–35% of transplanted subjects (24, 30). Post-transplant diabetes mellitus defined as persistently high blood sugar with an abnormal glucose tolerance test is seen in 4–22% of patients (2, 30, 33, 34). Evaluation of this side effect was difficult in 11 of our cases with known insulin-dependent diabetes mellitus, since by definition these subjects were hyperglycemic even before they received Tacrolimus. Considering only patients transplanted for diseases other than diabetes, 4/11 patients with Tacrolimus nephrotoxicity had hyperglycemia defined as blood glucose exceeding 7.7 mmol/l (140 mg/dl) on at least three occasions (35). Intravenous methylprednisolone had been administered empirically to one patient while the result of an allograft needle biopsy was pending. The remaining 3 patients were on stable maintenance doses of steroids, and the hyperglycemia was likely a manifestation of Tacrolimus toxicity.

In summary, this study has shown that reversible Tacrolimus nephrotoxicity accounts for 17% of renal allograft dysfunction episodes investigated by needle biopsy. The diagnosis of Tacrolimus nephrotoxicity was based on rigorous criteria, namely a rise in serum creatinine requiring biopsy, absence of histopathologic changes of acute rejection, and clinical response to reduction in the dose of Tacrolimus. It was noted that Tacrolimus toxicity could occur both early and late post-transplant. Plasma or whole-blood Tacrolimus levels were typically high at the time of clinical diagnosis, and the peak Tacrolimus level preceded the peak in serum creatinine. A reduction in dosage led to an improved serum creatinine within 1–14 d. Hyperkalemia and hyperglycemia were noted in several cases during the episodes of nephrotoxicity.

Prograf

SIDE EFFECTS

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 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)

PROGRAF/MMF
(N = 212)
Cyclosporine/MMF
(N = 212)
Gastrointestinal Disorders
Diarrhea 44% 26%
Nausea 39% 47%
Constipation 36% 41%
Vomiting 26% 25%
Dyspepsia 18% 15%
Injury, Poisoning, and Procedural Complications
Post-Procedural Pain 29% 27%
Incision Site Complication 28% 23%
Graft Dysfunction 24% 18%
Metabolism and Nutrition Disorders
Hypomagnesemia 28% 22%
Hypophosphatemia 28% 21%
Hyperkalemia 26% 19%
Hyperglycemia 21% 15%
Hyperlipidemia 18% 25%
Hypokalemia 16% 18%
Nervous System Disorders
Tremor 34% 20%
Headache 24% 25%
Blood and Lymphatic System Disorders
Anemia 30% 28%
Leukopenia 16% 12%
Miscellaneous
Edema Peripheral 35% 46%
Hypertension 32% 35%
Insomnia 30% 21%
Urinary Tract Infection 26% 22%
Blood Creatinine Increased 23% 23%

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

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)

PROGRAF Granules
(N = 91)
Cyclosporine
(N = 90)
Body as a Whole
Fever 46% 51%
Infection 25% 29%
Sepsis 22% 20%
CMV Infection 15% 24%
EBV Infection 26% 11%
Ascites 17% 20%
Peritonitis 12% 7%
Cardiovascular System
Hypertension 39% 47%
Digestive System
Liver Function Tests Abnormal 37% 28%
Diarrhea 26% 26%
Vomiting 15% 13%
Gastrointestinal Hemorrhage 11% 12%
Bile Duct Disorder 12% 8%
Gastroenteritis 12% 4%
Hemic and Lymphatic System
Anemia 29% 19%
Metabolic and Nutritional Disorders
Hypomagnesemia 40% 29%
Acidosis 26% 17%
Hyperkalemia 12% 10%
Respiratory System
Pleural Effusion 22% 19%
Bronchitis 11% 8%
Urogenital System
Kidney Function Abnormal 13% 14%

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)

PROGRAF/AZA
(N = 157)
Cyclosporine/AZA
(N = 157)
Cardiovascular System
Hypertension 62% 69%
Pericardial Effusion 15% 14%
Body as a Whole
CMV Infection 32% 30%
Infection 24% 21%
Metabolic and Nutritional Disorders
Diabetes Mellitus 26% 16%
Hyperglycemia 23% 17%
Hyperlipemia 18% 27%
Hemic and Lymphatic System
Anemia 50% 36%
Leukopenia 48% 39%
Urogenital System
Kidney Function Abnormal 56% 57%
Urinary Tract Infection 16% 12%
Respiratory System
Bronchitis 17% 18%
Nervous System
Tremor 15% 6%

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%).

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

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

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

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

Read the entire FDA prescribing information for Prograf (Tacrolimus)

Prograf Side Effects

Generic Name: tacrolimus

Medically reviewed by Drugs.com. Last updated on Nov 26, 2018.

  • Overview
  • Side Effects
  • Dosage
  • Professional
  • Interactions
  • More

Note: This document contains side effect information about tacrolimus. Some of the dosage forms listed on this page may not apply to the brand name Prograf.

In Summary

Common side effects of Prograf include: opportunistic infection, diabetes mellitus, infection, headache, hyperglycemia, hyperkalemia, increased blood urea nitrogen, increased serum creatinine, mental status changes, nephrotoxicity, sensation disorder, and tremor. See below for a comprehensive list of adverse effects.

For the Consumer

Applies to tacrolimus: oral capsule, oral capsule extended release, oral tablet extended release

Other dosage forms:

  • intravenous solution

Warning

Oral route (Capsule, Extended Release; Capsule; Granule)

Increased risk for developing serious infections and malignancies with tacrolimus extended-release or other immunosuppressants that may lead to hospitalization or death. Increased mortality in female liver transplant patients with tacrolimus extended-release; not approved for use in liver transplantation.Increased risk for developing serious infections and malignancies with tacrolimus oral capsules, oral granules, or other immunosuppressants that may lead to hospitalization or death.

Oral route (Tablet, Extended Release)

Increased risk for developing serious infections and malignancies with tacrolimus extended-release tablets or other immunosuppressants that may lead to hospitalization or death.

Along with its needed effects, tacrolimus (the active ingredient contained in Prograf) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking tacrolimus:

More common

  • Abnormal dreams
  • agitation
  • chills
  • confusion
  • cough
  • diarrhea
  • dizziness
  • fever
  • frequent urination
  • general feeling of discomfort or illness
  • headache
  • itching, skin rash
  • joint pain
  • loss of appetite
  • loss of energy or weakness
  • mental depression
  • muscle aches and pains
  • muscle trembling or twitching
  • nausea
  • pale skin
  • runny nose
  • seeing or hearing things that are not there
  • seizures
  • shivering
  • skin rash
  • sore throat
  • stomach pain
  • swelling of the feet or lower legs
  • tingling
  • trembling and shaking of the hands
  • trouble sleeping
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • vomiting

Less common

  • Blurred vision
  • chest pain
  • increased sensitivity to pain
  • muscle cramps
  • numbness or pain in the legs
  • ringing in the ears
  • sweating

Rare

  • Enlarged heart
  • flushing of the face or neck
  • weight loss

Incidence not known

  • Black, tarry stools
  • blistering, peeling, loosening of the skin
  • bloating
  • bloody urine
  • constipation
  • drowsiness
  • fainting
  • fast, slow, or irregular heartbeat
  • heartburn
  • increased thirst
  • indigestion
  • joint pain
  • lightheadedness
  • lower back or side pain
  • pinpoint red spots on the skin
  • pounding or rapid pulse
  • red skin lesions, often with a purple center
  • red, irritated eyes
  • skin sores
  • ulcers or white spots in the mouth or on the lips
  • weakness
  • weight gain
  • yellow eyes or skin

Some side effects of tacrolimus may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

  • Belching
  • difficulty with moving
  • lack or loss of strength
  • muscle stiffness

Less common

  • Body aches or pain
  • burning or stinging of the skin
  • cracks in the skin
  • crying
  • depersonalization
  • dysphoria
  • excessive muscle tone
  • false beliefs that cannot be changed by facts
  • false or unusual sense of well-being
  • feeling of constant movement of self or surroundings
  • feeling that others are watching you or controlling your behavior
  • feeling that others can hear your thoughts
  • increased sensitivity of the skin to sunlight
  • large, flat, blue or purplish patches in the skin
  • muscle tension or tightness
  • painful blisters on the trunk of the body
  • painful cold sores or blisters on the lips, nose, eyes, or genitals
  • paranoia
  • poor insight and judgment
  • problems with memory or speech
  • quick to react or overreact emotionally
  • rapidly changing moods
  • redness or other discoloration of the skin
  • restlessness
  • scaly skin
  • sensation of spinning
  • severe mood or mental changes
  • severe sunburn
  • sleepiness or unusual drowsiness
  • sore mouth or tongue
  • sores on the skin
  • swelling or inflammation of the mouth
  • tender, swollen glands in the neck
  • trouble recognizing objects
  • trouble thinking and planning
  • trouble walking
  • unusual behavior
  • white patches in the mouth, tongue, or throat

Incidence not known

  • Change in color vision
  • decreased weight
  • difficulty seeing at night
  • feeling hot and cold
  • hearing loss

For Healthcare Professionals

Applies to tacrolimus: intravenous solution, oral capsule, oral capsule extended release, oral granule for reconstitution, oral tablet extended release

General

Some of the most commonly reported side effects include hypertension, diarrhea, hyperglycemia, anemia, headache, tremor, insomnia, pain, and asthenia.

Cardiovascular

Very common (10% or more): Hypertension (89%), peripheral edema (36%), chest pain (19%), pericardial effusion (15%)

Frequency not reported: Angina pectoris, bradycardia, cardiac fibrillation, cardiomyopathy, cardiopulmonary failure, deep thrombophlebitis, ECG abnormalities, echocardiogram abnormalities, heart rate decreased, hemorrhage, hypotension, myocardial hypertrophy, peripheral vascular disorder, phlebitis, tachycardia, thrombosis, vasodilation

Postmarketing reports: Cardiac arrest, myocardial infarction, ventricular fibrillation, congestive cardiac failure, pericardial effusion, supraventricular extrasystoles, supraventricular tachycardia, bradycardia, Torsade de Pointes, QT prolongation

Gastrointestinal

Very common (10% or more): Diarrhea (72%), nausea (46%), constipation (36%), vomiting (29%), dyspepsia (28%)

Frequency not reported: Abdomen enlarged, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, GI hemorrhage, GI perforation, ileus, oral moniliasis, pancreatic pseudocyst, peritonitis, rectal disorder, stomatitis, ulcerative esophagitis, ulcer

Metabolic

Frequency not reported: Abnormal healing, acidosis, alkalosis, appetite increased, bicarbonate decreased, dehydration, gout, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increased, weight gain

Hematologic

Very common (10% or more): Anemia (65%), leukopenia (48%), leukocytosis (32%), thrombocytopenia (24%)

Frequency not reported: Coagulation disorder, ecchymosis, hematocrit increased, hemoglobin abnormal, hypochromic anemia, polycythemia, prothrombin decreased, serum iron decreased

Postmarketing reports: Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, hemolytic-uremic syndrome, neutropenia, pancytopenia, pure red cell aplasia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura

Nervous system

Very common (10% or more): Headache (64%), tremor (56%), paresthesia (40%), dizziness (19%), fatigue (16%)

Frequency not reported: Amnesia, aphasia, convulsion, encephalopathy, hemorrhagic stroke, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, psychomotor skills impaired, quadriparesis, seizures, somnolence, vertigo, writing impaired

Postmarketing reports: Coma, dysarthria, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), status epilepticus, quadriplegia, flaccid paralysis, hemiparesis, aphasia, syncope, carpal tunnel syndrome, nerve compression, mutism, dysarthria

Psychiatric

Very common (10% or more): Insomnia (64%)

Frequency not reported: Abnormal dreams, agitation, anxiety, confusion, crying, depression, emotional lability, hallucinations, mental status changes, mood elevated, nightmares, psychosis, thinking abnormal

Postmarketing reports: Mutism

Other

Very common (10% or more): Pain (63%), asthenia (54%), fever (48%)

Frequency not reported: Abscess, accidental injury, chills, ear pain, fall, feeling abnormal, generalized edema, hernia, otitis media, sepsis, temperature intolerance, tinnitus

Renal

Very common (10% or more): Serum creatinine increased (45%), BUN increased (30%)

Frequency not reported: BK nephropathy, hydronephrosis, renal failure, toxic nephropathy, tubular necrosis

Respiratory

Very common (10% or more): Pleural effusion (36%), dyspnea (29%), atelectasis (28%), cough increased (18%), bronchitis (17%)

Frequency not reported: Asthma, emphysema, hiccups, lung disorder, pharyngitis, pneumonia, pneumothorax, pulmonary edema, rhinitis, sinusitis, voice changes

Postmarketing reports: Interstitial lung disease, pulmonary hypertension, lung infiltration, hiccups

Hepatic

Very common (10% or more): Liver function tests abnormal (36%)

Frequency not reported: Cholangitis, cholestatic jaundice, GGT increased, granulomatous hepatitis, hepatitis, jaundice

Dermatologic

Very common (10% or more): Pruritus (36%), rash (24%)

Frequency not reported: Alopecia, cellulitis, hirsutism, photosensitivity, sweating

Postmarketing reports: Hyperpigmentation

Genitourinary

Very common (10% or more): Urinary tract infection (34%), oliguria (19%)

Frequency not reported: Albuminuria, bladder spasm, cystitis, dysuria, hematuria, nocturia, pyuria, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis, hemorrhagic cystitis, urinary retention

Immunologic

Very common (10% or more): Cytomegalovirus infection (12%)

Frequency not reported: Flu syndrome, graft versus host disease (acute and chronic)

Oncologic

Postmarketing reports: Epstein-Barr virus associated lymphoproliferative disorder, hepatosplenic T-cell lymphoma, leukemia, lymphoma, melanoma, post-transplant lymphoproliferative disorder (PTLD)

Musculoskeletal

Frequency not reported: Arthralgia, generalized spasm, joint disorder, leg cramps, mobility decreased, myasthenia, myalgia, osteoporosis

Postmarketing reports: Rhabdomyolysis, polyarthritis, pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS)

Hypersensitivity

Frequency not reported: Hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Ocular

Frequency not reported: Abnormal vision, amblyopia, blindness, optic atrophy, photophobia

1. Cerner Multum, Inc. “Australian Product Information.” O 0

2. Cerner Multum, Inc. “UK Summary of Product Characteristics.” O 0

3. “Product Information. Prograf (tacrolimus).” Fujisawa, Deerfield, IL.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Some side effects may not be reported. You may report them to the FDA.

Medical Disclaimer

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Other brands: Envarsus XR, Astagraf XL, Hecoria

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Related treatment guides

  • Organ Transplant, Rejection Prophylaxis
  • Organ Transplant, Rejection Reversal

Tacrolimus

Tacrolimus is the generic version of the brand name drug Prograf, which is used along with other medicines to prevent organ rejection in people who’ve had a kidney, liver, or heart transplant.

The drug is also sometimes used to treat Crohn’s disease (a condition where the body attacks the lining of the digestive tract).

Prograf (tacrolimus) is an immunosuppressant. It works by blocking the action of certain blood cells that can prompt the body to reject a transplanted organ.

The Food and Drug Administration (FDA) approved tacrolimus in 1994. Prograf is manufactured by Astellas Pharma US.

Tacrolimus Warnings

Tacrolimus contains a black-box warning because it may increase your risk of infection and your chances of developing skin cancer or lymphoma.

Tell your doctor right away if you notice any of the following symptoms while taking tacrolimus:

  • Signs of infection, which may include fever, chills, or sore throat
  • Unusual growths or lumps
  • Any changes in the appearance or size of a mole
  • Night sweats
  • Unusual tiredness or weakness
  • Swollen lymph nodes in the neck, armpits, or groin
  • Weight loss
  • Trouble breathing
  • Chest pain
  • Cough
  • Pain, swelling, or fullness in the stomach area

To lower your risk of skin cancer, avoid tanning beds and unnecessary exposure to sunlight while taking this drug. Wear protective clothing and sunscreen if you must be outdoors.

This medicine should only be given under the supervision of a physician who is experienced in treating organ transplant patients and administering drugs that decrease the activity of the immune system.

Before taking tacrolimus, tell your doctor if you have or have had:

  • Kidney disease
  • Heart disease
  • Pure red blood cell aplasia (a type of anemia)
  • Long QT syndrome (a heart rhythm disorder)
  • Liver disease
  • A history of infections
  • High blood pressure
  • Diabetes
  • High levels of potassium in the blood
  • A weakened immune system
  • Skin cancer or a family history of skin cancer
  • Allergies to medications

Be sure to tell your physician about all the drugs you take. Some medications may increase your chances of developing QT prolongation (a type of irregular heartbeat).

Also, tell your healthcare provider if you take or if you’ve recently stopped taking the drug Gengraf, Neoral or Sandimmune (cyclosporine).

Your physician will probably tell you not to start tacrolimus until 24 hours after your last dose of cyclosporine.

Tacrolimus may cause high blood pressure. Your doctor will need to monitor your blood pressure carefully during your treatment.

The medicine may also increase your chances of developing diabetes during treatment. Hispanics and African Americans who’ve had kidney transplants are at an especially high risk.

Tell your physician if you or anyone in your family has ever had diabetes, and tell your doctor immediately if you experience any of the following symptoms:

  • Excessive thirst or hunger
  • Frequent urination
  • Blurred vision
  • Confusion

Let your healthcare provider know you’re taking this medicine before having any type of surgery, including a dental procedure.

Don’t receive any vaccination while taking tacrolimus without first talking to your doctor.

Continue to take tacrolimus even if you feel well. Don’t stop using this medicine without first talking to your doctor.

Keep all appointments with your healthcare provider while taking this drug. Your doctor will want to frequently monitor your body’s response to the therapy.

Pregnancy and Tacrolimus

Tacrolimus may cause harm to an unborn baby.

Tell your doctor if you’re pregnant or might become pregnant before taking this medicine.

The drug can be found in breast milk. Don’t breastfeed a baby while taking tacrolimus.

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