Applies to tacrolimus: intravenous solution, oral capsule, oral capsule extended release
Respiratory side effects have included pleural effusion (30% to 32%), atelectasis (5% to 28%), dyspnea (3% to 29%), interstitial lung disease, voice changes, asthma, bronchitis, increased cough, emphysema, hiccups, lung disorder, pneumothorax, pulmonary edema, pharyngitis, pneumonia, respiratory disorder, rhinitis, sinusitis, and voice alteration. Bronchial anastomotic dehiscence has also been reported, including fatal cases in lung transplant patients treated with a combination of tacrolimus (the active ingredient contained in Prograf) sirolimus, and corticosteroids. In addition, a case of bronchiolitis obliterans organizing pneumonia has been reported, although the role of tacrolimus in this case is not clear.
Nephrotoxicity has been reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving tacrolimus (the active ingredient contained in Prograf) in the U.S. and European randomized trials, respectively, and in 59% of heart transplantation patients in a European randomized trial. Use of tacrolimus with sirolimus in heart transplantation patients in a US study was associated with increased risk of renal function impairment, and is not recommended. More overt nephrotoxicity is seen early after transplantation, characterized by increasing serum creatinine and a decrease in urine output.
In 61 patients receiving tacrolimus for orthotopic liver transplantation, early postoperative renal insufficiency (as defined by creatinine 1.5-3.0 mg/dl occurring between post-op day 0 and 30) was observed in 43% of patients. Early acute renal failure (as defined by creatinine greater than 3.0 mg/dL) was observed in 18% of patients treated with tacrolimus. Approximately 8% of patients with acute renal failure required hemodialysis. New onset of late renal failure (as defined by creatinine greater than 3.0 mg/dl occurring between post-op day 30 to 365) was observed in 7% of patients receiving tacrolimus. The late onset renal failure seemed to occur as a result of severe infection with concomitant multi-organ failure syndrome. These data suggest that the etiology of early and late renal failure associated with tacrolimus therapy may be different.
The mechanism of tacrolimus-induced renal dysfunction is not well established. Animal data indicate that tacrolimus may cause efferent arteriolar vasoconstriction which leads to a reduction in glomerular filtration rate. Renal toxicity appears to be dose-related, although toxicity may still occur even at suggested therapeutic concentrations.
The use of a 24 hour continuous intravenous infusion as opposed to a short intravenous infusion may reduce the incidence and severity of renal toxicity.
Renal side effects have included elevations in serum creatinine (up to 39%) and blood urea nitrogen (up to 30%), and renal failure (up to 20%), sometimes requiring hemodialysis. In addition, oliguria and hematuria have been reported.
Nervous system side effects including headache (22% to 64%), tremors (24% to 56%), and paresthesias or dysesthesias (21% to 40%) have been reported. More serious nervous system effects have included posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML),
mental status changes, seizures, encephalopathy, coma, dysarthria, aphasia, akinetic mutism, and neuropathy. In addition, dizziness, fatigue, incoordination, and hypertonia have also been reported. Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, dizziness, elevated mood, emotional lability, encephalopathy, hemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuropathy, flaccid paralysis, impaired psychomotor skills, psychosis, quadriparesis, somnolence, abnormal thinking , and impaired writing have been reported less frequently.
In 61 patients receiving tacrolimus for orthotopic liver transplantation, moderate to severe CNS toxicity in the early post-op course occurred in 21% of patients. Late toxicity occurred in 13% of patients. Most patients recovered following drug withdrawal or dose reduction. However, late neurotoxicity was highly associated with severe infections and multi-organ failure. Intravenous or high levels of tacrolimus may contribute to drug-associated neurotoxicity, but this remains to be confirmed.
Leukoencephalopathy has been reported in 3 patients receiving liver or lung transplants. Headaches, nausea, vomiting and fever accompanied by generalized seizures were thought to be due to an immunosuppression related demyelinating syndrome caused by tacrolimus toxicity. Another report details a patient who was switched from tacrolimus to cyclosporine therapy but developed the same syndrome. Neurological signs and symptoms should resolve within 1 to 2 weeks after discontinuation or dose reduction of tacrolimus. The mechanism by which tacrolimus (and cyclosporine) result in CNS demyelination is unknown, but may involve binding to intracellular protein ligands and inhibition of calcineurin activity.
Psychiatric side effects including insomnia (28% to 64%), nightmares (5% to 7%), depression, irritability, agitation, anxiety, hallucinations, abnormal dreams, and psychosis have been reported.
Infectious complications result in significant morbidity and mortality in immunosuppressed patients. Some studies have found a lower incidence of infection in tacrolimus-treated patients compared to cyclosporine-treated patients, however, comparisons were usually with historical controls. Other studies have failed to find any difference in the incidence of infectious complications.
Cytomegalovirus is the most frequently encountered viral pathogen in patients treated with tacrolimus (the active ingredient contained in Prograf) Patients who receive CMV-positive grafts are at increased risk of invasive CMV infection.
Bacterial infections, primarily gram-positive and gram-negative aerobes, and fungal infections are also encountered.
Immunologic side effects have included infectious complications as a result of immunosuppression.
In one patient who developed severe anemia, a bone marrow biopsy revealed selective hypoplasia of erythropoiesis. Erythropoietin levels were normal. The anemia resolved following infusions of erythrocyte concentrates and discontinuation of tacrolimus (the active ingredient contained in Prograf) The authors of this case report suggested a direct toxic effect of tacrolimus on the bone marrow.
Immune-mediated mechanisms have been suggested in other forms of tacrolimus-induced blood dyscrasias, such as hemolytic anemias and thrombocytopenia.
Hematologic side effects including anemia, leukocytosis, thrombocytopenia, ecchymoses, thrombotic thrombocytopenia purpura, coagulation disorder, ecchymosis, hematocrit increased, hemoglobin abnormal, hypochromic anemia, leukocytosis, leukopenia, polycythemia, prothrombin decreased, serum iron decreased, hemolytic anemia, and hemolytic uremic syndrome have been reported. Postmarketing adverse event reports have included agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, pancytopenia, pure red cell aplasia, thrombocytopenic purpura, and thrombotic thrombocytopenic purpura.
Hyperkalemia may be severe. In some patients, potassium-restricted diets, potassium binding resins, and/or mineralocorticoids may be required to control the hyperkalemia. Potassium-sparing diuretics should be avoided.
The mechanism by which tacrolimus (the active ingredient contained in Prograf) produces hyperglycemia is not known. However, tacrolimus is concentrated in the pancreas and it may inhibit pancreatic insulin secretion.
Insulin therapy is only temporarily required in some patients, while long-term use is necessary in others. In one study of 52 liver transplants in 46 patients, 7 patients (13.6%) who were not diabetic prior to transplantation required insulin therapy after transplantation. Three of these patients required insulin for three months. Two remained normoglycemic after discontinuing insulin while the other was controlled on an oral hypoglycemic.
In another study of 81 liver transplant recipients, 17% of tacrolimus-treated patients required insulin therapy at 3 months posttransplant and 17.5% of cyclosporine-treated patients required insulin therapy at 3 months posttransplant.
Posttransplant diabetes mellitus has been reported in a greater percentage of tacrolimus-treated versus cyclosporine-treated kidney transplant patients (20% versus 4%, respectively). Insulin dependence was reversible in 15% of tacrolimus patients at one year and in 50% at two years. A similar warning should be noted for liver transplant patients.
Hypomagnesemia in renal transplant recipients results from renal magnesium wasting.
Metabolic side effects have included hyperglycemia (29% to 47%), sometimes requiring insulin therapy, hyperkalemia (10% to 46%), hypokalemia (11% to 29%), hypomagnesemia (15% to 48%), hyperlipidemia, acidosis, alkalosis, hyperphosphatemia, hypocalcemia, hypophosphatemia, hyponatremia, and hypoproteinemia.
In one study of 936 transplant patients receiving tacrolimus (the active ingredient contained in Prograf) as primary immunosuppressive therapy, posttransplant lymphoproliferative disease (PTLD) occurred in 15 (1.6%) patients. Serologic evidence of Epstein-Barr virus infections was found in all 15 patients. The median time between transplant and diagnosis of PTLD was 4.4 months. Disseminated PTLD was associated with a poor prognosis.
Oncologic side effects, or the development of new malignancies, are of particular concern in posttransplant patients. Lymphoproliferative disorders are most commonly encountered. Lymphadenopathy and monoclonal and polyclonal B cell hyperplasia as well as malignant, often fatal, B cell lymphomas have been reported.
Cardiovascular side effects have included hypertension (31% to 62%) and peripheral edema (10% to 26%) as well as chest pain, pericardial effusion, hypotension, ECG abnormalities, tachycardia, Torsades de pointes, QT prolongation, myocardial hypertrophy, and hypertrophic cardiomyopathy. Angina pectoris, cardiac fibrillation, cardiopulmonary failure, chest pain, deep thrombophlebitis, abnormal ECG, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart rate decreased, hemorrhage, hypotension, postural hypotension, peripheral vascular disorder, phlebitis, tachycardia, thrombosis, and vasodilatation have been reported less frequently. One case of bradycardia has been reported.
Tacrolimus-induced hypertension, while typically mild to moderate, may be severe in some patients. Treatment with antihypertensive agents may be necessary. However, potassium-sparing diuretics should be avoided due to the potential for tacrolimus to cause hyperkalemia.
Gastrointestinal side effects have included diarrhea, nausea, vomiting, and constipation. Anorexia, cholangitis, duodenitis, dyspepsia, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, jaundice, GI perforation, ileus, increased appetite, ulcerative esophagitis, oral moniliasis, pancreatic pseudocyst, rectal disorder, and stomatitis have been reported less frequently.
Hepatic side effects have included elevations in liver function tests in up to 36% of patients. More serious hepatotoxicity, including jaundice, cholestatic jaundice, granulomatous hepatitis, hepatitis, have been uncommon.
Dermatologic effects such as pruritus (11% to 36%), rash (8% to 24%), alopecia, hirsutism, photosensitivity, and sweating have been reported. A case of eyelash trichomegaly has also been reported.
Acute rhabdomyolysis occurred on day 128 in an 18 month old female receiving tacrolimus (the active ingredient contained in Prograf) for bone marrow transplantation prophylaxis and control of graft-versus-host-disease. Tacrolimus blood trough levels were elevated at 30 to 60 ng/mL (normal 10-20 ng/mL) for a 3 week period. The patient died on day 130 due to acute renal failure due to severe acute rhabdomyolysis.
Musculoskeletal side effects have been uncommon. Rhabdomyolysis, arthralgia, myalgia, generalized spasm, leg cramps, myasthenia, and osteoporosis have been reported.
Other side effects of tacrolimus (the active ingredient contained in Prograf) therapy have included pain, fever, asthenia, enlarged abdomen, abscess, accidental injury, cellulitis, chills, fall, feeling abnormal, flu syndrome, generalized edema, hernia, decreased mobility, peritonitis, sepsis, temperature intolerance, ulcer, ear pain, otitis media, and tinnitus.
Ocular side effects including abnormal vision and amblyopia have been reported infrequently.
Genitourinary side effects including 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, BK nephropathy, and vaginitis have been reported infrequently.
Hypersensitivity side effects including allergic reaction have been reported infrequently.