Prograf Side Effects

Generic Name: tacrolimus

Please note - some side effects for Prograf may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Prograf - for the Consumer

Prograf

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Prograf:

Back pain; constipation; diarrhea; dizziness; headache; joint pain; loss of appetite; nausea; stomach pain or upset; trouble sleeping; vomiting.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); dark urine; decreased coordination; chest pain; diabetes (frequent urination, increased thirst or hunger); fast or irregular heartbeat; fever, chills, or sore throat; mental or mood changes (eg, anxiety, confusion) one-sided weakness; painful urination or changes in the amount of urine; red, swollen, blistered, or peeling skin; seizures; severe or persistent dizziness or headache; shortness of breath; swelling of the hands, feet, or legs; tingling or numbness in the hands or feet; tremor; trouble speaking; unusual bruising or bleeding; unusual lumps or skin lesions; unusual weakness or tiredness; vision changes; yellowing of the skin or eyes.

Prograf Capsules

All medicines cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Prograf Capsules:

Back pain; constipation; diarrhea; dizziness; headache; joint pain; loss of appetite; nausea; stomach pain or upset; trouble sleeping; vomiting.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; dark urine; decreased coordination; diabetes (frequent urination, increased thirst or hunger); fast or irregular heartbeat; fever, chills, or sore throat; mental or mood changes (eg, anxiety, confusion); one-sided weakness; painful urination or changes in the amount of urine; red, swollen, blistered, or peeling skin; seizures; severe or persistent dizziness or headache; shortness of breath; swelling of the hands, feet, or legs; tingling or numbness in the hands or feet; tremor; trouble speaking; unusual bruising or bleeding; unusual lumps or skin lesions; unusual weakness or tiredness; vision changes; yellowing of skin or eyes.

Prograf Side Effects - for the Professional

Prograf

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.

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:

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:

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:

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%), hypertriglyceridemia (65.4%), anemia (hemoglobin <10.0 g/dL) (65.4%), fasting blood glucose >140 mg/dL (on two separate occasions) (60.7%), 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.

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

Abnormal vision, amblyopia, ear pain, otitis media, tinnitus

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

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

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

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

Cushing’s syndrome, diabetes mellitus

Coagulation disorder, ecchymosis, haematocrit increased, haemoglobin abnormal, hypochromic anemia, leukocytosis, leukopenia, polycythemia, prothrombin decreased, serum iron decreased, thrombocytopenia

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

Arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis

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

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.

Other events include:

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

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

Disseminated intravascular coagulation, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura

Glycosuria, increased amylase including pancreatitis, weight decreased

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

Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, quadriplegia, speech disorder, syncope

Acute respiratory distress syndrome, lung infiltration, respiratory distress, respiratory failure

Stevens-Johnson syndrome, toxic epidermal necrolysis

Blindness, blindness cortical, hearing loss including deafness, photophobia

Acute renal failure, cystitis haemorrhagic, hemolytic-uremic syndrome, micturition disorder.

Side Effects by Body System

Respiratory

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, 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.

Renal

Nephrotoxicity has been reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving tacrolimus 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

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

Psychiatric side effects including insomnia (28% to 64%), nightmares (5% to 7%), depression, irritability, agitation, anxiety, hallucinations, abnormal dreams, and psychosis have been reported.

Immunologic

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. 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.

Hematologic

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 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.

Metabolic

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 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 post-transplant and 17.5% of cyclosporine-treated patients required insulin therapy at 3 months post-transplant.

Post-transplant 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.

Oncologic

In one study of 936 transplant patients receiving tacrolimus as primary immunosuppressive therapy, post-transplant 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 post-transplant 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

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

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

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

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.

Musculoskeletal

Acute rhabdomyolysis occurred on day 128 in an 18 month old female receiving tacrolimus 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

Other side effects of tacrolimus 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

Ocular side effects including abnormal vision and amblyopia have been reported infrequently.

Genitourinary

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

Hypersensitivity side effects including allergic reaction have been reported infrequently.

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