Tacrolimus Adverse Reactions
- abdominal pain
- acne vulgaris
- acneiform rash
- acute respiratory distress syndrome (ARDS)
- agitation
- alopecia
- amblyopia
- amnesia
- anaphylactoid reactions
- anemia
- angina
- anorexia
- anxiety
- azotemia
- back pain
- bladder spasm
- blurred vision
- bradycardia
- bullous rash
- candidiasis
- cardiomyopathy
- chest pain (unspecified)
- cholangitis
- coagulopathy
- coma
- confusion
- constipation
- cough
- cystitis
- delirium
- depression
- diabetes mellitus
- diaphoresis
- diarrhea
- dizziness
- drowsiness
- dysarthria
- dyspepsia
- dysphagia
- dysuria
- ecchymosis
- edema
- elevated hepatic enzymes
- emotional lability
- encephalopathy
- erythema
- esophagitis
- exfoliative dermatitis
- flushing
- folliculitis
- GI bleeding
- GI perforation
- hallucinations
- headache
- hematuria
- hemolytic anemia
- hemolytic-uremic syndrome
- hepatitis
- hiccups
- hirsutism
- hyperbilirubinemia
- hypercalcemia
- hypercholesterolemia
- hyperesthesia
- hyperglycemia
- hyperkalemia
- hyperlipidemia
- hyperphosphatemia
- hypertension
- hypertonia
- hyperuricemia
- hypocalcemia
- hypoglycemia
- hypokalemia
- hypomagnesemia
- hyponatremia
- hypophosphatemia
- hypotension
- ileus
- infection
- insomnia
- jaundice
- leukocytosis
- leukoencephalopathy
- leukopenia
- lymphadenopathy
- metabolic acidosis
- metabolic alkalosis
- myoclonia
- nausea/vomiting
- neutropenia
- nocturia
- oliguria
- otalgia
- pancreatitis
- pancytopenia
- paresis
- paresthesias
- peripheral edema
- pharyngitis
- phlebitis
- photophobia
- photosensitivity
- pneumothorax
- polycythemia
- pruritus
- psychosis
- pulmonary edema
- pyuria
- QT prolongation
- rash (unspecified)
- renal failure (unspecified)
- renal tubular necrosis
- respiratory arrest
- rhinitis
- secondary malignancy
- seizures
- sinus tachycardia
- sinusitis
- skin discoloration
- skin irritation
- skin ulcer
- Stevens-Johnson syndrome
- stomatitis
- stroke
- thrombocytopenia
- thrombosis
- thrombotic thrombocytopenic purpura (TTP)
- tinnitus
- torsade de pointes
- toxic epidermal necrolysis
- tremor
- urinary incontinence
- urinary retention
- urinary urgency
- vaginitis
- visual impairment
- weight gain
Tacrolimus Adverse Reactions
Nephrotoxicity was reported in approximately 52% of kidney transplant patients and in 40% and 36% of liver transplant patients in the U.S. and European clinical trials, respectively, who received tacrolimus. Tacrolimus-induced nephrotoxicity manifests as creatinine increase, BUN increase (azotemia), interstitial fibrosis, and oliguria. Renal failure (unspecified) may be seen early after transplantation and is characterized by an increase in serum creatinine and a decrease in urine output. Nephrotoxic effects may be mediated by the inhibitory effect of tacrolimus on calcineurin, which regulates cellular calcium channels. In patients with persistent elevations of serum creatinine who are unresponsive to tacrolimus dosage adjustments, consideration should be given to changing from tacrolimus to another immunosuppressive agent. Other urogenital adverse reactions occurring in < 15% of tacrolimus-treated patients include albuminuria, cystitis, dysuria, hematuria, hydronephrosis, nocturia, pyuria, renal tubular necrosis, bladder spasm, toxic nephropathy, urinary urgency (urge incontinence), urinary retention, vaginitis, urinary frequency, and urinary incontinence. Echocardiographic evaluation and reduction or discontinuation of tacrolimus should be considered in patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus.
Mild to severe hyperkalemia was reported in 31% of kidney transplant patients and in 45% and 13% of liver transplant patients in the U.S. and European trials, respectively, who received tacrolimus. Other abnormalities reported during tacrolimus therapy include hypercalcemia, hyperphosphatemia, hyperuricemia, hypocalcemia, hyponatremia, hypokalemia, hypomagnesemia, hypophosphatemia, metabolic acidosis, and metabolic alkalosis. Treatment of electrolyte abnormalities may be required. Serum electrolytes should be monitored during tacrolimus therapy.
Neurotoxicity including headache (64%), insomnia (64%), tremor (56%), paresthesias (40%), and dizziness (19%) is commonly associated with tacrolimus therapy. Approximately 55% of liver transplant patients experienced neurotoxicity and other changes in motor function, mental status, and sensory function during clinical trials. Tremor occurred more often in tacrolimus-treated kidney transplant patients than those treated with cyclosporine. Tremor and headache have been associated with high whole blood concentrations of tacrolimus; tremor and headache may respond to a reduction in dose. Seizures have occurred in adult and pediatric patients receiving tacrolimus. Coma and delirium have also been associated with high concentrations of tacrolimus. Leukoencephalopathy with symptoms of altered mental status, seizures, headaches, and visual impairment (abnormalities) has been reported in adults and children. Other neurotoxic adverse effects occurring in < 15% of tacrolimus-treated patients include abnormal dreams, agitation, amnesia, anxiety, blurred vision, confusion, depression, dysarthria (slurred speech), emotional lability, encephalopathy, hallucinations, crying, elevated mood, hemorrhagic stroke, paresis, nerve compression, neuropathy, flaccid paralysis, impaired psychomotor skills, quadriparesis, abnormal thinking, writing impaired, amblyopia, otalgia, otitis media, hypertonia, incoordination, myoclonia, photophobia, psychosis, tinnitus, and drowsiness.
Hypertension occurs in about 50% of patients receiving tacrolimus. Mild or moderate hypertension is more common than severe hypertension. Antihypertensive therapy may be required. Chest pain (unspecified) has been reported in 19% of kidney transplant patients. Other cardiovascular events occurring in < 15% of tacrolimus-treated patients include angina pectoris, deep thrombophlebitis, abnormal ECG, cardiac fibrillation, cardiopulmonary failure, sinus bradycardia, vasodilation, hemorrhage, hypotension, peripheral edema, peripheral vascular disorder, phlebitis, sinus tachycardia, and thrombosis. Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, flushing, myocardial infarction, myocardial ischemia, pericardial effusion, deep venous thrombosis, ventricular extrasystoles, and ventricular fibrillation have been noted during the post-marketing surveillance period, but a reliable estimate of the frequency or establishment of a causal relationship to tacrolimus cannot be done because these reactions are reported voluntarily. Also, a few case reports of QT prolongation and torsade de pointes have been reported during therapy with tacrolimus. Further, rare cases of myocardial hypertrophy (i.e., cardiomyopathy) associated with clinically manifested ventricular dysfunction have been reported in patients receiving tacrolimus. Myocardial hypertrophy (i.e., cardiomyopathy) is usually manifested as concentric increases in the left ventricular posterior wall and interventricular septum thickness. Hypertrophy has been reported in infants, children, and adults receiving tacrolimus. Of 20 infants, children, and adults with evidence of myocardial hypertrophy and pre- and post-treatment echocardiograms, the mean tacrolimus whole blood concentrations during the period prior to diagnosis of myocardial hypertrophy ranged from 11 to 53 ng/ml in infants, 4 to 46 ng/ml in children, and 11 to 24 ng/ml in adults. Myocardial hypertrophy appears to be reversible in most cases following dose reduction or therapy discontinuance. Echocardiographic evaluation and reduction or discontinuation of tacrolimus should be considered in patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus.
Hyperglycemia was reported in 47% and 33% of liver transplant patients in the U.S. and European trials, respectively, and may require treatment. Insulin-dependent post-transplant diabetes mellitus was reported in 20% of tacrolimus-treated renal transplant patients. The median time to onset was 68 days and was reversible in 15% of these patients at one year and in 50% at two years post transplant. Black and Hispanic renal transplant patients were at an increased risk of development of post-transplant diabetes mellitus. The risk of development of post-transplant diabetes mellitus increased with increasing whole blood trough concentrations of tacrolimus and increasing doses of corticosteroids. Insulin-dependent post-transplant diabetes mellitus was reported in 18% and 11% of tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at one year post transplant, in U.S. and European studies, respectively.
Gastrointestinal adverse reactions commonly reported during tacrolimus therapy include abdominal pain (33 - 59%), anorexia (34%), constipation (24 - 35%), diarrhea (44 - 72%), dyspepsia (28%), elevated hepatic enzymes (36%), and nausea/vomiting (38 - 46%/27 - 29%). Other GI adverse reactions occurring in < 15% of patients treated with tacrolimus include cholangitis, cholestatic jaundice, dysphagia, duodenitis, esophagitis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, increased appetite, liver damage, ulcerative esophagitis, oral moniliasis, pancreatic pseudocyst, flatulence, gastritis, GI bleeding, GI perforation, hepatitis, hypercholesterolemia, hyperbilirubinemia, hyperlipidemia, hypoglycemia, ileus, stomatitis, and weight gain. During the post-marketing surveillance period, bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastroesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, fatty liver, mouth ulceration, hemorrhagic pancreatitis, necrotizing pancreatitis, stomach ulcer, and venoocclusive liver disease were reported. Because these reactions are reported voluntarily, it is impossible to reliably estimate the frequency or establish a causal relationship to tacrolimus.
Hematologic adverse reactions reported during tacrolimus therapy include anemia (30 - 59%), leukocytosis (32%), leukopenia (15%), and thrombocytopenia (24%). Other hematologic reactions that occurred in < 15% of patients receiving tacrolimus include coagulopathy, ecchymosis, coagulation disorder, increased hematocrit, abnormal hemoglobin, hypochromic anemia, decreased prothrombin, decreased serum iron, and polycythemia. Rarely, hemolytic anemia or hemolytic-uremic syndrome have been reported. During the post-marketing surveillance period, neutropenia, pancytopenia, thrombocytopenic purpura, and thrombotic thrombocytopenic purpura (TTP) were reported. Because these reactions are reported voluntarily, it is impossible to reliably estimate the frequency or establish a causal relationship to tacrolimus.
The most common adverse reactions seen with topical tacrolimus include skin irritation (e.g., burning, stinging, soreness, tingling) (26 - 58%) and pruritus (25 - 46%). Localized symptoms are most common during the first few days of topical tacrolimus therapy and usually improve as the lesions heal. The duration of skin irritation varies between 2 minutes and 3 hours (median 15 minutes); pruritus usually does not last as long. Other adverse reactions reasonably associated with topical tacrolimus include flu-like symptoms, skin erythema, headache, folliculitis, rash (unspecified), alcohol intolerance (flushing of face), acneiform rash, vesiculo-bullous rash, hyperesthesia, skin warts, back pain, myalgia, and cysts. Pruritus (7 - 36%) and rash (unspecified) (12 - 24%) have been reported during systemic tacrolimus therapy. Other skin reactions reported in < 15% of patients treated with systemic tacrolimus include acne vulgaris, acneiform rash, alopecia, cellulitis, exfoliative dermatitis, fungal dermatitis, hirsutism, photosensitivity, skin discoloration, skin ulcer, and diaphoresis. The incidence of hirsutism is less during tacrolimus therapy as compared to cyclosporine therapy. During the post-marketing surveillance period, Stevens-Johnson syndrome and toxic epidermal necrolysis were reported. Because these reactions are reported voluntarily, it is impossible to reliably estimate the frequency or establish a causal relationship to tacrolimus.
Infection is commonly seen during systemic tacrolimus therapy and may occur at any site. More frequently reported infections include bronchitis, herpes simplex, oral candidiasis, peritonitis, pharyngitis, pneumonia, rhinitis, sepsis, sinusitis, and urinary tract infection. During treatment with topical tacrolimus herpes simplex (up to 12%) and varicella zoster (up to 5%) infections have been reported. Sinusitis (2 - 7%) has also been reported in patients receiving topical tacrolimus.
As with other immunosuppressives, a secondary malignancy, especially lymphomas and skin cancers, may develop in patients receiving tacrolimus. As of December 2004, the FDA has received 19 post-marketing reports of cancer-related adverse events (9 lymphomas and 10 cutaneous tumors) associated with topical tacrolimus use; 3 cases occurred in patients up to 16 years of age, and 16 cases occurred in adults. Six of the 19 cases were associated with lymphadenopathy. Of the 10 cutaneous tumors (squamous cell carcinoma, cutaneous sarcoma, malignant melanoma, and other tumor types), 7 occurred at the site of tacrolimus application. The median time until diagnosis after initiation of treatment with Protopic® was 150 days (range, 21 - 790 days). Due to the post-marketing nature of the reports, a causal relationship between cancer development and topical tacrolimus has not been established; the role of topical tacrolimus in the development of lymphomas and skin cancers is uncertain. For example, of the 19 cases, 2 were associated with pre-existing serious conditions; 4 were associated with a recurrence or aggravation of a pre-existing malignancy; and 3 were associated with possible confounders including environmental exposure or possible pre-existing, pre-malignant conditions. Furthermore, the extent of systemic absorption and subsequent immunosuppression, if any, in each case is unknown. In addition to secondary malignancy, patients receiving tacrolimus may develop lymphoproliferative disorders (LPDs). In some cases the lymphoproliferative disorder has been related to Epstein-Barr virus (EBV) infection. The risk of LPD is greatest in young children who are at risk for primary EBV infection while immunosuppressed or who are switched to tacrolimus following long-term immunosuppression. In a retrospective analysis, the incidence density rate of LPDs was 5-fold higher in pediatric patients receiving primary tacrolimus therapy (4.86 ± 1.2 per 100 patient-years, 15/141) when compared to a similar group of patients treated with primary cyclosporine therapy (0.93 ± 0.2 per 100 patient-years, 15/251). The mortality of LPD was 20% in this analysis irrespective of primary immunosuppressive therapy.
Anaphylactoid reactions have been reported in patients receiving tacrolimus injection. Although the exact cause is not known, other drugs with castor oil derivatives in the formulation have been associated with anaphylaxis. Because of the risk of anaphylaxis, tacrolimus injection should be reserved for patients unable to take the capsules. Allergic reactions (unspecified) have been reported with topical tacrolimus.
Respiratory adverse reactions reported in < 15% of patients during tacrolimus clinical trials include asthma, emphysema, hiccups, pneumothorax, pulmonary edema, cough, and voice alteration. During the post-marketing surveillance period, acute respiratory distress syndrome (ARDS), lung infiltration, and respiratory arrest (failure) were reported. Because these reactions are reported voluntarily, it is impossible to reliably estimate the frequency or establish a causal relationship to tacrolimus.
[ Last revised: 2/16/2006 4:58:00 PM ]
References
. Younes BS, McDiarmid SV, Martin MG, et al. The effect of immunouppression on posttransplant lymphoproliferative disease in pediatric liver transplant patients. Transplantation 2000;70:94 - 9.
. Hodak SP, Moubarak JB, Rodriguez I, et al. QT Prolongation and near fatal cardiac arrhythmia after intravenous tacrolimus administration: a case report. Transplantation 1998;66:535 - 7.
. Johnson MC, So S, Marsh JW, et al. QT prolongation and Torsades de Pointes after administration of FK506. Transplantation 1992;53:929 - 30.
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