What are the side effects of tacrolimus (immunosuppressive medication)?

Side Effects of Tacrolimus

Tacrolimus carries an FDA black box warning for increased susceptibility to infection and possible development of lymphoma, and is associated with serious organ toxicities including nephrotoxicity, neurotoxicity, new-onset diabetes mellitus, hypertension, and cardiac complications. 1, 2

Life-Threatening and Serious Side Effects

Malignancy and Infection Risk

• Increased susceptibility to infection and lymphoma development are the most serious risks, warranting FDA black box warnings 1
• Prophylaxis against Pneumocystis jiroveci must be implemented when using tacrolimus 1
• Avoid live vaccines during tacrolimus therapy 2

Metabolic Complications

• New-onset diabetes mellitus occurs in 10.4% of tacrolimus-treated patients, representing a significant metabolic complication 1, 3
• Hyperglycemia is common and requires regular blood glucose monitoring 1, 2
• Symptoms include frequent urination, increased thirst/hunger, blurred vision, confusion, drowsiness, fruity breath smell, and nausea/vomiting 2

Renal Toxicity

• Nephrotoxicity is a serious and common side effect requiring regular monitoring of renal function 1, 2
• Serum creatinine and kidney function should be monitored at least every 4-6 weeks 1
• For patients developing renal dysfunction, reduction in target tacrolimus concentration is recommended 1

Neurological Complications

• Neurotoxicity is a serious and common side effect manifesting as headache, confusion, seizures, vision changes, behavior changes, coma, tremors, numbness, and tingling 1, 2, 4
• Tremors occur frequently and are among the most common adverse effects 2
• Immediate medical attention is required if neurological symptoms develop 2

Cardiovascular Effects

• Systemic hypertension is a serious and common side effect requiring blood pressure monitoring and often antihypertensive therapy 1, 2
• Cardiac toxicity including myocardial hypertrophy can occur, presenting as shortness of breath, chest pain, lightheadedness, or fainting 2
• QT prolongation (changes in electrical heart activity) has been reported 2
• Rare cases of acute coronary syndrome have been associated with elevated tacrolimus levels 5

Hematologic and Electrolyte Abnormalities

Blood Disorders

• Bone marrow suppression leading to anemia (low red blood cell count) and leukopenia (low white blood cell count) 1, 2
• Blood clotting problems presenting as fever, bruising (appearing as red dots), unexplained tiredness, confusion, jaundice, or decreased urination 2
• Thrombotic microangiopathy is a rare but severe complication that can affect multiple organ systems 6
• CBC count should be monitored intermittently to detect bone marrow suppression 1

Electrolyte Disturbances

• Hyperkalemia (high potassium levels) requires regular serum potassium monitoring 1, 2
• Hypomagnesemia (low magnesium levels) is common and necessitates magnesium level monitoring 1
• Low phosphate levels can occur 2

Other Common Side Effects

Gastrointestinal Effects

• Constipation and diarrhea are among the most common side effects 2
• Nausea, vomiting, and stomach pain occur frequently 2
• Rare cases of diffuse gastrointestinal ulcerations have been reported 7

Metabolic and Lipid Abnormalities

• Dyslipidemia (high blood fat levels) requiring lipid profile monitoring 1, 2
• Hepatic dysfunction may occur, necessitating liver function monitoring 1

Dermatologic and Other Effects

• Acne, increased hair growth, and skin sensitivity to sunlight 1
• Limit sun exposure and use high SPF sunscreen; avoid UV tanning machines 2
• Swelling of hands, legs, ankles, or feet (edema) 2
• Weakness, pain, and general malaise 2
• Fever and airway inflammation (bronchitis) 2
• Fluid accumulation around the heart 2

Critical Drug Interactions and Monitoring

CYP3A4-Mediated Interactions

• Tacrolimus is metabolized through the hepatic CYP3A4 system, making it highly susceptible to drug interactions 1
• Imidazole antifungals and other CYP3A4 inhibitors increase tacrolimus levels 1
• CYP3A4 inducers (including St. John's wort) decrease tacrolimus levels 1
• Tacrolimus itself inhibits CYP3A4, potentially affecting clearance of digoxin, colchicine, and HMG-CoA reductase inhibitors 1
• Drug levels must be monitored closely when CYP3A4 inducers or inhibitors are added or discontinued 1

Food Interactions

• High-fat meals decrease oral absorption by 37% with a 77% decrease in maximum plasma concentration 1, 8
• Grapefruit and grapefruit juice must be avoided during tacrolimus therapy 2

Monitoring Requirements

Laboratory Surveillance

• Tacrolimus trough levels: target 5-15 ng/mL for transplant recipients 1, 9, 8
• Daily monitoring until steady state is achieved, then every 2-3 days until discharge 1, 8
• After stabilization, monitor every 1-2 weeks for the first 1-2 months, then every 1-2 months 1, 8
• At least every 4-6 weeks, monitor: CBC count, renal function, glucose, potassium, magnesium, lipid profile, and hepatic function 1, 9
• Blood pressure should be measured frequently 1

Special Precautions

• Medication errors can occur—tacrolimus extended-release formulations are not interchangeable with immediate-release capsules 2
• Verify correct formulation with each prescription refill 2
• Do not open or crush tacrolimus capsules 2

Pregnancy and Lactation Considerations

• FDA Pregnancy Category C for all trimesters 1
• Crosses the placenta but no causal relationship with teratogenic effects has been identified in humans 1
• Not recommended unless maternal benefit justifies potential fetal risk 1
• Enters breast milk and may cause immune suppression in nursing infants 1