tacrolimus

Mechanism

Amiodarone blocks CYP3A4 and P-glycoprotein – two key tacrolimus clearance routes. Tacrolimus plasma levels rise 2- to 3-fold. Additional risk of additive QT prolongation.

Symptoms

Acute nephrotoxicity: rising creatinine and falling glomerular filtration rate. Tremor, headache, hypertension, hyperglycaemia, hyperkalaemia. In transplant patients: accelerated graft function decline.

Management

When combined, reduce tacrolimus by 30–50%; check trough (C0) at days 3 and 7. ECG before start and at 2 weeks; maintain potassium and magnesium. Alternative antiarrhythmic in transplant patients: a beta-blocker for rate control or catheter ablation.

Mechanism

Carbamazepine strongly induces CYP3A4 and P-glycoprotein. Tacrolimus plasma levels fall 2- to 3-fold; immunosuppression is lost, raising rejection risk.

Symptoms

Rejection symptoms depend on the organ: fever, graft tenderness, rising creatinine (kidney); jaundice and rising liver enzymes (liver). Symptoms appear 1–3 weeks after starting carbamazepine.

Management

Avoid the combination. Alternative anticonvulsants without induction: levetiracetam, lamotrigine, gabapentin. If carbamazepine is unavoidable, raise tacrolimus 2- to 3-fold with trough (C0) twice weekly.

Mechanism

Celecoxib (a selective COX-2 inhibitor) reduces renal blood flow via prostaglandin suppression. Tacrolimus is nephrotoxic in its own right. Additive acute kidney injury risk, especially with borderline renal function.

Symptoms

Reduced urine output, rising creatinine, potassium accumulation. In kidney transplant patients: accelerated graft function decline.

Management

Avoid chronic celecoxib on tacrolimus. For analgesia post-transplant, use paracetamol (up to 2 g/day) or a short opioid course. For neuropathic pain, gabapentin or pregabalin. Check creatinine monthly.

Mechanism

Tacrolimus prolongs the QT interval, especially with hypomagnesaemia (common on calcineurin inhibitors). Citalopram also prolongs QT dose-dependently (FDA caps at 40 mg/day). Effects add up.

Symptoms

QT prolongation on ECG, dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk rises with hypokalaemia and hypomagnesaemia.

Management

Avoid the combination. Alternative antidepressants with minimal QT effect post-transplant: mirtazapine, agomelatine, sertraline (up to 100 mg/day). ECG before start and at 2 weeks; maintain potassium and magnesium.

Mechanism

Tacrolimus and colchicine are both P-glycoprotein substrates. Competition at this transporter raises colchicine levels, especially in transplant patients with borderline renal function.

Symptoms

Profuse diarrhoea, vomiting, abdominal pain. With prolonged combination: muscle weakness, peripheral neuropathy, falling leukocytes and platelets. In transplant patients: accelerated graft decline.

Management

For acute gout in transplant patients, a short colchicine course (3–5 days) at 0.3 mg every other day with muscle symptom and blood count monitoring. For chronic gout, allopurinol. For acute attacks, intra-articular glucocorticoid.

Mechanism

Diclofenac (NSAID) suppresses renal prostaglandin synthesis maintaining glomerular perfusion. Tacrolimus is nephrotoxic in its own right. Additive acute kidney injury risk in transplant patients.

Symptoms

Reduced urine output, rising creatinine, potassium accumulation. In kidney transplant patients: accelerated graft function decline.

Management

Avoid chronic diclofenac on tacrolimus. For analgesia post-transplant, use paracetamol (up to 2 g/day) or a short opioid course. For neuropathic pain, gabapentin or pregabalin.

Mechanism

Dronedarone blocks the P-glycoprotein transporter – the main tacrolimus clearance route. Tacrolimus plasma levels rise. Additional risk of additive QT prolongation.

Symptoms

Acute nephrotoxicity: rising creatinine and falling glomerular filtration rate. Tremor, headache, hypertension, hyperglycaemia, hyperkalaemia. In transplant patients: accelerated graft function decline.

Management

Avoid the combination. Alternative antiarrhythmics in transplant patients: a beta-blocker for rate control or catheter ablation. If unavoidable, reduce tacrolimus by 30% and check level at days 3 and 7.

Mechanism

Tacrolimus prolongs the QT interval, especially with hypomagnesaemia (typical on calcineurin inhibitors). Escitalopram also prolongs QT dose-dependently (FDA caps at 20 mg/day). Effects add up.

Symptoms

QT prolongation on ECG, dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

Limit the combination: cap escitalopram at 10 mg/day. ECG before start and at 2 weeks; maintain potassium and magnesium. Alternative antidepressant with minimal QT effect: mirtazapine or agomelatine.

Mechanism

Esomeprazole inhibits CYP2C19. Tacrolimus is minimally metabolised by CYP2C19, but in patients with slow metabolism (CYP2C19 genetic polymorphism) this route becomes the main one. In such patients tacrolimus plasma levels rise.

Symptoms

Acute nephrotoxicity: rising creatinine and falling glomerular filtration rate. Tremor, headache, hypertension, hyperglycaemia, hyperkalaemia. In transplant patients: accelerated graft function decline.

Management

In most patients, no clinically significant effect. In East Asian patients (high frequency of CYP2C19 slow metabolisers), alternative PPIs: pantoprazole or rabeprazole (weaker CYP2C19 effect). Check tacrolimus trough (C0) 1 week after starting esomeprazole.

Mechanism

Fluconazole at 200 mg/day or above blocks CYP3A4 – the main tacrolimus metabolic route. Tacrolimus plasma levels rise 2- to 3-fold, with nephrotoxicity and neurotoxicity risks.

Symptoms

Acute nephrotoxicity: rising creatinine and falling glomerular filtration rate. Tremor, headache, hypertension, hyperglycaemia, hyperkalaemia. In transplant patients: accelerated graft function decline.

Management

For short fluconazole courses (up to 7 days), reduce tacrolimus by 30% and check trough (C0) daily. For prolonged systemic therapy, alternative antifungals (echinocandins) or titrate tacrolimus to level.

Mechanism

Additive nephrotoxicity via two distinct mechanisms. Gentamicin (an aminoglycoside) directly injures proximal renal tubules. Tacrolimus (calcineurin inhibitor) causes afferent arteriolar vasoconstriction. Co-administration sharply raises acute kidney injury risk, especially in transplant patients.

Symptoms

Reduced urine output, rising creatinine and urea. In kidney transplant patients: accelerated graft decline. Gentamicin ototoxicity too: tinnitus, hearing loss.

Management

Avoid the combination. Alternative antibiotics: a cephalosporin, carbapenem, or vancomycin (with its own renal monitoring). If gentamicin is irreplaceable: minimum effective dose, daily creatinine checks, and gentamicin level monitoring per protocol.

Mechanism

Additive QT prolongation. Haloperidol strongly prolongs QT, especially parenterally (IV). Tacrolimus prolongs QT with hypomagnesaemia. Combined action raises torsades de pointes risk.

Symptoms

QT prolongation on ECG, dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

Avoid the combination, especially IV haloperidol. Alternative antipsychotics with minimal QT effect post-transplant: olanzapine or aripiprazole. For acute delirium: dexmedetomidine (no QT effect).

Mechanism

Ibuprofen reduces renal blood flow via PGE2 inhibition. Tacrolimus is nephrotoxic in its own right. Additive acute kidney injury risk in transplant patients.

Symptoms

Reduced urine output, rising creatinine and potassium, oedema. Symptoms appear earlier in older patients and in chronic kidney disease.

Management

Avoid prolonged combination. For analgesia post-transplant, use paracetamol (up to 2 g/day) or a short opioid course. For neuropathic pain: gabapentin or pregabalin.

Mechanism

Contrast (iopromide) and nephrotoxic immunosuppressant (tacrolimus) – high contrast-induced nephropathy risk. The effect is stronger in transplant patients due to already reduced renal function.

Symptoms

Reduced urine output, rising creatinine and potassium, oedema. Symptoms appear earlier in older patients and chronic kidney disease.

Management

For planned contrast studies, provide adequate hydration with saline (1 mL/kg/h for 12 hours before and after). Check tacrolimus trough (C0) 1–3 days after contrast. Alternative imaging: non-gadolinium MRI.

Mechanism

Ketoconazole is the most potent CYP3A4 inhibitor available – the main tacrolimus metabolic route. Tacrolimus plasma levels rise 3- to 5-fold. The narrow therapeutic window makes any rise clinically dangerous.

Symptoms

Acute nephrotoxicity: rising creatinine and falling glomerular filtration rate. Tremor, headache, hypertension, hyperglycaemia, hyperkalaemia. In transplant patients: accelerated graft function decline.

Management

Avoid the combination. Alternative antifungals: terbinafine for dermatophytosis or echinocandins for systemic mycoses. If unavoidable, reduce tacrolimus 2- to 3-fold and check trough (C0) levels daily.

Mechanism

Ketorolac is the most nephrotoxic NSAID, limited to 5 days of use. Tacrolimus is nephrotoxic in its own right. Additive acute kidney injury risk multiplies in transplant patients.

Symptoms

Reduced urine output, rising creatinine and potassium, oedema. Symptoms appear earlier in older patients and chronic kidney disease.

Management

The combination is not prescribed. For post-transplant analgesia: paracetamol (up to 2 g/day), metamizole, or a short opioid course. For neuropathic pain: gabapentin or pregabalin.

Mechanism

NSAID (meloxicam) + nephrotoxic calcineurin inhibitor (tacrolimus) – additive acute kidney injury risk in transplant patients.

Symptoms

Reduced urine output, rising creatinine and potassium, oedema. Symptoms appear earlier in older patients and chronic kidney disease.

Management

Avoid prolonged combination. For post-transplant analgesia: paracetamol (up to 2 g/day) or a short opioid course. For neuropathic pain: gabapentin or pregabalin.

Mechanism

Dual immunosuppression plus additive nephrotoxicity. The combination is used in rheumatoid arthritis patients on methotrexate when tacrolimus is added (e.g., in ANCA vasculitis), requiring careful monitoring.

Symptoms

Stomatitis, diarrhoea, falling leukocyte, platelet, and erythrocyte counts. Severe cases: fatal pancytopenia, nephrotoxicity.

Management

The combination is possible in rheumatic disease with careful monitoring. Check full blood count, creatinine, and liver enzymes every 2 weeks for the first 3 months, then monthly. Keep tacrolimus trough (C0) at the lower end of target range.

Mechanism

NSAID (naproxen) + nephrotoxic calcineurin inhibitor (tacrolimus) – additive acute kidney injury risk in transplant patients.

Symptoms

Reduced urine output, rising creatinine and potassium, oedema. Symptoms appear earlier in older patients and chronic kidney disease.

Management

Avoid prolonged combination. For post-transplant analgesia: paracetamol (up to 2 g/day) or a short opioid course. For neuropathic pain: gabapentin or pregabalin.

Mechanism

Omeprazole blocks CYP2C19. In CYP2C19 slow metabolisers (genetic polymorphism), tacrolimus is predominantly metabolised by CYP2C19, and plasma levels may double.

Symptoms

Acute nephrotoxicity: rising creatinine, hypertension, tremor, headache. In transplant patients: accelerated graft function decline.

Management

In most patients, no clinically significant effect. In East Asian patients (high frequency of CYP2C19 slow metabolisers), alternative PPIs: pantoprazole or rabeprazole (weaker CYP2C19 effect). Check tacrolimus trough (C0) 1 week after starting omeprazole.

Mechanism

Rifampicin is the strongest known CYP3A4, CYP2C9, and P-glycoprotein inducer. Tacrolimus is a CYP3A4 and P-gp substrate with a narrow therapeutic window (target trough 5–15 ng/mL). Tacrolimus exposure drops 3- to 7-fold; acute graft rejection risk is high.

Symptoms

Graft rejection on biochemistry and biopsy. There are no symptoms from reduced tacrolimus exposure itself – the loss of immunosuppression is silent.

Management

Avoid the combination. For tuberculosis in transplant recipients use rifampicin-free regimens (isoniazid + ethambutol + pyrazinamide) or rifabutin (much weaker CYP3A4 induction). If rifampicin is essential – empirically increase tacrolimus 2- to 5-fold with trough monitoring every 2–3 days for the first 2 weeks, then weekly.

Mechanism

Spironolactone retains potassium via aldosterone receptor blockade. Tacrolimus reduces renal potassium secretion via a distal tubular inhibitory effect. Additive hyperkalaemia.

Symptoms

Muscle weakness, paraesthesia, slowed pulse, arrhythmias. ECG: peaked T waves, widened QRS. Severe cases progress to cardiac arrest.

Management

Avoid the combination in transplant patients. Alternative diuretics: furosemide (loop, removes potassium) or hydrochlorothiazide. If spironolactone is needed, check potassium and creatinine every 1–2 weeks.