Tacrolimus

Mechanism

Tacrolimus can prolong QT and cause torsade, in the words of its SmPC, which also calls for caution in patients already on QT-prolonging drugs. The citalopram SmPC lists ongoing treatment with any drug capable of prolonging the QT interval among its contraindications, with no exceptions.

Symptoms

QTc prolongation on ECG, palpitations, dizziness, syncope. The end point is polymorphic ventricular tachycardia of the torsade type progressing to ventricular fibrillation. The risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, decompensated heart failure and in women.

Management

The pair sits in the citalopram SmPC contraindications, so the question is which drug stays, not how far to cut the dose. Tacrolimus is not withdrawn after transplantation, so the antidepressant is chosen around it rather than the other way round. With QT-prolonging co-medication the tacrolimus label explicitly requires ECG monitoring and blood level control.

Mechanism

Tacrolimus can prolong QT and cause torsade, in the words of its SmPC, which also calls for caution in patients already on QT-prolonging drugs. The escitalopram SmPC contraindicates any QT-prolonging drug alongside it: the ban is written broadly, and the classes in brackets are examples.

Symptoms

QTc prolongation on ECG, palpitations, dizziness, syncope. The end point is polymorphic ventricular tachycardia of the torsade type progressing to ventricular fibrillation. The risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, decompensated heart failure and in women.

Management

The pair sits in the escitalopram SmPC contraindications, so the question is which drug stays, not how far to cut the dose. Tacrolimus is not withdrawn after transplantation, so the antidepressant is chosen around it rather than the other way round. With QT-prolonging co-medication the tacrolimus label explicitly requires ECG monitoring and blood level control.

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 and potassium, fluid retention, raised blood pressure. The risk is higher in older patients, in impaired renal or liver function or heart failure, and with diuretics, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.

Management

Avoid using tacrolimus with drugs known to harm the kidneys, including non-steroidal anti-inflammatory drugs (NSAIDs) such as celecoxib (tacrolimus SmPC). If celecoxib cannot be avoided, monitor renal function and other adverse effects and adjust the tacrolimus dose if needed (tacrolimus SmPC); renal function must be monitored with this combination (celecoxib SmPC). The US Food and Drug Administration (FDA) also advises monitoring renal function and tacrolimus blood concentrations when tacrolimus is used with nephrotoxic drugs (US tacrolimus label). NSAIDs are highly bound to plasma proteins, so check tacrolimus trough concentrations and adjust the dose if needed (tacrolimus SmPC). Measure blood pressure at the start of celecoxib and during treatment (celecoxib SmPC).

Mechanism

Tacrolimus, an immunosuppressant used after organ transplantation, is cleared by CYP3A4 in the liver and gut. Clarithromycin strongly inhibits CYP3A4. According to the tacrolimus SmPC, a strong CYP3A4 inhibitor raises tacrolimus levels rapidly and sharply, within 1–3 days and even after an immediate dose reduction, and overall exposure may increase more than 5-fold. With a narrow therapeutic range such a rise is dangerous: the label lists nephrotoxicity, neurotoxicity and 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

The tacrolimus SmPC advises avoiding the combination, so the first step is to replace clarithromycin, usually with azithromycin if the spectrum fits. If clarithromycin cannot be avoided, a transplant specialist runs the regimen. Per the label, omitting the tacrolimus dose on the day clarithromycin starts is considered, and tacrolimus is restarted the next day at a reduced dose guided by blood levels. Trough levels are measured at baseline, frequently from the first days of co-administration, when clarithromycin stops and afterwards, because the effect lasts several days. Creatinine and the QT interval on ECG are monitored in parallel.

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 is a moderate CYP3A4 inhibitor and a potent P-glycoprotein inhibitor (dronedarone label). Tacrolimus is metabolized mainly by CYP3A4 in the liver and gut wall, so its blood levels can rise with dronedarone (tacrolimus and dronedarone labels). The second mechanism is electrical: dronedarone moderately prolongs the QT interval, and tacrolimus can itself prolong QT and cause torsades de pointes (labels of both drugs).

Symptoms

Signs of tacrolimus excess: worsening kidney function with rising creatinine, tremor, headache, and raised blood pressure, blood glucose and potassium (tacrolimus label). The combination prolongs the QT interval on the ECG; marked prolongation can lead to torsades de pointes with palpitations, dizziness and fainting (tacrolimus and dronedarone labels).

Management

Give CYP3A4 inhibitors with tacrolimus only after consulting a transplant specialist (tacrolimus label). Measure tacrolimus blood levels often from the first days of co-administration and adjust the dose (tacrolimus and dronedarone labels). For CYP3A4 inhibitors that also prolong the QT interval, the FDA tacrolimus label recommends a lower tacrolimus dose, frequent level checks and QT monitoring. Monitor kidney function and the ECG closely during the combination (tacrolimus label). Correct low potassium and magnesium before and during dronedarone treatment, and stop dronedarone if QTc reaches 500 ms or more (dronedarone label).

Mechanism

Erythromycin inhibits CYP3A4 and P-glycoprotein (erythromycin SmPC). CYP3A4 breaks down tacrolimus, and the tacrolimus SmPC places erythromycin in the same group as strong CYP3A4 inhibitors: tacrolimus levels can rise sharply within 1–3 days, and overall exposure can increase more than 5-fold. The effect can last several days after co-administration ends (tacrolimus SmPC). Both drugs can prolong the QT interval (both SmPCs).

Symptoms

Signs of tacrolimus excess: rising creatinine and worse kidney function, tremor, headache and other signs of neurotoxicity. QT prolongation on the ECG with a risk of torsades de pointes (both SmPCs).

Management

The erythromycin SmPC does not recommend giving it with tacrolimus, and the tacrolimus SmPC advises avoiding the combination. If erythromycin cannot be avoided, treatment is managed by a transplant specialist. Consider skipping the tacrolimus dose on the day erythromycin starts and restart the next day at a reduced dose guided by blood levels. Measure tacrolimus trough levels at baseline, check them often from the first days of co-treatment and reassess after erythromycin is stopped, adjusting the dose to these values. Monitor kidney and graft function, the QT interval on the ECG and signs of neurotoxicity closely (tacrolimus SmPC). Erythromycin is contraindicated with a history of QT prolongation or ventricular arrhythmia and with low potassium or magnesium (erythromycin SmPC). The tacrolimus SmPC classes azithromycin as a moderate or weak CYP3A4 inhibitor: it can also raise tacrolimus levels and needs the same monitoring.

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. The risk is higher in older patients, in kidney disease, heart failure or liver dysfunction, and with diuretics or angiotensin-converting enzyme inhibitors.

Management

Avoid using tacrolimus with drugs known to harm the kidneys; the list names non-steroidal anti-inflammatory drugs (NSAIDs) and ibuprofen specifically (tacrolimus SmPC). If ibuprofen cannot be avoided, monitor renal function and other adverse effects and adjust the tacrolimus dose if needed (tacrolimus SmPC); monitor renal function closely (ibuprofen SmPC). The US Food and Drug Administration (FDA) also advises monitoring renal function and tacrolimus blood concentrations when tacrolimus is used with nephrotoxic drugs (US tacrolimus label). NSAIDs are highly bound to plasma proteins, so check tacrolimus trough blood concentrations and adjust the dose if needed (tacrolimus SmPC). Use ibuprofen at the lowest dose for the shortest time; it is contraindicated in severe renal impairment (glomerular filtration rate below 30 mL/min) (ibuprofen SmPC).

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

Itraconazole is a strong CYP3A4 inhibitor. Tacrolimus rises 5+ fold – severe nephrotoxicity.

Symptoms

Rising creatinine, hypertension, tremor within 3-7 days.

Management

Reduce tacrolimus by 75% with frequent blood level monitoring. If possible, switch itraconazole to an echinocandin.

Mechanism

Strong CYP3A4 inhibitor – tacrolimus rises 4-5 fold.

Symptoms

Nephrotoxicity.

Management

Reduce tacrolimus by 75%.

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

Phenytoin induces CYP3A4. Tacrolimus level falls 2–3 fold with transplant rejection risk.

Symptoms

Tacrolimus trough below target, laboratory signs of rejection.

Management

For post-transplant epilepsy: levetiracetam or lacosamide as alternative. If phenytoin is needed, increase tacrolimus 2–3 fold with frequent monitoring.

Mechanism

Posaconazole is a strong CYP3A4 inhibitor. Tacrolimus rises 4-5 fold.

Symptoms

Nephrotoxicity, tremor.

Management

Reduce tacrolimus by 67%, check blood level on days 3-5.

Mechanism

Strong CYP3A4 inducer. Tacrolimus falls 3-fold – transplant rejection risk.

Symptoms

Rejection signs, rising creatinine.

Management

For TB in transplant patient – increase tacrolimus 3-5 fold with blood level monitoring. Alternative – rifabutin (weaker).

Mechanism

Tacrolimus is almost entirely cleared via hepatic CYP3A4. Ritonavir is the strongest CYP3A4 inhibitor available. Tacrolimus plasma levels can rise 50-fold or more. Acute nephrotoxicity and neurotoxicity with encephalopathy have been reported.

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 where possible, as the tacrolimus SmPC states. If ritonavir cannot be avoided, the SmPC advises considering omitting the tacrolimus dose on the day ritonavir starts. Tacrolimus is restarted the next day at a reduced dose guided by blood levels. Trough levels (C0) are checked often from the first days and again after ritonavir is stopped, and the dose follows them. Renal function and the QT interval on ECG are monitored as well. Transplant patients are managed jointly by transplant and infectious diseases teams. Where possible, switch to a ritonavir-free antiretroviral regimen, for example one based on dolutegravir or bictegravir.

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.

Mechanism

Voriconazole inhibits CYP3A4. Tacrolimus concentration rises 3-fold with risk of nephrotoxicity and neurotoxicity (tremor, headache, paresthesia). FDA requires reducing tacrolimus to one third of baseline and frequent blood-level monitoring.

Symptoms

Rising creatinine, tremor, headache, paresthesia, hypertension within 7 days. Tacrolimus trough above target range.

Management

Reduce tacrolimus to one third of baseline. Check trough after 2 days, then weekly. Up-titrate after voriconazole withdrawal.

Mechanism

Tacrolimus is a weak CYP3A4 inhibitor; alprazolam is a CYP3A4 substrate. Alprazolam levels may rise moderately. Additive sedative effect.

Symptoms

Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk.

Management

On starting the combination, begin alprazolam at 0.25 mg at bedtime. In transplant patients, prefer buspirone or CBT for anxiety over benzodiazepines. If unavoidable, tacrolimus monitoring is unchanged, but check sedation at 1 and 2 weeks after starting alprazolam.

Mechanism

Tacrolimus prolongs QT; the TCA does the same independently via a quinidine-like effect on cardiomyocyte Na/K channels. Additive ventricular arrhythmia risk.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Maximum risk in older transplant patients with electrolyte disturbances.

Management

Avoid in prior QT prolongation or electrolyte disturbance. For neuropathic pain, alternatives: gabapentin or pregabalin (minimal QT effect). For depression: sertraline (minimal QT effect). If unavoidable: ECG before starting amitriptyline and at 1 and 4 weeks. Keep potassium and magnesium in the upper half of normal range.

Mechanism

Tacrolimus and amlodipine are both CYP3A4 substrates competing for the enzyme. Tacrolimus plasma levels may rise.

Symptoms

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

Management

The combination is acceptable in post-transplant patients with hypertension. Check tacrolimus trough (C0) 1 week after starting or changing amlodipine. Alternative: an ARB or α-blocker (no CYP3A4 dependence).

Mechanism

Tacrolimus is a weak CYP3A4 inhibitor and P-glycoprotein substrate. P-glycoprotein competition may slightly raise apixaban levels; clinical effect is minimal.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

Management

No dose adjustment needed. In post-transplant patients with chronic kidney disease, watch for any bleeding signs and check creatinine clearance every 4 weeks — if it falls below 50 mL/min, reduce apixaban to 2.5 mg twice daily.

Mechanism

Tacrolimus is a weak CYP3A4 inhibitor; atorvastatin is a substrate. Atorvastatin plasma levels rise by 30–50%, raising myalgia risk. Tacrolimus itself can cause myopathy.

Symptoms

Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Symptoms usually appear 2–6 weeks after starting the combination.

Management

For transplant patients needing a statin, use pravastatin up to 20 mg/day or fluvastatin (minimal tacrolimus interaction). Atorvastatin is acceptable when no alternative exists, capped at 10 mg/day with creatine kinase every 4 weeks.

Mechanism

Additive QT prolongation (tacrolimus prolongs QT in hypomagnesaemia, common on calcineurin inhibitors).

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Rarely: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.

Management

For short azithromycin courses post-transplant: check magnesium and replete if needed. ECG before start if other QT-prolonging drugs are on board. Alternative antibiotics: a cephalosporin or doxycycline.

Mechanism

Tacrolimus is metabolised by CYP3A4 in the liver and gut wall (tacrolimus SmPC). The tacrolimus SmPC classes omeprazole as a moderate or weak CYP3A4 inhibitor that can raise tacrolimus trough blood concentrations, sometimes rapidly. The omeprazole SmPC also reports higher tacrolimus concentrations with omeprazole but lists the mechanism as unknown.

Symptoms

Signs of tacrolimus excess: tremor, tingling in the limbs, headache, changes in mental status, rising creatinine and potassium. QT prolongation on the electrocardiogram is possible, with a risk of dangerous arrhythmia.

Management

The combination is acceptable with monitoring. From the first days of co-administration, check tacrolimus trough blood concentrations frequently and reduce the dose if needed; closely monitor renal function, the QT interval on the electrocardiogram (ECG) and other adverse effects (tacrolimus SmPC). The omeprazole SmPC also advises closer monitoring of tacrolimus concentrations and renal function (creatinine clearance), with tacrolimus dose adjustment if needed (omeprazole SmPC). The US Food and Drug Administration (FDA) gives the same approach: monitor trough concentrations and reduce the dose if needed (US tacrolimus label).