Tacrolimus Interactions
- Acyclovir
- Adefovir
- Alfuzosin
Aminoglycosides
- Amiodarone
- Amoxapine
- Amphotericin B
Angiotensin-converting enzyme inhibitors (ACE inhibitors)
Antacids
Anti-retroviral protease inhibitors
Antidiabetic Agents
- Aprepitant
- Astemizole
- Bacitracin
Barbiturates
- Bepridil
Beta-agonists
- Bismuth Subsalicylate
- Bosentan
- Bromocriptine
- Carbamazepine
- Carboplatin
- Caspofungin
- Chloramphenicol
- Chloroquine
- Chlorpromazine
- Cidofovir
- Cimetidine
- Ciprofloxacin
- Cisapride
- Cisplatin
- Clarithromycin
Class IA antiarrhythmics
Class III antiarrhythmics
- Clotrimazole
- Clozapine
- Conivaptan
Corticosteroids
- Cyclobenzaprine
- Cyclosporine
- Dalfopristin; Quinupristin
- Danazol
- Delavirdine
- Diltiazem
- Dolasetron
- Droperidol
- Efavirenz
- Entecavir
- Erythromycin
- Ethanol
- Ethinyl Estradiol
- Felodipine
- Flecainide
- Fluconazole
- Fluoxetine
- Fluphenazine
- Fluvoxamine
- food
- Foscarnet
- Fosphenytoin
- Ganciclovir
- Gatifloxacin
- Gemifloxacin
- grapefruit juice
- Grepafloxacin
- Halofantrine
Halogenated anesthetics
- Haloperidol
HMG-CoA reductase inhibitors
- Imatinib, STI-571
Immunosuppressives
- Infliximab
- Itraconazole
- Ketoconazole
- Lansoprazole
- Levofloxacin
- Levomethadyl
Local Anesthetics
- Maprotiline
- Mesoridazine
- Methadone
- Metoclopramide
- Metronidazole
- Mifepristone, RU-486
- Moxifloxacin
- Mycophenolate
- Nefazodone
- Nevirapine
- Nicardipine
- Nifedipine
Nonsteroidal antiinflammatory drugs (NSAIDs)
- Norfloxacin
- Octreotide
- Ofloxacin
- Omeprazole
- Oxcarbazepine
- Palonosetron
- Pamidronate
- Pemetrexed
- Pentamidine
- Perphenazine
- Phenytoin
- Pimozide
- Polymyxin B
Potassium-sparing diuretics
- Probucol
- Prochlorperazine
- Propafenone
- Quinidine
- Ranolazine
- Rifabutin
- Rifampin
- Rifapentine
- Risperidone
Salicylates
- Sertindole
- Sildenafil
- Sirolimus
- Sparfloxacin
- St. John’s Wort, Hypericum perforatum
- Telithromycin
- Terfenadine
- Theophylline, Aminophylline
- Thioridazine
Tricyclic antidepressants
- Trifluoperazine
- Troleandomycin
Vaccines
- Vancomycin
- Vardenafil
- Verapamil
- Voriconazole
- Ziprasidone
- Zoledronic Acid
Tacrolimus Interactions
The extent of absorption of tacrolimus when given orally with food is reduced as compared with administration in the fasted state. The systemic exposure (mean AUC) of tacrolimus was decreased by 37% when given with a high-fat meal. The systemic exposure was reduced to a similar extent when tacrolimus was given immediately after or 1.5 hours after meal ingestion as compared with the fasted state. While patients may take tacrolimus with food, it is critical that they always take tacrolimus consistently with or without food to ensure consistent whole blood concentrations.
Grapefruit juice inhibits the enterocyte CYP3A4 isoenzyme and may decrease tacrolimus metabolism. Thus, grapefruit and grapefruit juice consumption by patients receiving tacrolimus should be avoided.
Tacrolimus is metabolized via the hepatic cytochrome P-450 (CYP) 3A4, and ketoconazole is a CYP3A4 inhibitor. In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14 ± 5% vs. 30 ± 8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone. Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole coadministration, although it was highly variable between patients. Close monitoring of tacrolimus blood levels is warranted. This interaction has been used clinically to reduce the nephrotoxicity and high cost of tacrolimus therapy.
Tacrolimus is metabolized via the hepatic cytochrome P-450 (CYP) 3A4. Drugs that inhibit this isoenzyme can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects. Voriconazole is known to inhibit CYP3A4. The manufacturer of voriconazole recommends that the dosage of tacrolimus be reduced by two-thirds (i.e., administer one-third of the pre-voriconazole dose) when initiating therapy with voriconazole. Tacrolimus concentrations should be frequently assessed. When voriconazole is discontinued, tacrolimus concentrations should be carefully monitored and the dose increased as needed. In all cases, renal function in these patients should be carefully monitored.
Concurrent administration of erythromycin, troleandomycin or clarithromycin and tacrolimus may result in elevated tacrolimus concentrations resulting in nephrotoxicity. Tacrolimus is metabolized via the hepatic cytochrome P-450 (CYP) 3A4, and erythromycin, troleandomycin, and clarithromycin inhibit this isoenzyme and can thus, decrease the metabolism of tacrolimus. In one case, the whole blood tacrolimus concentration was > 60 ng/ml following 3 days of therapy with erythromycin (prior tacrolimus concentration 9.8 ng/ml). Furthermore, clarithromycin, erythromycin, troleandomycin (based on interactions with macrolides), and tacrolimus can cause QTc prolongation. If concomitant therapy is necessary, close monitoring of tacrolimus blood concentrations is warranted.
Nefazodone (a potent CYP3A4 inhibitor) decreases the elimination of tacrolimus (a CYP3A4 substrate). Delirium, renal failure and high tacrolimus serum concentrations (46.4 ng/ml) were reported in a patient receiving tacrolimus and nefazodone. The patient discontinued nefazodone and was started on paroxetine instead. Three days after stopping the nefazodone the tacrolimus level was 10.2 ng/ml. In a separate report, a patient on stable doses of tacrolimus for 2 years developed headache, confusion and ‘gray areas’ in her vision without ophthalmologic findings 1 week after switching from sertraline to nefazodone for persistent depression. Her serum creatinine increased 1.5 mg/dl from baseline and her 12-hour trough tacrolimus level was > 30 ng/ml. The tacrolimus was held for 4 days and the patient restarted on sertraline with resolution of symptoms. Because of the potential toxicity of tacrolimus, nefazodone should be used cautiously, if at all, in patients receiving tacrolimus. Monitoring of serum tacrolimus concentrations is recommended.
Certain calcium channel blockers (i.e., diltiazem, felodipine, nicardipine, nifedipine, and verapamil) and tacrolimus are all are metabolized by cytochrome P450 3A4. Furthermore, diltiazem, nicardipine, and verapamil inhibit CYP3A4. When coadministered with nifedipine, tacrolimus whole blood trough concentrations are increased. In a retrospective study of liver transplant patients with hypertension, nifedipine decreased the daily and cumulative dosage requirements of tacrolimus by 26%, 29%, and 38% at 3, 6, and 12 months, respectively, compared with the dosage for patients who did not receive nifedipine. One case report describes a patient with increased tacrolimus serum concentrations (up to 55 ng/ml) and tacrolimus toxicity (delirium, confusion, and agitation) after adding diltiazem to stabilized tacrolimus regimen. Per the manufacturer of felodipine, blood concentrations of tacrolimus may be increased when given in combination with felodipine. Tacrolimus blood concentrations should be monitored closely, as dosage adjustments may be needed.
Tacrolimus is metabolized via the hepatic cytochrome P-450 (CYP) 3A4. Drugs that inhibit CYP3A4 can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects. Examples of CYP3A4 inhibitors include: amiodarone, aprepitant (CYP3A4 inhibitor or inducer), cimetidine, chloramphenicol, clotrimazole, conivaptan, dalfopristin; quinupristin, danazol, delavirdine, efavirenz (inhibits or induces), ethinyl estradiol, fluconazole, fluoxetine, fluvoxamine, imatinib, STI-571, itraconazole, and mifepristone, RU-486. This list is not inclusive of all agents that inhibit CYP3A4.
Tacrolimus and quinidine are both metabolized by cytochrome P450 3A4. Decreased metabolism of either of these agents may result in toxicity. Close monitoring of blood concentrations is warranted with concurrent therapy. In addition, tacrolimus has been associated with a possible risk for QT prolongation and/or torsades de pointes. Until further data are available, use tacrolimus cautiously with drugs such as quinidine that may prolong the QT interval and increase the risk of torsades de pointes.
Concomitant use of levofloxacin with tacrolimus may result in increased serum concentrations of tacrolimus. In renal transplant patients stabilized on tacrolimus, addition of levofloxacin resulted in reduced metabolism of tacrolimus. Higher AUC values for tacrolimus were observed but increased adverse reactions and supratherapeutic serum concentrations were not noted. Serum concentrations of tacrolimus should be monitored and changes made only if adverse reactions or supratherapeutic concentrations occur. Also, concomitant use of tacrolimus and levofloxacin may increase the risk of cardiac arrhythmias since both drugs are associated with QT prolongation.
Tacrolimus has been associated with a possible risk for QT prolongation and/or torsades de pointes based on a few case reports; however, data are currently lacking to establish causality in association with torsades de pointes. Until further data are available, use tacrolimus cautiously with drugs that may prolong the QT interval or increase the risk of torsades de pointes. These agents may include: Class IA antiarrhythmics; Class III antiarrhythmics; alfuzosin; astemizole; beta-agonists; amoxapine; bepridil; certain quinolones (e.g., ofloxacin, ciprofloxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, moxifloxacin, norfloxacin, and sparfloxacin); cisapride; chloroquine; clozapine; cyclobenzaprine; dolasetron; droperidol; flecainide; halofantrine; haloperidol; halogenated anesthetics; levomethadyl; local anesthetics; maprotiline; methadone; octreotide; palonosetron; pentamidine; chlorpromazine; fluphenazine; mesoridazine; perphenazine; prochlorperazine; pimozide; probucol; propafenone; risperidone; ranolazine, sertindole; terfenadine; thioridazine; trifluoperazine; tricyclic antidepressants when given in excessive doses or overdosage; vardenafil; or ziprasidone. This list is not inclusive of all agents that can cause QT interval prolongation.
Anti-retroviral protease inhibitors (e.g., amprenavir, atazanavir, fosamprenavir, indinavir, ritonavir, nelfinavir, saquinavir, tipranavir) inhibit CYP3A4, increasing whole blood concentrations of tacrolimus and leading to the potential for nephrotoxicity or other tacrolimus-related side effects. In one case, lopinavir; ritonavir was added to a patients’ tacrolimus-containing medication regimen. Three days after initiating lopinavir; ritonavir, tacrolimus concentrations rose to toxic concentrations. Subsequently, the tacrolimus dosage was decreased from 5 mg twice daily to 0.5 mg once weekly in order to maintain appropriate tacrolimus blood concentrations. In another study, an average 16-fold reduction in the tacrolimus dosage was required when given with nelfinavir. Extreme caution must be used when administering tacrolimus concomitantly with any anti-retroviral protease inhibitor. Tacrolimus concentrations can be maintained with appropriate monitoring and dosage adjustment.
Patients receiving tacrolimus and systemic corticosteroids concomitantly should be carefully monitored for alterations in tacrolimus whole blood concentrations. Methylprednisolone is an inhibitor of CYP3A4, therefore inhibiting tacrolimus metabolism and leading to increased tacrolimus blood concentrations. Conversely, in one study the addition of prednisone or prednisolone to tacrolimus-containing medication regimens resulted in decreased tacrolimus blood concentrations; patients required higher doses of tacrolimus to maintain appropriate tacrolimus blood concentrations.
Drugs such as barbiturates, bosentan, carbamazepine, nevirapine, oxcarbazepine, rifabutin, rifampin, and rifapentine, which can induce cytochrome P-450 3A4, can decrease whole blood concentrations of tacrolimus. This list is not inclusive of all agents that induce CYP3A4. In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14 ± 6% vs. 7 ± 3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance with concomitant rifampin administration. In vitro and in vivo enzyme induction studies have suggested less enzyme induction potential with rifapentine as compared with rifampin and more enzyme induction potential with rifapentine as compared with rifabutin. Induction of enzyme activities occurred within 4 days after the first rifapentine dose. Enzyme activities returned to baseline levels 14 days after rifapentine discontinuation. The magnitude of enzyme induction is dose and dosing frequency dependent. For example, less enzyme induction occurred with 600 mg every 72 hours as compared with daily usage. Monitoring of tacrolimus whole blood concentrations is recommended if any of the hepatic enzyme inducing agents are used concurrently with tacrolimus.
Plasma protein binding is independent of the tacrolimus concentration between 5 - 50 ng/ml. Tacrolimus is approximately 99% bound largely to albumin and alpha-1-acid glycoprotein. Concomitant administration of two highly protein bound drugs may affect the serum concentration of one or both drugs. For example, the serum concentration of phenytoin may be increased by tacrolimus. Also, phenytoin can induce cytochrome P-450 3A4, which can decrease whole blood concentrations of tacrolimus. Similar interactions would be expected with fosphenytoin, which is a prodrug of phenytoin.
Concurrent use of cyclosporine and tacrolimus may increase the risk of nephrotoxicity due to synergistic or additive effects. Concomitant tacrolimus and cyclosporine usage is not recommended. When switching patients from cyclosporine to tacrolimus, wait at least 24 hours after the last dose of cyclosporine before beginning tacrolimus therapy. In the presence of elevated tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be delayed until the concentration falls into the normal range.
Additive effects may be seen with other immunosuppressives or antineoplastic agents when given concurrently with tacrolimus. While therapy is designed to take advantage of this effect, patients may be predisposed to develop over-immunosuppression resulting in an increased risk of infection or other side effects. The risk appears to be due to the intensity and duration of immunosuppression rather than to a specific agent.
The immune response of the immunocompromised patient to vaccines is decreased, and higher doses or more frequent boosters may be required. Despite dose increases, the immune response may still be suboptimal. Live virus vaccines are contraindicated during therapy with immunosuppressive agents due to the potentiation of virus replication, adverse reactions to the virus, and the immunocompromised status of the patient. To a lesser extent, killed virus vaccines are associated with increased adverse reactions to the virus. Those undergoing immunosuppressive therapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV).
The concurrent use of tacrolimus with potassium-sparing diuretics is not recommended because tacrolimus can cause hyperkalemia.
Antacids, such as aluminum hydroxide; magnesium hydroxide may increase the blood concentration of tacrolimus. As determined by a single-dose, crossover study, the mean AUC increased 21% after concurrent administration with tacrolimus as compared with tacrolimus alone. The interaction may not be clinically significant, as the systemic exposure was within the range of expected values. Absence of a clinically significant interaction is supported by data from patients that each received tacrolimus alone, with aluminum hydroxide, and with magnesium hydroxide in a randomized, crossover fashion. The respective systemic exposures over 24 hours were 125 ± 43 ng hr/ml, 131 ± 46 ng hr/ml, and 144 ± 39 ng hr/ml. Although retrospective data, no increase in the tacrolimus dosage or decrease in tacrolimus blood concentrations was observed from patients that received tacrolimus concomitantly with either a histamine-2 receptor antagonist, a proton pump inhibitor, sodium bicarbonate, or magnesium oxide as compared with patients that did not receive any of these drugs. However, based on in vitro data, separation of an antacid and oral tacrolimus by at least 2 hours was advised. Magnesium salts (e.g., magnesium oxide), calcium carbonate, aluminum hydroxide, and sodium bicarbonate significantly reduce the concentration of tacrolimus in solution. The mechanism may be due to binding or pH-mediated degrading of tacrolimus. The data are consistent with the chemical instability of tacrolimus for intravenous infusion in alkaline media (see Administration). Separation of the oral tacrolimus and antacid doses by at least 2 hours may not be necessary, but more data are needed. Tacrolimus concentrations can be maintained with appropriate monitoring and dosage adjustment.
St. John’s wort, Hypericum perforatum may increase the metabolism of tacrolimus through induction of the hepatic CYP3A4 isoenzyme and decreased serum concentrations of tacrolimus would be expected if St. John’s wort was coadministered. St. John’s wort in all forms, including teas, should be avoided in patients treated with tacrolimus. Strict monitoring of tacrolimus whole blood concentrations is recommended if St. John’s wort is used concurrently with tacrolimus.
Caspofungin may decrease the blood concentration of tacrolimus. Tacrolimus concentrations are reduced approximately 25% in patients receiving concurrent caspofungin. The mechanism of this interaction has not been identified; monitor tacrolimus blood concentrations. Increased dosage of tacrolimus may be required. The pharmacokinetic parameters of caspofungin are not altered by tacrolimus.
A 33 year-old man had elevation in serum creatinine and in trough concentrations of tacrolimus after initiation of theophylline 600 mg daily. The serum creatinine and tacrolimus trough concentrations further increased despite theophylline dosage reduction to 300 mg daily for 4 days each week. Although the theophylline serum concentrations ranged from 2 - 6.7 mg/L, theophylline was discontinued with subsequent normalization of serum creatinine and tacrolimus trough concentrations. On rechallenge, addition of theophylline 125 mg daily to a stable drug regimen increased the systemic tacrolimus exposure from 25 to 142 ng/h/ml over the first 10 hours after a tacrolimus dose. The peak theophylline concentration was 4.3 mg/L. The mechanism for the proposed interaction is not known but is hypothesized to be due to inhibition of CYP3A4 by tacrolimus. Closely monitor serum tacrolimus concentrations, serum creatinine concentrations, and renal function in patents who are stabilized on tacrolimus if theophylline or aminophylline is added, changed or discontinued.
Many serious infections during infliximab therapy have occurred in patients who received concurrent immunosuppressives that, in addition to their underlying Crohn’s disease or rheumatoid arthritis, predisposed patients to infections. The impact of concurrent infliximab therapy and immunosuppression on the development of malignancies is unknown. In clinical trials, the use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to infliximab and appeared to reduce infusion reactions.
Sildenafil is metabolized principally by the hepatic CYP3A4 (major route) and 2C9 (minor route) isoenzymes. The coadministration of tacrolimus with sildenafil has been associated with an increase in the AUC, Cmax, and half-life of sildenafil in one report; the interaction may have resulted from inhibition of CYP3A4 metabolism by tacrolimus. Decreases in blood pressure were also observed. Until further data are available, it may be prudent to reduce the initial dosage of sildenafil in patients who are concurrently taking tacrolimus.
A possible interaction has been reported with metronidazole and tacrolimus. A renal transplant patient reportedly had an increase in tacrolimus and cyclosporine serum concentrations when metronidazole was added to the drug regimen. Although previously reported as an inhibitor of CYP3A4 based on assumptions inferred from isolated case reports, metronidazole does not significantly inhibit CYP3A4 activity (evaluated via erythromycin breath test). Thus, the mechanism of any interaction between metronidazole and tacrolimus is uncertain. If metronidazole is added to or taken away from a drug regimen containing tacrolimus, careful monitoring of the tacrolimus concentration is warranted.
Increased tacrolimus whole blood concentrations may be observed if GI prokinetic agents like metoclopramide or cisapride are added to therapy. Limited data indicate these agents may increase the mean bioavailability of oral tacrolimus. The mechanism is thought to involve an increased rate of oral tacrolimus absorption in the small bowel secondary to alterations in gut transit times. Tacrolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4 and P-glycoprotein. A women with subtherapeutic tacrolimus concentrations thought to be due to impaired gastric motility developed supratherapeutic tacrolimus concentrations 1 day after beginning metoclopramide 20 mg four times daily. Monitor tacrolimus serum concentrations carefully if a GI prokinetic agent is used concomitantly.
Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs. Assessment of renal function in patients who have received tacrolimus is recommended, as the tacrolimus dosage may need to be reduced (see Dosage). Patients with reduced renal function may have significant impairment of pemetrexed elimination, as most of the drug is eliminated unchanged in the urine. Pemetrexed should not be used in patients with a creatinine clearance less than 45 ml/minute. Other examples of drugs that can adversely affect renal function include acyclovir, adefovir, amphotericin B , angiotensin-converting enzyme inhibitors (ACE inhibitors), systemic aminoglycosides , carboplatin, cisplatin , foscarnet , ganciclovir , nonsteroidal antiinflammatory drugs (NSAIDs) , salicylates, bismuth subsalicylate, systemic bacitracin, pamidronate, polymyxin B, IV pentamidine parenteral vancomycin , and zoledronic acid.
The administration of cidofovir with another potentially nephrotoxic agent, such as tacrolimus is contraindicated. Tacrolimus should be discontinued at least 7 days prior to beginning cidofovir.
There does not appear to be an interaction between mycophenolate mofetil (MMF) and tacrolimus; however, more data are needed. Although there does not appear to be an effect of MMF on the pharmacokinetic parameters of tacrolimus, an increased exposure to mycophenolic acid concentrations when tacrolimus is substituted for cyclosporin is apparent. The systemic exposure of tacrolimus may increase significantly in a patient that switches from cyclosporin to tacrolimus-based immunosuppression. If tacrolimus is substituted for cyclosporin in a drug regimen containing MMF, careful monitoring of the mycophenolic acid concentrations is warranted. A reduced MMF dose may be needed.
The concomitant use of sirolimus with a calcineurin inhibitor, such as tacrolimus or cyclosporine, may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy. Development of biopsy-proven thrombotic microangiopathy in the absence of vascular rejection occurred in 2 of 33 patients who received tacrolimus and sirolimus and in 6 of 29 patients who received cyclosporine and sirolimus. In contrast, only 2 of 54 patients who received cyclosporine and mycophenolate mofetil and 3 of 233 patients who received tacrolimus and mycophenolate mofetil developed the adverse event. In addition to a potential increased risk of thrombotic microangiopathy, sirolimus may decrease the blood concentration of tacrolimus. Concomitant usage of tacrolimus 0.2 mg/kg/day and sirolimus 1 mg daily for 2 weeks did not affect the pharmacokinetic parameter values of tacrolimus as compared with tacrolimus monotherapy. However, the systemic exposure (AUC) of tacrolimus decreased approximately 30% relative to baseline when either sirolimus 2 mg or 5 mg daily was coadministered. The data are in agreement with data from another study. Receipt of tacrolimus to a serum trough concentration of 3 - 7 ng/ml and sirolimus 2 mg/day or higher to a serum trough concentration of 6 - 12 ng/ml did not affect the systemic exposure of either drug as compared with baseline values. The data suggest a reduction of the tacrolimus AUC when coadministered with a sirolimus dosage of greater than 1 mg/day. Tacrolimus concentrations can be maintained with appropriate monitoring and dosage adjustment.
The risk of developing myopathy during therapy with HMG-CoA reductase inhibitors may be increased when used with tacrolimus. Systemic cerivastatin exposure increased 35% after 12 weeks of use with tacrolimus as compared with systemic cerivastatin exposure after the first dose. The mechanism of the interaction is unknown. The pharmacokinetic parameters of tacrolimus were unaltered.
Telithromycin is a competitive substrate and inhibitor of CYP3A4, however, it has been shown not to form inhibitory complexes with the enzyme in vitro. Coadministration of telithromycin with other drugs metabolized by CYP3A4 (e.g, tacrolimus) may result in increased plasma concentrations of the other drugs that could increase or prolong both the therapeutic and adverse effects. Tacrolimus has been associated with a possible risk for QT prolongation and/or torsades de pointes based on a few case reports. Until further data are available, use tacrolimus cautiously with drugs that may prolong the QT interval. Telithromycin has the potential to prolong the QT interval in some patients. However, no cardiovascular morbidity or mortality attributable to QT prolongation occurred during clinical efficacy trials (n=4780) of telithromycin, including 204 patients having a prolonged QT interval at baseline. The potential for telithromycin, by itself, to produce cardiac arrhythmias is thought to be very small, but the risk can be reduced further by avoiding usage in patients with other multiple risk factors for serious events resulting from QT prolongation.
Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
A flushing syndrome (alcohol intolerance) has been reported in patients treated with topical tacrolimus or pimecrolimus upon ingestion of ethanol. The flushing occurred in the face or at the sites of medication application, usually within 5 - 15 minutes of ethanol ingestion, and lasted for an average duration of 1 hour. Patients describe redness and warm sensations, which sometimes result in discomfort. The reaction does not appear to occur in all patients; roughly 3 - 7% report a notable effect. The possible mechanism of the effect is the inhibition of acetaldehyde dehydrogenase, leading to increased acetaldehyde dehydrogenase concentrations in the skin. Aspirin appears useful in attenuation of the reaction in those patients for whom the reaction is bothersome.
In a small pilot study of entecavir in HBV-infected liver transplant recipients on stable doses of cyclosporine (n=5) or tacrolimus (n=4), entecavir exposure was approximately 2-fold the exposure in healthy subjects with normal renal function. Altered renal function contributed to the increase in entecavir exposure in these patients. The potential for pharmacokinetic interactions between entecavir and cyclosporine or tacrolimus was not formally evaluated; however, renal function must be carefully monitored both before and during treatment with entecavir in liver transplant recipients who have received or are receiving an immunosuppressant that may affect renal function.
Concomitant administration of omeprazole and tacrolimus may increase the serum concentrations of tacrolimus.
Bromocriptine has been used clinically along with immunosuppressant drugs to inhibit prolactin-dependent immune augmentation. However, bromocriptine may decrease the clearance of tacrolimus or sirolimus with the potential to either reduce immunosuppressant dosage requirements or cause drug-related toxicity. All drugs are substrates for CYP3A4. Additionally, bromocriptine has been shown to inhibit P-glycoprotein mediated drug transport, which may lead to decreased intestinal metabolism and increased oral absorption of these immunosuppressant drugs. Close monitoring of tacrolimus or sirolimus concentrations is recommended if bromocriptine is coadministered.
Tacrolimus is metabolized via the hepatic cytochrome P-450 (CYP) 3A4. Lansoprazole may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations. In addition to being a CYP3A4 substrate, lansoprazole is also a CYP2C19 substrate. Patients who are intermediate or poor CYP2C19 metabolizers as compared to those patients who are efficient CYP2C19 metabolizers may have more dramatic increases in their tacrolimus whole blood concentrations. Increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
[ Last revised: 5/2/2006 8:44:00 PM ]
References
42. Wilt JL, Minnema AM, Johnson RF et al. Torsade de pointes associated with the use of intravenous haloperidol. Ann Intern Med 1993;119:391 - 4.
140. Simons FER, Kesselman MS, Giddins NG et al. Astemizole-induced torsade de pointes. Lancet 1988 Sept 10; 2(8611):624.
141. Monahan BP, Ferguson CL, Killeavy ES et al. Torsades de pointes occurring in association with terfenadine use. JAMA 1990;264:2788 - 90.
168. Green PT, Reents S, Harman E et al. Pentamidine-induced torsades de pointes in a renal tranplant recipient with Pneumocystis carinii pneumonia. S Med J 1990;83:481 - 4.
228. Conner CS. Calcium for verapamil overdose. Drug Intel Clin Pharm 1982;16:624.
231. Pratt CM et al. Risk of developing life-threatening ventricular arrhythmia associated with terfenadine in comparison with over-the-counter antihistamines, ibuprofen and clemastine. Am J Cardiol 1984;73:346 - 52.
331. Lui HK, Lee G, Dietrich P et al. Flecainide-induced QT prolongation and ventricular tachycardia. Am Heart J 1982;103:567 - 9.
335. Wharton JM, Demopulos PA, Goldschlager N. Torsade de pointes during administration of pentamidine isethionate. Am J Med 1987;83:571 - 6.
336. Kriwisky M, Perry GY, Tarchitsky D, et al. Haloperidol-induced torsades de pointes. Chest 1990;98:482 - 3.
1514. Seifeldin RA, Marcos-Alvarez A, Gordon FD et al. Nifedipine interaction with tacroliums in liver transplant recipients. Ann Pharmacother 1997;31:571 - 5.
2359. Campo JV, Smith C, Perel JM. Tacrolimus toxic reaction associated with the use of nefazodone; Paroxetine as an alternative agent. Arch Gen Psychiatry 1998;55:1050 - 2.
2360. Olyaei AJ, deMattos AM, Norman DJ, et al. Interaction between tacrolimus and nefazodone in a stable renal transplant recipient. Pharmacotherapy 1998;18:1356 - 9.
2553. ebert MF and Lam AY. Diltiazem increases tacrolimus concentrations. Ann Pharmacother 1999;33:680 - 2.
Related entries
Syndicate
|
