Tacrograf

Tacrograf 0.5: Light yellow/Light yellow hard gelatin capsules, size "4" imprinted with "TCR" on cap & "ABZ 0.5" on body containing white to off-white granular powder
Each capsule contains Tacrolimus 0.5 mg.
Tacrograf 1: White/White hard gelatin capsules, size "4" imprinted with "TCR" on cap & "ABZ 1" on body containing white to off-white granular powder.
Each capsule contains Tacrolimus 1 mg.

Pharmacology: Pharmacodynamics: Tacrolimus suppresses cellular immunity by inhibiting T-lymphocyte activation.
Mechanism of Action: Tacrolimus binds to an intracellular protein, FKBP-12 and complexes with calcineurin dependent proteins to inhibit calcineurin phosphatase activity.
Pharmacokinetics: Absorption: Incomplete and variable; the rate and extent of absorption is decreased by food (particularly a high-fat meal). Oral absorption may be variable in stem cell transplant patients with mucositis due to the conditioning regimen. Better in resected patients with a closed stoma: unlike cyclosporine, clamping of the T-tube in liver transplant patients does not alter trough concentrations or area under the curve (AUC).
Bioavailability: Children: 7-55%; Adults: 7-32%.
Time to peak, plasma: 0.5-6 hours.
Distribution: Volume of distribution: Children: 0.5-4.7 L/kg; Adults: 0.55-2.47 L/kg.
Protein binding: Approximately 99% primarily to albumin and alpha-1-acid glycoprotein.
Metabolism: Extensively hepatic via CYP3A4 to 8 possible metabolites.
Major metabolite: 31-demethyl tacrolimus shows same activity as tacrolimus in vitro.
Excretion: Half-life elimination: variable, 23-46 hours in healthy volunteers; 2.1-36 hours in transplant patients: prolonged in patients with severe hepatic impairment.
Major excretion pathway: Feces (approximately 93%): urine (less than 1% as unchanged drug).
Special populations: Hepatic function impairment: The mean clearance was substantially lower in patients with severe hepatic impairment.
Pediatric: Children younger than 12 years need higher doses than adults to achieve similar trough concentrations.
Race: Kidney transplant patients who are black require a higher tacrolimus dose to attain trough concentrations similar to white patients.

Tacrograf is indicated for: prophylaxis of organ rejection in patients receiving allogeneic liver or kidney transplants. It is recommended that Tacrograf be used concomitantly with adrenal corticosteroids. In kidney transplant recipients, it is recommended that Tacrograf be used in conjunction with azathioprine or mycophenolate mofetil (MMF). The safety and efficacy of the use of Tacrograf with sirolimus has not been established.
Lupus nephritis (in a case where the effect of steroids is insufficient or administration of steroids is difficult because of their adverse reactions). For lupus nephritis, the efficacy and safety of this product for patients in an acute phase with high disease activity has not been established.

Recommended Doses: General dosing considerations: Because of inter-subject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Frequent monitoring of tacrolimus trough concentrations is recommended in the early transplant period to ensure adequate drug exposure. (See Therapeutic drug monitoring as follows).
Tacrolimus extended release (ER) is not interchangeable or substitutable with Tacrograf.
Adult: Organ transplant: Initial dosage: Kidney transplant: 0.2 mg/kg/day in combination with azathioprine or 0.1 mg/kg/day in combination with mycophenolate mofetil and interleukin-2 receptor antagonist. Administer in 2 divided doses given every 12 hours.
Initial dose may be administered within 24 hours of transplantation but should be delayed until renal function has recovered.
Liver transplant: 0.1-0.15 mg/kg/day in 2 divided doses every 12 hours. The initial dose should be administered no sooner than 6 hours after transplantation.
Dosage titration: Titrate dose based on clinical assessments of rejection and tolerability. Reduce dose if nephrotoxicity develops.
Maintenance dosage: Lower dosages than the recommended initial dosage may be sufficient as maintenance therapy.
Concomitant therapy: Adjunct therapy with adrenal corticosteroids is recommended early post-transplant. In kidney transplant recipients, it is recommended that Tacrograf also be used in conjunction with azathioprine or mycophenolate mofetil.
Lupus nephritis: For adults, usually, a dose of 3 mg as tacrolimus is orally administered, once daily after supper.
In order to avoid development of adverse reactions in patients with lupus nephritis, it is recommended that the blood levels be monitored monthly for 3 months after the start of tacrolimus therapy; thereafter, the blood levels approximately 12 hours after the administration should be monitored periodically, and the dosage should be adjusted. If this product does not improve the clinical signs of nephritis, such as urine protein excretion, or the immunological finding after continuous treatment for 2 months, the treatment with this product should be discontinued, or the patients should be switched to another product. If the treatment with this product is sufficiently effective, it is recommended that the dose should be reduced to the lowest level possible that will still allow the effect to be maintained.
Pediatric: Organ transplant: Initial dosage: Liver transplant: 0.15 to 0.2 mg/kg/day in 2 divided doses every 12 hours. The initial dose should be administered no sooner than 6 hours after transplantation.
Special populations: Renal function impairment: Give consideration to dosing Tacrograf at the lower end of the therapeutic dosing range in patients who have received a liver transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required.
In kidney transplant patients with post-operative oliguria, the initial dose of Tacrograf should be administered no sooner than 6 hours and within 24 hours, but may be delayed until renal function shows evidence of recovery.
Hepatic function impairment: Patients with severe hepatic impairment (Child-Pugh score of 10 or more) may require lower doses. Close monitoring of blood concentrations is warranted.
The use of Tacrograf in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood concentrations of tacrolimus. Monitor these patients closely and consider dosage adjustments. Some evidence suggests that lower doses should be used in these patients.
Special risk patients: Black patients: Black kidney transplant patients may require higher doses of tacrolimus to attain comparable trough concentrations. (See also Therapeutic drug monitoring as follows).
Conversion: Conversion from another immunosuppressive therapy: Tacrograf should not be used simultaneously with cyclosporine. Tacrograf or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be further delayed.
Use with sirolimus is not recommended in liver transplant. The safety and efficacy of tacrolimus with sirolimus have not been established in kidney transplant.
Therapeutic drug monitoring: The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations; therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure. (See Tables 1 and 2.)

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Mode of Administration: Administer Tacrograf consistently with or without food.

Overdose: Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Occasionally, acute overdosage has been followed by adverse reactions consistent with those listed in Adverse Reactions except in one case where transient urticaria and lethargy were observed. In acute oral toxicity studies, mortalities were seen at or above the following doses: in adult rats 52X the recommended human oral dose; in immature rats, 16X the recommended oral dose (all based on body surface area corrections).
Treatment: Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

Tacrograf is contraindicated in patients with hypersensitivity to tacrolimus or any component of the formulation.

Management: Only health care providers experienced in immunosuppressive therapy and management of organ transplant patients should prescribe tacrolimus. Manage patients receiving the drug in facilities equipped and staffed with adequate laboratory and supportive medical resources. The health care provider responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.
Based on immunosuppressive effects of tacrolimus, inhalation or direct contact with skin or mucous membrane of powder contained in tacrolimus products should be avoided. If such contact occurs, wash the skin and eyes.
Lymphomas and other malignancies: Patients receiving tacrolimus are at an increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.
As usual for patients with increased risk of skin cancer, exposure to sunlight and ultraviolet (UV) light should be avoided or limited by wearing protective clothing and using a sunscreen with a high protection factor.
Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein-Barr virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population that includes many young children.
Infections: Immunosuppressant agents, including tacrolimus, increase the risk of infection; the risk of developing bacterial, viral (including cytomegalovirus (CMV)), fungal, and protozoal infections, including opportunistic infections, is increased. Infections may result in serious and fatal outcomes. Latent viral infections may be activated, including BK virus (associated with polyomavirus-associated nephropathy (PVAN)) and JC virus (associated with progressive multifocal leukoencephalopathy (PML)); may result in serious adverse effects. Immunosuppression increases the risk for CMV viremia and/or CMV disease; the risk of CMV disease is increased for patients who are CMV-seronegative prior to transplant and receive a graft from a CMV-seropositive donor. Monitor for development of infection; consider reduction in immunosuppression if PVAN, PML, CMV viremia and/or CMV disease occurs.
Medication errors: Tacrolimus ER is not interchangeable or substitutable with tacrolimus immediate release. Medication and dispensing errors, including inadvertent or unintentional substitution between tacrolimus immediate release and ER, have been observed. This has led to serious adverse events, including graft rejection, or other adverse reactions, which could be a consequence of either under or overexposure to tacrolimus.
New-onset diabetes: Tacrolimus caused new-onset diabetes mellitus after kidney and liver transplantation. New-onset diabetes after transplantation may be reversible in some patients. Black and Hispanic kidney transplant patients are at an increased risk. Closely monitor blood glucose concentrations in patients using tacrolimus.
Nephrotoxicity: Tacrolimus can cause acute or chronic nephrotoxicity, particularly when used in high doses. Acute nephrotoxicity is most often related to vasoconstriction of the afferent renal arteriole, is characterized by increasing serum creatinine, hyperkalemia, and/or a decrease in urine output, and is typically reversible. Chronic calcineurin-inhibitor nephrotoxicity is associated with increased serum creatinine, decreased kidney graft life, and characteristic histologic changes observed on renal biopsy; the changes associated with chronic calcineurin-inhibitor nephrotoxicity are typically progressive. Closely monitor patients with impaired renal function because the dosage of tacrolimus may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consider changing to another immunosuppressive therapy.
Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving tacrolimus in the US and European randomized trials, respectively.
Due to the potential for additive or synergistic impairment of renal function, take care when administering tacrolimus with drugs that may be associated with renal dysfunction. Similarly, exercise care when administering with CYP3A4 inhibitors that will result in increased tacrolimus whole blood concentrations due to inhibition of tacrolimus metabolism. (See Interactions).
Neurotoxicity: Tacrolimus may cause a spectrum of neurotoxicities, particularly when used in high doses.
The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure, and coma. Patients treated with tacrolimus have been reported to develop PRES. Symptoms indicating PRES include headache, altered mental status, seizures, visual disturbances, and hypertension. Diagnosis may be confirmed by radiological procedure. If PRES is suspected or diagnosed, maintain blood pressure control; immediate reduction of immunosuppression is advised. This syndrome is characterized by reversal of symptoms upon reduction or discontinuation of immunosuppression.
Coma and delirium, in the absence of PRES, have also been associated with high plasma concentrations of tacrolimus. Seizures have occurred in adult and pediatric patients receiving tacrolimus.
Less severe neurotoxicities include tremors, paresthesia, headache, and other changes in motor function, mental status, and sensory function. Tremor and headache have been associated with high whole blood concentrations of tacrolimus and may respond to dosage adjustment.
Hyperkalemia: Hyperkalemia has been reported. Monitor serum potassium levels. Give careful consideration prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-receptor blockers (ARBs)) during tacrolimus therapy.
Hypertension: Hypertension is a common adverse reaction, and antihypertensive therapy may be required. The control of blood pressure can be accomplished with any of the common antihypertensive agents, though give careful consideration prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin-receptor blockers).
Calcium channel blocking agents may increase tacrolimus blood concentrations and, therefore, require dosage reduction of tacrolimus.
QT prolongation: Prolongation of the QT/QTc interval and torsade de pointes may occur; avoid use in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment.
Myocardial hypertrophy: Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus, consider echocardiographic evaluation. If myocardial hypertrophy is diagnosed, consider dosage reduction or discontinuation of tacrolimus.
Vaccinations: Patients should be brought up to date with all immunizations before initiating therapy. Patients should not be immunized with live vaccines during or shortly after treatment and should avoid close contact with recently vaccinated (live vaccine) individuals. Inactivated vaccines may be administered (response may be diminished).
Pure red cell aplasia (PRCA): Cases of pure red cell aplasia (PRCA) have been reported. A mechanism for tacrolimus induced PRCA has not been elucidated. All patients reported risk factors for PRCA, such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed, consider discontinuation of tacrolimus.
Gastrointestinal (Gl) perforation: GI perforation may occur, all reported cases were considered to be a complication of transplant surgery or accompanied by infection, diverticulum, or malignant neoplasm. GI perforation may be serious or life-threatening, promptly institute appropriate medical/surgical management.
Hypersensitivity reactions: Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome.
Renal function impairment: Consider dosing tacrolimus at the lower end of the therapeutic dosing range in patients who have received a liver transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required.
Hepatic function impairment: Close monitoring of tacrolimus trough concentrations is warranted in patients with hepatic impairment.
Monitoring: The relative risk of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentration is recommended to assist in the clinical evaluation of toxicity and efficacy failure. (See also Therapeutic drug monitoring under Dosage & Administration).
Assess blood pressure, serum creatinine, electrolytes (magnesium, potassium, calcium), and blood glucose regularly.
Closely monitor patients with impaired renal function and/or hepatic impairment. Monitor patients for QT prolongation and consider electrocardiographic evaluation in patients who develop renal failure, electrolyte abnormalities, or clinical manifestations of ventricular dysfunction.
Use in Children: The safety and efficacy of tacrolimus in pediatric kidney transplant patients have not been established. Successful liver transplants have been performed in pediatric patients (up to 16 years) using tacrolimus. Pediatric patients generally required higher doses of tacrolimus to maintain blood trough concentration of tacrolimus similar to those of adult patients.
Use in the Elderly: Use with caution.

Pregnancy: US Pregnancy category C: Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.
Lactation: Tacrolimus is distributed into milk. Because of the potential for serious adverse reactions to tacrolimus in nursing infants, nursing should be avoided in women receiving the drug.

Very common: Cardiovascular: angina pectoris, atrial fibrillation, atrial flutter, bradycardia, cardiac arrest, cardiac arrhythmia, cardiac failure, cardiorespiratory arrest, cerebral infarction, cerebral ischemia, chest pain, decreased heart rate, deep vein thrombophlebitis, deep vein thrombosis, ECG abnormality (QRS or ST segment or T wave), edema, flushing, hemorrhagic stroke, hypertension, hypertrophic cardiomyopathy, hypotension, ischemic heart disease, localized phlebitis, myocardial infarction, orthostatic hypotension, pericardial effusion, peripheral edema ((Calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) have been reported (with concurrent sirolimus)), peripheral vascular disease, phlebitis, syncope, tachycardia, thrombosis, vasodilatation, ventricular premature contractions.
Central nervous system (CNS): abnormal dreams, abnormality in thinking, agitation, amnesia, anxiety, aphasia, ataxia, brain disease, Carpal Tunnel syndrome, chills, confusion, convulsions, depression, dizziness, drowsiness, emotional lability, excessive crying, falling, fatigue, flaccid paralysis, hallucination, headache, hypertonia, hypoesthesia, insomnia, mental status changes, mood elevation, myasthenia, myoclonus, nervousness, neuropathy (including compression), neurotoxicity, nightmares, pain, paresis, paresthesia, peripheral neuropathy, psychosis, seizure, vertigo, voice disorder, writing difficulty.
Dermatologic: acne vulgaris, alopecia, cellulitis, condyloma acuminatum, dermal ulcer, dermatitis (including fungal), dermatological reaction, diaphoresis, exfoliative dermatitis, hypotrichosis, pruritus, skin discoloration, skin photosensitivity, skin rash, tinea versicolor.
Endocrine and metabolic: acidosis, albuminuria, alkalosis, anasarca, Cushing's syndrome, decreased serum bicarbonate, decreased serum iron, dehydration, diabetes mellitus, gout, hirsutism, hypercalcemia, hypercholesterolemia, hyperglycemia, hyperkalemia, hyperlipidemia, hypertriglyceridemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, hypophosphatemia, increased gamma glutamyl transferase, increased lactate dehydrogenase, weight changes, weight gain.
Gastrointestinal (Gl): abdominal pain, anorexia, aphthous stomatitis, cholangitis, colitis, constipation, delayed gastric emptying, diarrhea, duodenitis, dyspepsia, dysphagia, enlargement of abdomen, esophagitis (including ulcerative), flatulence, gastric ulcer, gastritis, gastroesophageal reflux disease, gastrointestinal hemorrhage, gastrointestinal perforation, hernia, hiccups, increased appetite, intestinal obstruction, nausea, oral candidiasis, pancreatic disease (pseudocyst), pancreatitis (including hemorrhagic and necrotizing), peritonitis, rectal disease, stomach cramps, stomatitis, vomiting.
Genitourinary (GU): anuria, bladder spasm, cystitis, dysuria, hematuria, nocturia, oliguria, proteinuria, toxic nephrosis, urinary frequency, urinary incontinence, urinary retention, urinary tract infection, urinary urgency, vaginitis.
Hematologic and oncologic: anemia (hemoglobin <10 g/dL), blood coagulation disorder, bruise, decreased prothrombin time, hemolytic anemia, hemorrhage, hypochromic anemia, hypoproteinemia, increased hematocrit, increased INR, Kaposi's sarcoma, leukocytosis, leukopenia, malignant neoplasm of bladder, malignant neoplasm of thyroid, neutropenia, pancytopenia, polycythemia, skin neoplasm, thrombocytopenia.
Hepatic: abnormal hepatic function tests, ascites, cholestatic jaundice, hepatic injury, hepatitis (including acute, chronic, and granulomatous), hyperbilirubinemia, increased liver enzymes, increased serum alkaline phosphatase, jaundice.
Hypersensitivity: hypersensitivity reaction.
Immunologic: graft complications (kidney transplant).
Infection: abscess, bacterial infection, cytomegalovirus disease, Epstein-Barr infection, herpes simplex infection, infection, sepsis, serious infection.
Miscellaneous: fever, post-operative pain, post-operative wound complication, wound healing impairment.
Neuromuscular and skeletal: arthralgia, arthropathy, back pain, leg cramps, muscle spasm, muscle weakness of the extremities, myalgia, osteopenia, osteoporosis, tremor, weakness.
Ophthalmic: amblyopia, blurred vision, conjunctivitis, visual disturbance.
Otic: hearing loss, otalgia, ofitis externa, otitis media, tinnitus.
Renal: acute renal failure, hydronephrosis, increased blood urea nitrogen, increased serum creatinine, renal disease (BK nephropathy), renal function abnormality, renal tubular necrosis.
Respiratory: allergic rhinitis, asthma, atelectasis, bronchitis, cough, dyspnea, emphysema, flu-like symptoms, pharyngitis, pleural effusion, pneumonia, pneumothorax, pulmonary disease, pulmonary edema, pulmonary infiltrates, respiratory depression, respiratory failure, respiratory tract infection, rhinitis, sinusitis.
Common: Gastrointestinal (Gl): gastroenteritis.
Infection: polyoma virus infection.
Uncommon: Cardiovascular: Cerebrovascular accident, hepatic veno-occlusive disease, prolonged Q-T interval on ECG, supraventricular extrasystole, supraventricular tachycardia, torsades de pointes, venous thrombosis, ventricular fibrillation.
Central nervous system (CNS): coma, delirium, dysarthria, hemiparesis, leukoencephalopathy, mutism, progressive multifocal leukoencephalopathy, quadriplegia, reversible posterior leukoencephalopathy syndrome, status epilepticus.
Dermatologic: Hyperpigmentation, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), urticaria.
Endocrine and metabolic: decreased serum fibrinogen.
Gastrointestinal: biliary tract disease (stenosis).
Genitourinary: hemorrhagic cystitis.
Hematologic and oncologic: agranulocytosis, basal cell carcinoma, calcineurin inhibitor-induced hemolytic-uremic syndrome with concurrent sirolimus, calcineurin inhibitor-induced-thrombotic thrombocytopenic purpura concurrent sirolimus, disseminated intravascular coagulation, hemolytic-uremic syndrome, hepatosplenic T-cell lymphomas, immune thrombocytopenia, leukemia, lymphoproliferative disorder (post-transplant or related to EBV), malignant lymphoma, malignant melanoma, prolonged partial thromboplastin time, pure red cell aplasia, squamous cell carcinoma, thrombotic thrombocytopenic purpura.
Hepatic: hepatic cirrhosis, hepatic failure, hepatic necrosis, hepalotoxicity, liver steatosis.
Hypersensitivity: anaphylactoid reaction, anaphylaxis, angioedema.
Immunologic: graft versus host disease (acute and chronic).
Infection: septicemia.
Miscellaneous: multi-organ failure.
Neuromuscular and skeletal: osteomyelitis, polyarthritis, rhabdomyolysis.
Ophthalmic: blindness, optic atrophy, photophobia.
Otic: deafness.
Respiratory: adult respiratory distress syndrome, interstitial pulmonary disease, pulmonary hypertension.

Metabolism/transport effects: Substrate of CYP3A4 (major), P-glycoprotein; Note: Assignment of major/minor substrate status based on clinically relevant drug interaction potential; Inhibits P-glycoprotein.
QT Prolongation: An additive effect with other drugs that prolong the QT interval cannot be excluded. The following drugs are examples of agents that may prolong the QT interval and increase the risk of life-threatening cardiac arrhythmias, including torsades de pointes: antiarrhythmic agents (e.g., disopyramide, dofetilide, procainamide, quinidine, sotalol), arsenic trioxide, chlorpromazine, cisapride, citalopram, clarithromycin, dolasetron, droperidol, erythromycin, fluoxetine, levofloxacin, mesoridazine, moxifloxacin, pentamidine, pimozide, thioridazine, and ziprasidone. Unless contraindicated, coadminister these agents with caution.
Afatinib: P-glycoprotein/ABCB1 inhibitors may increase the serum concentration of afatinib.
Management: Per US labeling: reduce afatinib by 10 mg if not tolerated.
Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification.
Alcohol (ethyl): Alcohol (ethyl) may increase the absorption of tacrolimus (systemic). Consider therapy modification.
Antidepressants (serotonin reuptake inhibitor/antagonist (SARI)): Antidepressants (serotonin reuptake inhibitor/antagonist) may decrease the metabolism of tacrolimus (systemic).
Exceptions: trazodone. Consider therapy modification.
Antidiabetic agents: Hyperglycemia-associated agents may diminish the therapeutic effect of antidiabetic agents. Monitor therapy.
Aprepitant: Aprepitant may increase the serum concentration of CYP3A4 substrates. Monitor therapy.
Azithromycin (systemic): Azithromycin (systemic) may increase the serum concentration of tacrolimus (systemic). Monitor therapy.
Bacillus Calmette-Guérin (BCG) (intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (intravesical). Myelosuppressive agents may diminish the therapeutic effect of BCG (intravesical). Avoid combination.
Boceprevir: Boceprevir may increase the serum concentration of tacrolimus (systemic).
Management: Tacrolimus doses will need to be substantially reduced, and the tacrolimus dosing interval will likely need to be prolonged with concurrent boceprevir. Follow tacrolimus concentrations closely and monitor patients for evidence of tacrolimus toxicity. Consider therapy modification.
Bosentan: Bosentan may decrease the serum concentration of CYP3A4 substrates. Monitor therapy.
Bosutinib: P-glycoprotein/ABCB1 inhibitors may increase the serum concentration of bosutinib. Avoid combination.
Brentuximab vedotin: P-glycoprotein/ABCB1 inhibitors may increase the serum concentration of brentuximab vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy.
Calcium channel blockers (dihydropyridine): Calcium channel blockers (dihydropyridine) may increase the serum concentration of tacrolimus (systemic).
Exceptions: clevidipine. Monitor therapy.
Calcium channel calcium blockers (non-dihydropyridine): Calcium channel blockers (non-dihydropyridine) may decrease the metabolism of tacrolimus (systemic).
Exceptions: bepridil. Monitor therapy.
Caspofungin: Caspofungin may decrease the serum concentration of tacrolimus (systemic).
Monitor therapy.
Chloramphenicol: Chloramphenicol may increase the serum concentration of tacrolimus (systemic).
Management: Tacrolimus dose reductions will likely be required with initiation of concurrent chloramphenicol. Monitor tacrolimus concentrations and response closely following initiation and/or discontinuation of chloramphenicol. Consider therapy modification.
Cinacalcet: Cinacalcet may decrease the serum concentration of tacrolimus (systemic). Monitor therapy.
Clotrimazole (oral): Clotrimazole (oral) may increase the serum concentration of tacrolimus (systemic). Monitor therapy.
Clotrimazole (topical): Clotrimazole (topical) may increase the serum concentration of tacrolimus (systemic). Monitor therapy.
Clozapine: Myelosuppressive agents may enhance the adverse/toxic effect of clozapine. Specifically, the risk for neutropenia may be increased. Monitor therapy.
Coccidioides immitis skin test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis skin test. Monitor therapy.
Colchicine: P-glycoprotein/ABCB1 inhibitors may increase the serum concentration of colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased.
Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification.
Conivaptan: Conivaptan may increase the serum concentration of CYP3A4 Substrates. Avoid combination.
Crizotinib: Crizotinib may increase the serum concentration of tacrolimus (systemic). Avoid combination.
Cyclosporine (systemic): Tacrolimus (systemic) may enhance the nephrotoxic effect of cyclosporine (systemic). Cyclosporine (systemic) may enhance the nephrotoxic effect of tacrolimus (systemic). Tacrolimus (systemic) may increase the serum concentration of cyclosporine (systemic). Cyclosporine (systemic) may increase the serum concentration of tacrolimus (systemic). Avoid combination.
CYP3A4 inducers (moderate): CYP3A4 Inducers (moderate) may decrease the serum concentration of CYP3A4 substrates. Monitor therapy.
CYP3A4 inducers (strong): CYP3A4 inducers (strong) may increase the metabolism of CYP3A4 substrates.
Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consider therapy modification.
CYP3A4 inhibitors (moderate): CYP3A4 inhibitors (moderate) may decrease the metabolism of CYP3A4 substrates. Monitor therapy.
CYP3A4 inhibitors (strong): CYP3A4 inhibitors (strong) may increase the serum concentration of tacrolimus (systemic).
Management: Monitor clinical tacrolimus response closely and frequently monitor tacrolimus serum concentrations with concurrent use of any strong CYP3A4 inhibitor. Tacrolimus dose reductions and/or prolongation of the dosing interval will likely be required. Consider therapy modification.
Dabigatran etexilate: P-glycoprotein/ABCB1 inhibitors may increase serum concentrations of the active metabolite(s) of dabigatran etexilate.
Management: Dabigatran dose reductions may be needed. Specific recommendations vary. Refer to full monograph or dabigatran labeling. Consider therapy modification.
Dabrafenib: Dabrafenib may decrease the serum concentration of CYP3A4 substrates.
Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification.
Danazol: Danazol may increase the serum concentration of tacrolimus (systemic). Monitor therapy.
Dasatinib: Dasatinib may increase the serum concentration of CYP3A4 substrates. Monitor therapy.
Deferasirox: Deferasirox may decrease the serum concentration of CYP3A4 substrates. Monitor therapy.
Deferiprone: Myelosuppressive agents may enhance the neutropenic effect of deferiprone. Avoid combination.
Denosumab: Denosumab may enhance the adverse/toxic effect of immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy.
Dipyrone: Dipyrone may enhance the adverse/toxic effect of myelosuppressive agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased. Avoid combination.
Doxorubicin (conventional): P-glycoprotein/ABCB1 inhibitors may increase the serum concentration of doxorubicin (conventional).
Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification.
Dronedarone: Tacrolimus (systemic) may enhance the QTc-prolonging effect of dronedarone. Dronedarone may increase the serum concentration of tacrolimus (systemic).
Management: Monitor for increased serum tacrolimus concentrations, tacrolimus toxicity, and QTc interval prolongation if combined with dronedarone. Tacrolimus dose adjustments may be needed.
Consider therapy modification.
Echinacea: Echinacea may diminish the therapeutic effect of immunosuppressants. Consider therapy modification.
Edoxaban: P-glycoprotein/ABCB1 inhibitors may increase the serum concentration of edoxaban.
Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification.
Efavirenz: Efavirenz may decrease the serum concentration of tacrolimus (systemic).
Management: Closely monitor tacrolimus serum concentrations when starting, stopping, or changing doses of efavirenz, particularly during the first 2 weeks after any change. Dose adjustment of tacrolimus may be required. Consider therapy modification.
Efonidipine: Efonidipine may increase the serum concentration of tacrolimus (systemic). Monitor therapy.
Enzalutamide: Enzalutamide may decrease the serum concentration of tacrolimus (systemic). Avoid combination.
Eplerenone: Eplerenone may enhance the hyperkalemic effect of tacrolimus (systemic). Avoid combination.
Ertapenem: Ertapenem may increase the serum concentration of tacrolimus (systemic). Monitor therapy.
Erythromycin (systemic): Erythromycin (systemic) may increase the serum concentration of tacrolimus (systemic). Monitor therapy.
Everolimus: P-glycoprotein/ABCB1 inhibitors may increase the serum concentration of everolimus.
Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification.
Fenofibrate and derivatives: Tacrolimus (systemic) may enhance the nephrotoxic effect of fenofibrate and derivatives. Monitor therapy.
Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of fingolimod.
Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (e.g., infections). Consider therapy modification.
Fluconazole: Fluconazole may increase the serum concentration of tacrolimus (systemic).
Management: Monitor tacrolimus concentrations closely and adjust oral tacrolimus dose as necessary when concomitantly administered with fluconazole. Reduced doses of tacrolimus will likely be required. Consider therapy modification.
Fosaprepitant: Fosaprepitant may increase the serum concentration of CYP3A4 substrates. Monitor therapy.
Foscarnet: Foscarnet may enhance the nephrotoxic effect of tacrolimus (systemic). Avoid combination.
Fosphenytoin: Fosphenytoin may decrease the serum concentration of tacrolimus (systemic). Tacrolimus (systemic) may increase the serum concentration of fosphenytoin. Monitor therapy.
Fusidic acid (systemic): Fusidic acid (systemic) may increase the serum concentration of CYP3A4 substrates. Avoid combination.
Grapefruit juice: Grapefruit juice may decrease the metabolism of tacrolimus (systemic). Avoid combination.
Grazoprevir: Grazoprevir may increase the serum concentration of tacrolimus (systemic).
Monitor therapy.
Highest risk QTc-prolonging agents: QTc-prolonging agents (indeterminate risk and risk modifying) may enhance the QTc-prolonging effect of highest risk QTc-prolonging agents.
Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification.
Idelalisib: Idelalisib may increase the serum concentration of CYP3A4 substrates. Avoid combination.
Itraconazole: ltraconazole may increase the serum concentration of tacrolimus (systemic).
Management: Monitor tacrolimus concentrations closely and adjust dose as necessary when concomitantly administered with itraconazole. Tacrolimus dose reductions will likely be required. The magnitude of this interaction may be greater in older patients. Consider therapy modification
Ivacaftor: Ivacaftor may increase the serum concentration of CYP3A4 substrates. Monitor therapy.
Ketoconazole (systemic): Ketoconazole (systemic) may increase the serum concentration of tacrolimus (systemic).
Management: Tacrolimus dose adjustment may be required when taken with ketoconazole due to elevated plasma concentrations of tacrolimus. Monitor tacrolimus concentrations and clinical response closely. Consider therapy modification.
Ledipasvir: P-glycoprotein/ABCB1 inhibitors may increase the serum concentration of ledipasvir. Monitor therapy.
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased.
Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification.
Levofloxacin (systemic): Levofloxacin (systemic) may enhance the QTc-prolonging effect of tacrolimus (systemic). Levofloxacin (systemic) may increase the serum concentration of tacrolimus (systemic). Monitor therapy.
Luliconazole: Luliconazole may increase the serum concentration of CYP3A4 substrates. Monitor therapy.
Mifepristone: Mifepristone may enhance the QTc-prolonging effect of tacrolimus (systemic). Mifepristone may increase the serum concentration of tacrolimus (systemic).
Management: Avoid tacrolimus during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination.
Mitotane: Mitotane may decrease the serum concentration of CYP3A4 substrates.
Management: Doses of CYP3AA substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification.
Moderate risk QTc-prolonging agents: QTc-prolonging agents (indeterminate risk and risk modifying) may enhance the QTc prolonging effect of moderate risk QTc-prolonging agents. Monitor therapy.
Naloxegol: P-glycoprotein/ABCB 1 inhibitors may increase the serum concentration of naloxegol. Monitor therapy.
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination.
Nelfinavir: Nelfinavir may increase the serum concentration of tacrolimus (systemic). Avoid combination.
Netupitant: Netupitant may increase the serum concentration of CYP3A4 substrates. Monitor therapy.
Nivolumab: Immunosuppressants may diminish the therapeutic effect of nivolumab. Consider therapy modification.
Nonsteroidal anti-inflammatory agents (NSAIDs): Nonsteroidal anti-inflammatory agents (NSAIDs) may enhance the nephrotoxic effect of tacrolimus (systemic). Monitor therapy.
Ombitasvir, paritaprevir, and ritonavir: Ombitasvir, paritaprevir, and ritonavir may increase the serum concentration of tacrolimus (systemic).
Management: Do not administer tacrolimus on the day the ombitasvir/paritaprevir/ritonavir product is initiated. Beginning the day after initiation, restart tacrolimus at a reduced dose. Typical tacrolimus dose is 0.5 mg every 7 days. Consider therapy modification.
Ombitasvir, paritaprevir, ritonavir, and dasabuvir: Ombitasvir, paritaprevir, ritonavir, and dasabuvir may increase the serum concentration of tacrolimus (systemic).
Management: Do not administer tacrolimus on the day the ombitasvir/paritaprevir/ritonavir/dasabuvir product is initiated. Beginning the day after initiation, restart tacrolimus at a reduced dose. Typical tacrolimus dose is 0.5 mg every 7 days. Consider therapy modification.
Osimertinib: Osimertinib may increase the serum concentration of CYP3A4 substrates. Osimertinib may decrease the serum concentration of CYP3A4 substrates. Monitor therapy.
Palbociclib: Palbociclib may increase the serum concentration of CYP3A4 substrates. Monitor therapy.
Pazopanib: P-glycoprotein/ABCB1 inhibitors may increase the serum concentration of pazopanib. Avoid combination.
P-glycoprotein/ABCB1 inducers: P-glycoprotein/ABCB1 inducers may decrease the serum concentration of P-glycoprotein/ABCB1 substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy.
P-glycoprotein/ABCB1 inhibitors: P-glycoprotein/ABCB1 inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy.
P-glycoprotein/ABCB1 substrates: P-glycoprotein/ABCB1 inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy.
Phenytoin: Phenytoin may decrease the serum concentration of tacrolimus (systemic). Tacrolimus (systemic) may increase the serum concentration of phenytoin. Monitor therapy.
Pimecrolimus: Pimecrolimus may enhance the adverse/toxic effect of immunosuppressants. Avoid combination.
Posaconazole: Posaconazole may increase the serum concentration of tacrolimus (systemic).
Management: Reduce tacrolimus dose to approximately one third of original dose when starting posaconazole. Tacrolimus blood concentrations should be monitored closely during and at discontinuation of posaconazole. Consider therapy modification.
Potassium-sparing diuretics: Potassium-sparing diuretics may enhance the hyperkalemic effect of tacrolimus (systemic). Avoid combination.
Protease inhibitors (Pls): Protease inhibitors may decrease the metabolism of tacrolimus (systemic). Consider therapy modification.
Proton pump inhibitors (PPIs): Proton pump inhibitors may increase the serum concentration of tacrolimus (systemic).
Management: Tacrolimus dose adjustment may be required. Rabeprazole, pantoprazole, or selected H₂-receptor antagonists (i.e., ranitidine or famotidine) may be less likely to interact. Genetic testing may predict patients at highest risk.
Exceptions: Pantoprazole. Consider therapy modification.
Prucalopride: P-glycoprotein/ABCB1 inhibitors may increase the serum concentration of prucalopride. Monitor therapy.
Ranolazine: Ranolazine may increase the serum concentration of tacrolimus (systemic). Monitor therapy.
Rifamycin derivatives: Rifamycin derivatives may decrease the serum concentration of tacrolimus (systemic).
Management: Consider alternatives when possible. If these combination are used, monitor for reduced tacrolimus concentrations/effects following rifamycin initiation/dose increase, or increased concentrations/effects following rifamycin discontinuation/dose decrease. Consider therapy modification.
Rifaximin: P-glycoprotein/ABCB1 inhibitors may increase the serum concentration of rifaximin. Monitor therapy.
Ritonavir: Ritonavir may increase the serum concentration of tacrolimus (systemic).
Management: Tacrolimus dose reductions may be needed with concurrent ritonavir. Monitor tacrolimus concentrations closely to determine dose; doses of tacrolimus 0.5 mg to 1 mg every week may be adequate. Consider therapy modification.
Roflumilast: Roflumilast may enhance the immunosuppressive effect of immunosuppressants. Consider therapy modification.
Schisandra: Schisandra may increase the serum concentration of tacrolimus (systemic). Monitor therapy.
Sevelamer: Sevelamer may decrease the serum concentration of tacrolimus (systemic). Monitor therapy.
Silodosin: P-glycoprotein/ABCB1 inhibitors may increase the serum concentration of silodosin. Avoid combination.
Siltuximab: Siltuximab may decrease the serum concentration of CYP3A4 substrates. Monitor therapy.
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of sipuleucel-T. Monitor therapy.
Sirolimus: Tacrolimus (systemic) may enhance the adverse/toxic effect of sirolimus. Sirolimus may enhance the adverse/toxic effect of tacrolimus (systemic). Sirolimus may decrease the serum concentration of tacrolimus (systemic). Avoid combination.
St John's Wort: St John's Wort may decrease the serum concentration of tacrolimus (systemic). Consider therapy modification.
Stiripentol: Stiripentol may increase the serum concentration of CYP3A4 substrates.
Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity.
Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification.
Tacrolimus (topical): Tacrolimus (topical) may enhance the adverse/toxic effect of immunosuppressants. Avoid combination.
Telaprevir: Telaprevir may increase the serum concentration of tacrolimus (systemic).
Management: Significant tacrolimus dose reductions are likely to be required if used with telaprevir. Concurrent use should be performed with great caution and close monitoring of both tacrolimus concentrations and clinical response. Consider therapy modification.
Temsirolimus: Tacrolimus (systemic) may enhance the adverse/toxic effect of temsirolimus. Temsirolimus may enhance the adverse/toxic effect of tacrolimus (systemic). Temsirolimus may decrease the serum concentration of tacrolimus (systemic). Avoid combination.
Tocilizumab: Tocilizumab may decrease the serum concentration of CYP3A4 substrates. Monitor therapy.
Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of tofacitinib.
Management: Concurrent use with antirheumatic doses of methotrexate or non-biologic disease modifying antirheumatic drugs (DMARDSs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination.
Tofisopam: Tofisopam may increase the serum concentration of tacrolimus (systemic). Monitor therapy.
Topotecan: P-glycoprotein/ABCB1 inhibitors may increase the serum concentration of topotecan. Avoid combination.
Trastuzumab: Trastuzumab may enhance the neutropenic effect of immunosuppressants. Monitor therapy.
Vaccines (inactivated): Immunosuppressants may diminish the therapeutic effect of vaccines (inactivated).
Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification.
Vaccines (live): Immunosuppressants may enhance the adverse/toxic effect of vaccines (live).
Immunosuppressants may diminish the therapeutic effect of vaccines (live).
Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination.
Venetoclax: P-glycoprotein/ABCB1 inhibitors may increase the serum concentration of venetoclax.
Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification.
Vincristine (liposomal): P-glycoprotein/ABCB1 inhibitors may increase the serum concentration of vincristine (liposomal). Avoid combination.
Voriconazole: Voriconazole may increase the serum concentration of tacrolimus (systemic).
Management: When starting voriconazole in patients already receiving tacrolimus, reduce tacrolimus dose to one-third of the original dose. Monitor tacrolimus blood levels closely. Consider therapy modification.
Drug/Food interactions: Food decreases rate and extent of absorption. High-fat meals have most pronounced effect (37% decrease in AUC and 77% decrease in maximum serum concentration (C_max)). Grapefruit juice, a CYP3A4 inhibitor, may increase serum level and/or toxicity of tacrolimus.
Management: Administer with or without food, but be consistent. Avoid concurrent use of grapefruit juice.

Storage Condition: Store below 30°C.

Immunosuppressants

L04AD02 - tacrolimus ; Belongs to the class of calcineurin inhibitors. Used as immunosuppressants.

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