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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
Prograf® may be confused with Gengraf®, Prozac®
Tacrolimus may be confused with everolimus, pimecrolimus, sirolimus, temsirolimus
Pronunciation
(ta KROE li mus)
U.S. Brand Names
Index Terms
Generic Available
Yes: Capsule
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Oral/injection: Prevention of organ rejection in heart, kidney, or liver transplant recipients
Topical: Moderate-to-severe atopic dermatitis in patients not responsive to conventional therapy or when conventional therapy is not appropriate
Use: Dental
Topical: Treatment of severe ulcerative or vesicobullous lesions (usually in consult with patient's physician)
Use: Unlabeled/Investigational
Prevention of organ rejection in lung, small bowel transplant recipients; prevention and treatment of graft-versus-host disease (GVHD) in allogenic hematopoietic stem cell transplantation
Pregnancy Risk Factor
C
Pregnancy Considerations
Adverse events were observed in animal reproduction studies. Tacrolimus crosses the human placenta and is measurable in the cord blood, amniotic fluid, and newborn serum. Tacrolimus concentrations in the placenta may be higher than the maternal serum. No consistent pattern of congenital anomalies has been observed. Transient neonatal hyperkalemia and renal dysfunction have been reported.The National Transplantation Pregnancy Registry (NTPR, Temple University) is a registry for pregnant women taking immunosuppressants following any solid organ transplant. The NTPR encourages reporting of all immunosuppressant exposures during pregnancy in transplant recipients at 877-955-6877.
Lactation
Enters breast milk/not recommended
Breast-Feeding Considerations
Concentrations of tacrolimus in breast milk are lower than that of the maternal serum. The low bioavailability of tacrolimus following oral absorption may also decrease the amount of exposure to a nursing infant.
Contraindications
Hypersensitivity to tacrolimus or any component of the formulation
Warnings/Precautions
Boxed warnings:
• Systemic:
- Experienced physician: See “Other warnings/precautions” below.
- Infection: See “Concerns related to adverse effects” below.
- Malignancy: See “Concerns related to adverse effects” below.
• Topical: See “Dosage form specific issues” below.
Concerns related to adverse events:
• Anaphylaxis: Injection: Hypersensitivity reactions, including anaphylaxis, have been reported. Since the injection contains a castor oil derivative, its use should be limited to patients unable to take capsules. Monitor patient for a minimum of 30 minutes after initiation of infusion and then at frequent intervals; discontinue infusion if anaphylaxis occurs.
• Diabetes mellitus (post-transplant): Insulin-dependent post-transplant diabetes mellitus (PTDM) has been reported, including in patients without pretransplant history of diabetes mellitus; insulin dependence may be reversible; increased risk in African-American and Hispanic kidney transplant patients.
• Hyperkalemia: Mild-to-severe hyperkalemia may occur; monitor potassium levels and avoid use of potassium-sparing diuretics.
• Infection: [U.S. Boxed Warning]: Immunosuppressive agents, including tacrolimus, increase the risk of infection. Immune suppression may increase the risk of opportunistic infections. Latent viral infections may be activated (including BK virus which is associated with nephropathy and JC virus which is associated with progressive multifocal leukoencephalopathy) and result in serious adverse effects. Use caution with concurrent immunosuppressive therapy; oversuppression can increase the risk of infection.
• Malignancy: [U.S. Boxed Warning]: Immunosuppressive agents, including tacrolimus, may be associated with the development of lymphoma or other malignancies. Immunosuppressant therapy is associated with an increased risk of skin cancer; limit sun and ultraviolet light exposure; use appropriate sun protection.
• Nephrotoxicity: Nephrotoxicity may occur when used in high doses, in patients with impaired renal function, or with other nephrotoxic drugs (eg, sirolimus, cyclosporine).
• Neurotoxicity: Neurotoxicity may occur especially when used in high doses; tremor, headache, coma, and delirium have been reported and are associated with serum concentrations. Seizures may also occur.
• Posterior reversible encephalopathy syndrome (PRES): Development of PRES may occur during tacrolimus therapy; symptoms (altered mental status, headache, hypertension, seizures, and visual disturbances) are reversible with dose reduction or discontinuation of immunosuppressant therapy; stabilize blood pressure and reduce dose with suspected or confirmed PRES diagnosis.
Disease-related concerns:
• Cardiovascular: Myocardial hypertrophy has been reported; may be reversible with dose reduction or discontinuation.
• Hematologic malignancies: Absorption varies greatly in bone marrow transplantation relative to whether patients receive total body radiation and/or methotrexate.
• Hepatic impairment: Use with caution; utilize lowest recommended I.V. or oral dose; additional dose reductions may be necessary; severe hepatic impairment (Child-Pugh score ?10) may require decreased dose.
• Hypertension: Use with caution in patients with hypertension; mild-to-moderate hypertension may occur (severe hypertension is rare); antihypertensive treatment may be necessary; avoid use of potassium-sparing diuretics due to risk of hyperkalemia.
• Renal impairment: Due to potential for further nephrotoxicity, utilize lowest recommended I.V. or oral dose; additional dose reductions may be necessary; delay initiation (?48 hours) if postoperative oliguria occurs.
Concurrent drug therapy:
• Cyclosporine: Avoid concurrent use; a period of ?24 hours should elapse between discontinuation of tacrolimus or cyclosporine and initiation of the other. Delay initiation further with persistently elevated tacrolimus/cyclosporine levels
• Mycophenolate: Exposure to mycophenolic acid may be higher with concurrent tacrolimus or in patients changing therapy from cyclosporine to tacrolimus; increased risk of adverse effects.
• Sirolimus: Concurrent use not recommended; may result in an increased risk of wound healing complications, renal function impairment, and insulin-dependent post-transplant diabetes mellitus.
Special populations:
• Pediatrics: Successful liver transplants have been completed; limited experience in pediatric kidney and heart transplants. In general, for pediatric patients to maintain blood trough concentrations similar to adults, higher doses are required.
Dosage form specific issues:
• Injection: Each mL of injection contains polyoxyl 60 hydrogenated castor oil (HCO-60) (200 mg) and dehydrated alcohol USP 80% v/v. Anaphylaxis has been reported with the injection, use should be reserved for those patients not able to take oral medications.
• Topical: [U.S. Boxed Warning]: Topical calcineurin inhibitors have been associated with rare cases of malignancy (including skin and lymphoma), therefore it should be limited to short-term and intermittent treatment using the minimum amount necessary for the control of symptoms and only on involved areas. Use in children <2 years of age is not recommended, children ages 2-15 should only use the 0.03% ointment.Avoid use on malignant or premalignant skin conditions (eg cutaneous T-cell lymphoma). Should not be used in immunocompromised patients. Do not apply to areas of active bacterial or viral infection; infections at the treatment site should be cleared prior to therapy. Topical calcineurin agents are considered second-line therapies in the treatment of atopic dermatitis/eczema, and should be limited to use in patients who have failed treatment with other therapies. Patients with atopic dermatitis are predisposed to skin infections, and tacrolimus therapy has been associated with risk of developing eczema herpeticum, varicella zoster, and herpes simplex. If atopic dermatitis is not improved in <6 weeks, re-evaluate to confirm diagnosis. May be associated with development of lymphadenopathy; possible infectious causes should be investigated. Discontinue use in patients with unknown cause of lymphadenopathy or acute infectious mononucleosis. Acute renal failure has been observed (rarely) with topical use. Not recommended for use in patients with skin disease which may increase systemic absorption (eg, Netherton's syndrome). Minimize sunlight exposure during treatment. Safety not established in patients with generalized erythroderma. Safety of intermittent use for >1 year has not been established, particularly since the effect on immune system development is unknown.
Other warnings/precautions:
• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of a physician experienced in immunosuppressive therapy and organ transplantation in a facility appropriate for monitoring and managing therapy.
• Monitoring of concentrations: Closely monitor tacrolimus levels to assist in dose adjustment, monitor compliance, prevent organ rejection, and reduce drug-related toxicity.
Adverse Reactions
As reported for kidney, liver, and heart transplantation:
Oral, I.V.:
?15%:
Cardiovascular: Hypertension (13% to 62%), edema (peripheral 11% to 36%), chest pain (19%), edema (18%), pericardial effusion (heart transplant 15%)
Central nervous system: Headache (25% to 64%), insomnia (30% to 64%), pain (24% to 63%), fever (19% to 48%), postprocedural pain (kidney transplant 29%), dizziness (19%)
Dermatologic: Pruritus (15% to 36%), rash (10% to 24%)
Endocrine & metabolic: Hypophosphatemia (28% to 49%), hypomagnesemia (16% to 48%), hyperglycemia (21% to 47%), hyperkalemia (8% to 45%), hyperlipemia (10% to 31%), hypokalemia (13% to 29%), diabetes mellitus (24% to 26%)
Gastrointestinal: Diarrhea (24% to 72%), abdominal pain (29% to 59%), nausea (32% to 46%), constipation (23% to 36%), anorexia (7% to 34%), vomiting (14% to 29%), dyspepsia (18% to 28%)
Genitourinary: Urinary tract infection (16% to 34%)
Hematologic: Anemia (5% to 50%), leukopenia (13% to 48%), leukocytosis (8% to 32%), thrombocytopenia (14% to 24%)
Hepatic: Liver function tests abnormal (6% to 36%), ascites (7% to 27%)
Local: Incision site complication (kidney transplant 28%)
Neuromuscular & skeletal: Tremor (34% to 56%; heart transplant 15%), weakness (11% to 52%), paresthesia (17% to 40%), back pain (17% to 30%), arthralgia (25%)
Renal: Abnormal kidney function (36% to 56%), creatinine increased (23% to 45%), BUN increased (12% to 30%), oliguria (18% to 19%)
Respiratory: Atelectasis (5% to 28%), pleural effusion (30% to 36%), dyspnea (5% to 29%), cough increased (18%), bronchitis (17%)
Miscellaneous: Infection (24% to 45%), CMV infection (32%), graft dysfunction (kidney transplant 24%)
<15%:
Cardiovascular: Abnormal ECG (QRS or ST segment abnormal), arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiopulmonary failure, deep thrombophlebitis, heart failure, heart rate decreased, hemorrhage, hemorrhagic stroke, hypervolemia, hypotension, peripheral vascular disorder, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilation, ventricular fibrillation
Central nervous system: Abnormal dreams, abnormal thinking, agitation, amnesia, anxiety, chills, confusion, depression, emotional lability, encephalopathy, flaccid paralysis, hallucinations, mood elevated, nervousness, psychosis, quadriparesis, seizure, somnolence
Dermatologic: Acne, alopecia, bruising, cellulitis, exfoliative dermatitis, fungal dermatitis, hirsutism, photosensitivity reaction, skin discoloration, skin disorder, skin neoplasm, skin ulcer, wound healing impaired
Endocrine & metabolic: Acidosis, alkalosis, bicarbonate decreased, Cushing's syndrome, dehydration, gout, hypercholesterolemia, hyper-/hypocalcemia, hyperphosphatemia, hyperuricemia, hypoproteinemia, serum iron decreased
Gastrointestinal: Appetite increased, cramps, duodenitis, dysphagia, enlarged abdomen, esophagitis (including ulcerative), flatulence, gastritis, gastroesophagitis, GI perforation/hemorrhage, ileus, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis, weight gain
Genitourinary: Bladder spasm, cystitis, dysuria, nocturia, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis
Hematologic: Coagulation disorder, decreased prothrombin, hypochromic anemia, polycythemia
Hepatic: Alkaline phosphatase increased, bilirubinemia, cholangitis, cholestatic jaundice, GGT increased, hepatitis (including granulomatous), jaundice, LDH increased, liver damage
Local: Phlebitis
Neuromuscular & skeletal: Hypertonia, incoordination, joint disorder, leg cramps, myalgia, myasthenia, myoclonus, nerve compression, neuropathy, osteoporosis
Ocular: Abnormal vision, amblyopia
Otic: Ear pain, otitis media, tinnitus
Renal: Acute renal failure, albuminuria, BK nephropathy, hematuria, hydronephrosis, renal tubular necrosis, toxic nephropathy
Respiratory: Asthma, lung disorder, pharyngitis, pneumonia, pneumothorax, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration
Miscellaneous: Abscess, abnormal healing, allergic reaction, crying, diaphoresis, flu-like syndrome, generalized spasm, hernia, herpes simplex, peritonitis, sepsis, writing impaired
Topical (as reported in children and adults, unless otherwise noted):
>10%:
Central nervous system: Headache (5% to 20%), fever (1% to 21%)
Dermatologic: Skin burning (43% to 58%; tends to improve as lesions resolve), pruritus (41% to 46%), erythema (12% to 28%)
Respiratory: Increased cough (children 18%)
Miscellaneous: Flu-like syndrome (23% to 31%), allergic reaction (4% to 12%)
1% to 10%:
Cardiovascular: Peripheral edema (adults 3% to 4%)
Central nervous system: Hyperesthesia ( adults 3% to 7%), pain (1% to 2%)
Dermatologic: Skin tingling (2% to 8%), acne ( adults 4% to 7%), localized flushing (following ethanol consumption; adults 3% to 7%), folliculitis (2% to 6%), urticaria (1% to 6%), rash (2% to 5%), pustular rash (2% to 4%), vesiculobullous rash (children 4%), contact dermatitis (3% to 4%), cyst (adults 1% to 3%), eczema herpeticum (1% to 2%), fungal dermatitis (adults 1% to 2%), sunburn (adults 1% to 2%), alopecia (adults 1%), dry skin (children 1%)
Endocrine & metabolic: Dysmenorrhea (adult females 4%)
Gastrointestinal: Diarrhea (3% to 5%), dyspepsia (adults 1% to 4%), abdominal pain (children 3%), vomiting (adults 1%), gastroenteritis (adults 2%), nausea (children 1%), tooth disorder (adults 1%)
Neuromuscular & skeletal: Paresthesia (adults 3%), myalgia (adults 2% to 3%), weakness (adults 2% to 3%), arthralgia (adults 1% to 3%), back pain (adults 2%)
Ocular: Conjunctivitis (2% adults)
Otic: Otitis media (12% children)
Respiratory: Rhinitis (6% children), sinusitis (2% to 4% adults), bronchitis (2% adults), pneumonia (1% adults)
Miscellaneous: Varicella/herpes zoster (1% to 5%), lymphadenopathy (3% children)
Oral, I.V., topical: Postmarketing and/or case reports (limited to important or life-threatening): Acute renal failure, anaphylaxis, anaphylactoid reaction, angioedema, ARDS, arrhythmia, atrial fibrillation, atrial flutter, basal cell carcinoma, bile duct stenosis, blindness, cardiac arrest, cerebral infarction, cerebrovascular accident, deafness, delirium, DIC, hemiparesis, hemolytic-uremic syndrome, hemorrhagic cystitis, hepatic necrosis, hepatotoxicity, interstitial lung disease, leukoencephalopathy, lymphoproliferative disorder (related to EBV), malignant melanoma, myocardial hypertrophy (associated with ventricular dysfunction; reversible upon discontinuation), MI, neutropenia, osteomyelitis, pancreatitis (hemorrhagic and necrotizing), pancytopenia, paresthesia, photosensitivity reaction (topical), posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, QTc prolongation, respiratory failure, seizure, septicemia, skin discoloration (topical), squamous cell carcinoma, Stevens-Johnson syndrome, syncope, toxic epidermal necrolysis, thrombocytopenic purpura, torsade de pointes, TTP, veno-occlusive hepatic disease, venous thrombosis, ventricular fibrillation
Note: Calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) have been reported (with concurrent sirolimus).
Metabolism/Transport Effects
Substrate of CYP3A4 (major); Inhibits CYP3A4 (weak)
Drug Interactions
Alcohol (Ethyl): Tacrolimus may enhance the dermatologic adverse effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Antidepressants (Serotonin Reuptake Inhibitor/Antagonist): May decrease the metabolism of Tacrolimus. Exceptions: TraZODone. Risk D: Consider therapy modification
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Tacrolimus. Exceptions: Miconazole. Risk D: Consider therapy modification
Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Calcium Channel Blockers (Dihydropyridine): May increase the serum concentration of Tacrolimus. Exceptions: Clevidipine. Risk C: Monitor therapy
Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of Tacrolimus. Risk C: Monitor therapy
Caspofungin: May decrease the serum concentration of Tacrolimus. Risk C: Monitor therapy
Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Cinacalcet: May decrease the serum concentration of Tacrolimus. Risk C: Monitor therapy
Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Colchicine: P-Glycoprotein 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. Risk D: Consider therapy modification
CycloSPORINE: Tacrolimus may enhance the nephrotoxic effect of CycloSPORINE. CycloSPORINE may enhance the nephrotoxic effect of Tacrolimus. CycloSPORINE may increase the serum concentration of Tacrolimus. Tacrolimus may increase the serum concentration of CycloSPORINE. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dabigatran Etexilate: P-Glycoprotein Inhibitors may increase the serum concentration of Dabigatran Etexilate. Risk X: Avoid combination
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Fluconazole: May decrease the metabolism of Tacrolimus. Risk D: Consider therapy modification
Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification
Grapefruit Juice: May decrease the metabolism of Tacrolimus. Risk X: Avoid combination
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. Risk D: Consider therapy modification
Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Macrolide Antibiotics: May increase the serum concentration of Tacrolimus. Exceptions: Dirithromycin [Off Market]; Spiramycin. Risk C: Monitor therapy
MetroNIDAZOLE: May decrease the metabolism of Calcineurin Inhibitors. Risk C: Monitor therapy
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein 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.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein 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.). Risk C: Monitor therapy
P-Glycoprotein Substrates: P-Glycoprotein Inhibitors may increase the serum concentration of P-Glycoprotein 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.). Risk C: Monitor therapy
Phenytoin: May increase the metabolism of Tacrolimus. Tacrolimus may increase the serum concentration of Phenytoin. Risk C: Monitor therapy
Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination
Protease Inhibitors: May decrease the metabolism of Tacrolimus. Risk D: Consider therapy modification
Proton Pump Inhibitors: May increase the serum concentration of Tacrolimus. 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. Risk D: Consider therapy modification
QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification
QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Rifamycin Derivatives: May increase the metabolism of Tacrolimus. Risk D: Consider therapy modification
Rivaroxaban: P-Glycoprotein Inhibitors may increase the serum concentration of Rivaroxaban. Risk C: Monitor therapy
Silodosin: P-Glycoprotein Inhibitors may increase the serum concentration of Silodosin. Risk X: Avoid combination
Sirolimus: May enhance the adverse/toxic effect of Tacrolimus. Tacrolimus may enhance the adverse/toxic effect of Sirolimus. Sirolimus may decrease the serum concentration of Tacrolimus. Risk X: Avoid combination
St Johns Wort: May decrease the serum concentration of Tacrolimus. Risk D: Consider therapy modification
Temsirolimus: May enhance the adverse/toxic effect of Tacrolimus. An increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) has been described with concomitant sirolimus and tacrolimus use. Risk D: Consider therapy modification
Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination
Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
Topotecan: P-Glycoprotein Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live virus vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: Localized flushing (redness, warm sensation) may occur at application site of topical tacrolimus following ethanol consumption.
Food: Decreases rate and extent of absorption. High-fat meals have most pronounced effect (37% decrease in AUC, 77% decrease in Cmax). Grapefruit juice, CYP3A4 inhibitor, may increase serum level and/or toxicity of tacrolimus; avoid concurrent use.
Herb/Nutraceutical: St John's wort: May reduce tacrolimus serum concentrations (avoid concurrent use).
Storage
Injection: Prior to dilution, store at 5°C to 25°C (41°F to 77°F). Following dilution, stable for 24 hours in D5W or NS in glass or polyethylene containers.
Capsules and ointment: Store at room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Reconstitution
Dilute with 5% dextrose injection or 0.9% sodium chloride injection to a final concentration between 0.004 mg/mL and 0.02 mg/mL.
Compatibility
Variable stability (consult detailed reference) in D5W, NS (only in glass or polyethylene containers).
Y-site administration: Compatible: Aminophylline, amphotericin B, ampicillin, ampicillin/sulbactam, anidulafungin, benztropine, calcium gluconate, cefazolin, cefotetan, ceftazidime, ceftriaxone, cefuroxime, chloramphenicol, cimetidine, ciprofloxacin, clindamycin, co-trimoxazole, dexamethasone sodium phosphate, digoxin, diphenhydramine, dobutamine, dopamine, doxycycline, erythromycin lactobionate, esmolol, fluconazole, furosemide, gentamicin, haloperidol, heparin, hydrocortisone sodium succinate, hydromorphone, imipenem/cilastatin, insulin (regular), isoproterenol, leucovorin, lorazepam, methylprednisolone sodium succinate, metoclopramide, metronidazole, micafungin, morphine, multivitamins, nitroglycerin, oxacillin, penicillin G potassium, phenytoin, piperacillin, potassium chloride, propranolol, ranitidine, sodium bicarbonate, sodium nitroprusside, sodium tetradecyl sulfate, tobramycin, vancomycin. Incompatible: Acyclovir, ganciclovir.
Compatibility when admixed: Compatible: Cimetidine.
Mechanism of Action
Suppresses cellular immunity (inhibits T-lymphocyte activation), by binding to an intracellular protein, FKBP-12 and complexes with calcineurin dependant proteins to inhibit calcineurin phosphatase activity
Pharmacodynamics/Kinetics
Absorption: 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 AUC
Oral: Incomplete and variable; the rate and extent of absorption is affected by food and may be most pronounced with a high-fat meal
Topical: Minimally absorbed; serum concentrations range from undetectable to 20 ng/mL (~2 ng/mL in majority of adult patients studied)
Distribution: Vd: Children: 0.5-4.7 L/kg; Adults: 0.55-2.47 L/kg
Protein binding: 99% primarily to albumin and alpha1-acid glycoprotein glycoprotein
Metabolism: Extensively hepatic via CYP3A4 to eight possible metabolites (major metabolite, 31-demethyl tacrolimus, shows same activity as tacrolimus in vitro)
Bioavailability: Oral: Children: 7% to 55%, Adults: 7% to 32%; Topical: <0.5%; Absolute: Unknown
Half-life elimination: Variable, 23-46 hours in healthy volunteers; 2.1-36 hours in transplant patients
Time to peak: 0.5-6 hours
Excretion: Feces (~93%); urine (<2% as unchanged drug)
Dosage
Oral:
Prevention of organ rejection in transplant recipients: The initial dose of tacrolimus should begin no sooner than 6 hours post-transplant; adjunctive therapy with corticosteroids is recommended early post-transplant. I.V. route should only be used in patients not able to take oral medications and continued only until oral medication can be tolerated; anaphylaxis has been reported with I.V. administration. If switching from I.V. to oral, the oral dose should be started 8-12 hours after stopping the infusion.
Children: Patients without pre-existing renal or hepatic dysfunction have required (and tolerated) higher doses than adults to achieve similar blood concentrations. It is recommended that therapy be initiated at
high end
of the recommended adult I.V. and oral dosing ranges; dosage adjustments may be required.
Liver transplant: Initial dose: 0.15-0.20 mg/kg/day in 2 divided doses, given every 12 hours
Adults:
Heart transplant: Initial dose: 0.075 mg/kg/day in 2 divided doses, given every 12 hours. Use in combination with azathioprine or mycophenolate mofetil is recommended.
Kidney transplant: Initial dose: 0.2 mg/kg/day in combination with azathioprine or 0.1 mg/kg/day in combination with mycophenolate mofetil. Administer in 2 divided doses, given every 12 hours; initial dose may be given within 24 hours of transplant, but should be delayed until renal function has recovered; African-American patients may require larger doses to maintain trough concentration.
Liver transplant: Initial dose: 0.1-0.15 mg/kg/day in 2 divided doses, given every 12 hours
Prevention of graft-versus-host disease (unlabeled use): Children and Adults: Convert from I.V. to oral dose (1:4 ratio): Multiply total daily I.V. dose times 4 and administer in 2 divided oral doses per day, every 12 hours (Uberti 1999; Yanik, 2000).
Treatment of graft-versus-host disease (unlabeled use): Adults: 0.06 mg/kg twice daily (Furlong, 2000; Przepiorka, 1999)
I.V.:
Prevention of organ rejection in transplant recipients: The initial dose of tacrolimus should begin no sooner than 6 hours post-transplant; adjunctive therapy with corticosteroids is recommended early post-transplant. I.V. route should only be used in patients not able to take oral medications and continued only until oral medication can be tolerated; anaphylaxis has been reported with I.V. administration. If switching from I.V. to oral, the oral dose should be started 8-12 hours after stopping the infusion.
Children: It is recommended that therapy be initiated at the
high end
of the dosing range.
Liver transplant: Initial dose: 0.03-0.05 mg/kg/day as a continuous infusion
Adults: It is recommended that therapy be initiated at the
lower end
of the dosing range.
Heart transplant: Initial dose: 0.01 mg/kg/day as a continuous infusion. Use in combination with azathioprine or mycophenolate mofetil is recommended.
Kidney transplant: Initial dose: 0.03-0.05 mg/kg/day as a continuous infusion. Use in combination with azathioprine or mycophenolate mofetil is recommended.
Liver transplant: Initial dose: 0.03-0.05 mg/kg/day as a continuous infusion.
Prevention of graft-versus-host disease (unlabeled use): Children and Adults: Initial: 0.03 mg/kg/day (based on lean body weight) as continuous infusion. Treatment should begin at least 24 hours prior to stem cell infusion and continued only until oral medication can be tolerated (Przepiorka, 1999; Yanik, 2000).
Treatment of graft-versus-host disease (unlabeled use): Adults: Initial: 0.03 mg/kg/day (based on lean body weight) as continuous infusion (Furlong 2000, Przepiorka 1999)
Topical:
Atopic dermatitis (moderate-to-severe):
Children ?2 years: Apply minimum amount of 0.03% ointment to affected area twice daily; rub in gently and completely. Discontinue use when symptoms have cleared. If no improvement within 6 weeks, patients should be re-examined to confirm diagnosis.
Adults: Apply minimum amount of 0.03% or 0.1% ointment to affected area twice daily; rub in gently and completely. Discontinue use when symptoms have cleared. If no improvement within 6 weeks, patients should be re-examined to confirm diagnosis.
Dosing adjustment in renal impairment: Systemic therapy: Evidence suggests that lower doses should be used; patients should receive doses at the lowest value of the recommended I.V. and oral dosing ranges; further reductions in dose below these ranges may be required.
Tacrolimus therapy should usually be delayed up to 48 hours or longer in patients with postoperative oliguria.
Hemodialysis: Not removed by hemodialysis; supplemental dose is not necessary.
Peritoneal dialysis: Significant drug removal is unlikely based on physiochemical characteristics.
Dosing adjustment in hepatic impairment: Systemic therapy: Use of tacrolimus in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood levels of tacrolimus. The presence of moderate-to-severe hepatic dysfunction (serum bilirubin >2 mg/dL; Child-Pugh score ?10) appears to affect the metabolism of tacrolimus. The half-life of the drug was prolonged and the clearance reduced after I.V. administration. The bioavailability of tacrolimus was also increased after oral administration. The higher plasma concentrations as determined by ELISA, in patients with severe hepatic dysfunction are probably due to the accumulation of metabolites of lower activity. These patients should be monitored closely and dosage adjustments should be considered. Some evidence indicates that lower doses could be used in these patients.
Administration: Oral
Administer on an empty stomach; be consistent with timing and composition of meals if GI intolerance occurs and administration with food becomes necessary (per manufacturer). If dosed once daily (not common), administer in the morning. If dosed twice daily, doses should be 12 hours apart. If the morning and evening doses differ, the larger dose (differences are never >0.5-1 mg) should be given in the morning. If dosed 3 times/day, separate doses by 8 hours.
Administration: I.V.
If I.V. administration is necessary, administer by continuous infusion only. Do not use PVC tubing when administering diluted solutions. Tacrolimus is usually intended to be administered as a continuous infusion over 24 hours.
Administration: Topical
Do not use with occlusive dressings. Burning at the application site is most common in first few days; improves as atopic dermatitis improves. Limit application to involved areas. Continue as long as signs and symptoms persist; discontinue if resolution occurs; re-evaluate if symptoms persist >6 weeks.
Administration: I.V. Detail
Do not mix with solutions with a pH ?9 (eg, acyclovir or ganciclovir) due to chemical degradation of tacrolimus (use different ports in multilumen lines). Do not alter dose with concurrent T-tube clamping. Adsorption of the drug to PVC tubing may become clinically significant with low concentrations.
Monitoring Parameters
Renal function, hepatic function, serum electrolytes (especially potassium), glucose and blood pressure, measure 3 times/week for first few weeks, then gradually decrease frequency as patient stabilizes. Whole blood concentrations should be used for monitoring (trough for oral therapy). Signs/symptoms of anaphylactic reactions during infusion should also be monitored. Patients should be monitored during the first 30 minutes of the infusion, and frequently thereafter.
Reference Range
Heart: Typical whole blood trough concentrations:
Months 1-3: 10-20 ng/mL
Months ?4: 5-15 ng/mL
Kidney transplant: Whole blood trough concentrations:
In combination with azathioprine:
Months 1-3: 7-20 ng/mL
Months 4-12: 5-15 ng/mL
In combination with mycophenolate mofetil/IL-2 receptor antagonist (eg daclizumab): Months 1-2: 4-11 ng/mL
Liver transplant: Whole blood trough concentrations: Months 1-12: 5-20 ng/mL
Prevention of graft-versus-host disease (unlabeled use): 10-20 ng/mL (Uberti, 1999) although some institutions use a lower limit of 5 ng/mL and an upper limit of 15 ng/mL (Przepiorka, 1999; Yanik, 2000)
Dietary Considerations
Capsule: Take on an empty stomach; be consistent with timing and composition of meals if GI intolerance occurs and administration with food becomes necessary (per manufacturer). Avoid grapefruit juice.
Patient Education
Take as directed, on an empty stomach. Be consistent with timing and consistency of meals if GI intolerance occurs (per manufacturer). Do not take within 2 hours before or after antacids. Do not alter dose and do not discontinue without consulting prescriber. Maintain adequate hydration during entire course of therapy unless instructed to restrict fluid intake. You will be susceptible to infection (avoid crowds and exposure to infection). If you have diabetes, monitor glucose levels closely (drug may alter glucose levels). You may experience nausea, vomiting, loss of appetite (small frequent meals, frequent mouth care may help); diarrhea; constipation (increased exercise, fluids, fruit, fluid, or fiber may help; if unresolved, consult prescriber); or muscle or back pain (mild analgesics may be recommended). Report chest pain; acute headache or dizziness; symptoms of respiratory infection, cough, or respiratory difficulty; unresolved GI effects; fatigue, chills, fever, unhealed sores, white plaques in mouth, irritation in genital area; unusual bruising or bleeding; pain or irritation on urination or change in urinary patterns; rash or skin irritation; or other unusual effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.
Topical: Before applying, wash area gently and thoroughly. Apply in thin film to affected area. Do not cover skin with bandages. Wash hands only if not treating skin on the hands. Protect skin from sunlight or exposure to UV light.
Additional Information
Additional dosing considerations:
Switch from I.V. to oral therapy: Threefold increase in dose; initiate oral therapy 8-12 hours after discontinuation of I.V.
Pediatric patients: Dose requirements are about 2 times higher compared to adults
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: Additional dosing considerations:
Switch from I.V. to oral therapy: initiate oral therapy 8-12 hours after discontinuation of I.V.
Tacrolimus is associated with more neurotoxicity, nephrotoxicity, and glucose intolerance but less hypertension, dyslipidemia, gingival hyperplasia, or hirsutism than cyclosporine.
Cardiovascular Considerations
Tacrolimus administration has been associated with torsade de pointes. Use with caution in patients at higher risk for proarrhythmia. Correct any underlying conditions that may increase the risk of torsade de pointes prior to tacrolimus administration.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Stomatitis, oral moniliasis, dysphagia, and esophagitis (including ulcerative).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Insomnia is common
Mental Health: Effects on Psychiatric Treatment
Contraindicated with ziprasidone; barbiturates and carbamazepine may decrease the effects of tacrolimus
Nursing: Physical Assessment/Monitoring
Assess other medications patient may be taking for effectiveness and interactions. Monitor blood pressure frequently. Assess results of laboratory tests prior to, during, and following therapy. Monitor response to therapy and adverse reactions. Patients with diabetes should be advised to monitor glucose levels closely (this medication may alter glucose levels). Monitor/instruct patient on appropriate use, interventions to reduce side effects, to monitor for signs of opportunistic infection, and adverse reactions to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule: 0.5 mg, 1 mg, 5 mg
Prograf®: 0.5 mg, 1 mg, 5 mg
Injection, solution:
Prograf®: 5 mg/mL (1 mL) [contains dehydrated alcohol 80% and polyoxyl 60 hydrogenated castor oil]
Ointment, topical:
Protopic®: 0.03% (30 g, 60 g, 100 g); 0.1% (30 g, 60 g, 100 g)
Pricing: U.S. (www.drugstore.com)
Capsules (Prograf)
0.5 mg (120): $245.99
1 mg (100): $409.94
5 mg (60): $1404.07
Ointment (Protopic)
0.03% (30): $122.07
0.03% (60): $230.54
0.1% (30): $114.20
0.1% (60): $223.27
0.1% (100): $370.72
Extemporaneously Prepared
Tacrolimus 0.5 mg/mL oral suspension: Mix the contents of six 5-mg tacrolimus capsules with equal amounts of Ora-Plus® and Simple Syrup, N.F., to make a final volume of 60 mL. The suspension is stable for 56 days at room temperature in glass or plastic amber prescription bottles.
Esquivel C, So S, McDiarmid S, Andrews W, and Colombani PM, “Suggested Guidelines for the Use of Tacrolimus in Pediatric Liver Transplant Patients,” Transplantation, 1996, 61(5):847-8.
Foster JA, Jacobson PA, Johnson CE, et al, “Stability of Tacrolimus in an Extemporaneously Compounded Oral Liquid (Abstract of Meeting Presentation),” American Society of Health-System Pharmacists Annual Meeting, 1996, 53:P-52(E).
Tacrolimus 1 mg/mL oral suspension: Mix the contents of six 5-mg capsules in approximately 5 mL of sterile water; add capsule contents to an empty amber bottle first, then add sterile water and agitate bottle until drug disperses and a slurry is formed. Add equal parts of Ora-Plus® (suspending agent) and Ora-Sweet® (sweetening agent) to a total volume of 30 mL. The suspension is stable for 4 months at room temperature in plastic amber prescription bottles.
Elefante A, Muindi J, West K, et al, “Long-Term Stability of a Patient-Convenient 1 mg/mL Suspension of Tacrolimus for Accurate Maintenance of Stable Therapeutic Levels,” Bone Marrow Transplant, 2006, 37(8):781-4.
References
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International Brand Names
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Last full review/revision November 2009
Content last modified November 2009
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