tacrolimus (Rx)

Brand and Other Names:Prograf, Astagraf XL, more...Hecoria, Envarsus XR
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule, immediate-release (Prograf, Hecoria)

  • 0.5mg
  • 1mg
  • 5mg

capsule, extended-release (Astagraf XL)

  • 0.5mg
  • 1mg
  • 5mg

tablet, extended-release (Envarsus XR)

  • 0.75mg
  • 1mg
  • 4mg

injectable solution (Prograf)

  • 5mg/mL

granules for oral suspension (Prograf)

  • 0.2mg/packet
  • 1mg/packet

Heart Transplant

Prophylaxis of organ rejection in patients receiving allogeneic transplants; use with azathioprine or mycophenolate mofetil (MMF) recommended

IV: 0.01 mg/kg/day by continuous infusion initially  

PO (immediate-release): 0.075 mg/kg/day divided q12hr initially  

Administer initial dose no sooner than 6 hr after transplantation

Liver Transplant

Prophylaxis of organ rejection in patients receiving allogeneic transplants

IV: 0.03-0.05 mg/kg/day by continuous infusion initially  

PO (immediate-release): 0.1-0.15 mg/kg/day divided q12hr initially  

Administer initial dose no sooner than 6 hr after transplantation

Kidney Transplant

Prograf

  • Prophylaxis of organ rejection in patients receiving allogeneic kidney transplants; used concomitantly with azathioprine or MMF or interleukin (IL)-2 receptor antagonist (eg, basiliximab or daclizumab) and corticosteroids
  • PO (with azathioprine): 0.2 mg/kg/day divided q12hr initially  
  • PO (with MMF/IL-2 receptor antagonist): 0.1 mg/kg/day divided q12hr initially
  • IV: 0.03-0.05 mg/kg/day IV by continuous infusion initially  

Astagraf XL

  • Prophylaxis of organ rejection in patients receiving kidney transplants; used concomitantly with MMF and corticosteroids, with or without basiliximab induction
  • With basiliximab induction
    • MMF, corticosteroids, and initial tacrolimus dose may be administered before or within 48 hr after completion of renal transplantation but may be delayed until renal function has recovered
    • 15 mg/kg PO once daily
  • Without induction
    • When agent is used with MMF and corticosteroids, preoperative dose should be given as single dose within 12 hr before reperfusion; initial postoperative dose should be given ≥4 hr after preoperative dose and ≤12 hr after reperfusion
    • Preoperative: 0.1 mg/kg PO once daily
    • Postoperative: 0.2 mg/kg PO once daily
    • Postoperative oliguria: Initial postoperative dose should be administered ≥6 hr and ≤48 hr after transplantation but may be delayed until renal function shows evidence of recovery

Envarsus XR

  • Conversion from immediate-release tacrolimus
    • Indicated for prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations in combination with other immunosuppressants
    • Administer an Envarsus XR dose that is 80% of the total daily dose of the tacrolimus immediate-release product
    • Monitor whole blood tacrolimus levels and titrate to achieve target whole blood trough concentration ranges of 4-11 ng/mL
  • De novo kidney transplant
    • Indication for prophylaxis of organ rejection in de novo kidney transplant patients in combination with other immunosuppressants
    • Initiate at 0.14 mg/kg/day
    • Monitor whole blood tacrolimus levels and titrate to achieve target whole blood trough concentration ranges of 6-11 ng/mL (month 1) and 4-11 ng/mL (>month 1)

Dosage Modifications

CYP3A5*1 allele

  • African-American patients, compared to Caucasian patients, may need to be titrated to higher dosages to attain comparable trough concentrations
  • ~80% of the African-American patients are carriers of the active, wild type CYP3A5*1 allele, resulting in a higher rate of tacrolimus clearance because of rapid metabolism

Coadministration with CYP3A4 inducers or inhibitors

  • Dosage adjustment of Envarsus XR may be necessary
  • Monitor tacrolimus trough concentrations ≥2 times on separate days during first week after initiation of dosing and after any change in dosage, after a change in coadministration of CYP3A inducers and/or inhibitors

Renal impairment

  • Use lower end of dosing range
  • Monitor renal function and adjust dose according to whole blood concentrations and tolerability

Hepatic impairment

  • Mild: No dosage adjustment required
  • Moderate: Monitor whole blood concentrations and adjust dose accordingly
  • Severe (mean Child-Pugh score >10): Mean clearance of tacrolimus was substantially lower compared with normal hepatic function; dosage reduction recommended; administer 80% of preconversion daily dose of immediate release dosage form when converting from tacrolimus immediate release to extended release

Dosing Considerations

Capsules and granules are not interchangeable or substitutable with other tacrolimus extended-release products; owing to the rate of absorption following administration an extended-release tacrolimus is not equivalent to immediate-release tacrolimus drug product

Under- or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions

African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients

Dosage adjusted according to clinical response and observed tacrolimus whole-blood trough concentrations

  • Monitor serum potassium
  • Kidney transplant
    • Trough level, Prograf with azathioprine (months 1-3): 7-20 ng/mL
    • Trough level, Prograf with azathioprine (months 4-12): 5-15 ng/mL
    • Trough level, Prograf with MMF/IL-2 receptor antagonist (months 1-12): 4-11 ng/mL
    • Trough level, Astragraf XL with basiliximab induction (during month 1): 7-15 ng/mL
    • Trough level, Astragraf XL with basiliximab induction (months 2-6): 5-15 ng/mL
    • Trough level, Astragraf XL with basiliximab induction (months >6): 5-10 ng/mL
    • Trough level, Astragraf XL without induction (during month 1): 10-15 ng/mL
    • Trough level, Astragraf XL without induction (months 2-6): 5-15 ng/mL
    • Trough level, Astragraf XL without induction (months >6): 5-10 ng/mL
    • Trough level, Envarsus XR: 4-11 ng/mL
  • Liver transplant
    • Trough level, Prograf with corticosteroids only (months 1-12): 5-20 ng/mL
  • Heart transplant
    • Trough level, Prograf with azathioprine or MMF (months 1-3): 10-20 ng/mL
    • Trough level, Prograf with azathioprine or MMF (months ≥4): 5-15 ng/mL

Graft-Versus-Host Disease (Orphan)

Prophylaxis of GVHD

Orphan indication sponsor

  • Fujisawa USA, Inc, 3 Parkway North Center, Deerfield, IL 60015

Pulmonary Arterial Hypertension (Orphan)

Orphan designation for treatment of pulmonary arterial hypertension

Sponsor

  • Selten Pharma, Inc; 14435C Big Basin Way #246; Saratoga, CA 95070

Hemorrhagic Cystitis (Orphan)

Orphan designation for treatment of hemorrhagic cystitis

Sponsor

  • Lipella Pharmaceuticals Inc; 400 N. Lexington Ave, LL105; Pittsburgh, Pennsylvania 15208

Dosage Forms & Strengths

capsule, immediate-release (Prograf)

  • 0.5mg
  • 1mg
  • 5mg

injectable solution (Prograf)

  • 5mg/mL

granules for oral suspension (Prograf)

  • 0.2mg/packet
  • 1mg/packet

Liver Transplant

Prograf

Prophylaxis of organ rejection in patients receiving liver transplants without preexisting renal or hepatic impairment

Administer initial dose no sooner than 6 hr after transplantation

IV: 0.03-0.05 mg/kg/day by continuous infusion initially  

Oral capsules and granules

  • Capsules: 0.15-0.2 mg/kg/day divided q12hr initially  
  • Granules: 0.2 mg/kg/day divided in 2 doses, administered q12hr

Heart Transplant

Prograf

Prophylaxis of organ rejection in patients receiving allogeneic transplants, in combination with other immunosuppression

Administer initial dose no sooner than 6 hr after transplantation

IV: 0.01 mg/kg/day by continuous infusion initially

Oral capsules and granules

  • 0.3 mg/kg/day divided in 2 doses, administered q12hr

Kidney Transplant

Prograf

Prophylaxis of organ rejection in patients receiving allogeneic transplants, in combination with other immunosuppression

Administer initial dose no sooner than 24 hr after transplantation

IV: 0.03-0.05 mg/kg/day by continuous infusion initially

Oral capsules and granules

  • 3 mg/kg/day divided in 2 doses, administered q12hr

Dosage Modifications

CYP3A5*1 allele

  • African-American patients, compared to Caucasian patients, may need to be titrated to higher dosages to attain comparable trough concentrations ~80% of the African-American patients are carriers of the active, wild type CYP3A5*1 allele, resulting in a higher rate of tacrolimus clearance because of rapid metabolism

Renal impairment

  • Consider using lower end of dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment; may require further dose reductions below the targeted range
  • In kidney transplant patients with post-operative oliguria, administer initial dose no sooner than 6 hr and within 24 hr of transplantation, but may be delayed until renal function shows evidence of recovery

Hepatic impairment

  • Mild: No dosage adjustment required
  • Moderate: Monitor whole blood concentrations and adjust dose accordingly
  • Severe (mean Child-Pugh score >10): Mean clearance of tacrolimus was substantially lower compared with normal hepatic function; dosage reduction recommended; administer 80% of preconversion daily dose of immediate release dosage form when converting from tacrolimus immediate release to extended release

Dosing Considerations

Capsules and granules are not interchangeable or substitutable with other tacrolimus extended-release products; owing to the rate of absorption following administration an extended-release tacrolimus is not equivalent to immediate-release tacrolimus drug product

Under- or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions

Do not use without supervision of a physician with experience in immunosuppressive therapy

African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients

IV formulation

  • Intravenous use is recommended for patients who cannot tolerate oral formulations, and conversion from IV to PO tacrolimus is recommended as soon as oral therapy can be tolerated to minimize the risk of anaphylactic reactions that occurred with injectables containing castor oil derivatives
  • Patients receiving the injection should be under continuous observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter
  • If signs or symptoms of anaphylaxis occur, stop the infusion
  • Aqueous epinephrine solution and a source of oxygen should be available at the bedside
  • Adjust dose according to clinical response and trough tacrolimus concentration
    • Trough level (months 1-12): 5-20 ng/mL
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Interactions

Interaction Checker

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            Adverse Effects

            >10% (Prograf)

            Tremor (54%)

            Hypertension (50%)

            Hypophosphatemia (49%)

            Increased creatinine (45%)

            Infection (45%)

            Headache (44%)

            Diarrhea (44%)

            Nausea (38%)

            Peripheral edema (36%)

            Constipation (35%)

            Urinary tract infection (34%)

            Hypomagnesemia (34%)

            Asthenia (34%)

            Abdominal pain (33%)

            Pain (32%)

            Insomnia (32%)

            Hyperlipemia (31%)

            Hyperkalemia (31%)

            Anemia (30%)

            Vomiting (29%)

            Dyspepsia (28%)

            Fever (29%)

            Arthralgia (25%)

            Back pain (24%)

            Diabetes mellitus (24%)

            Paresthesia (23%)

            Hypokalemia (22%)

            Hyperglycemia (22%)

            Dyspnea (22%)

            Dizziness (19%)

            Chest Pain (19%)

            Increased cough (18%)

            Edema (18%)

            Skin rash (17%)

            Pruritus (15%)

            Leukopenia (15%)

            >10% (Envarsus XR)

            All infections (46%)

            Respiratory infections (26%)

            Diarrhea (14%)

            Increased creatinine (12%)

            >10% (Astagraf XL)

            All infections (69%)

            Diarrhea (45%)

            Constipation (40%)

            Nausea (36%)

            Peripheral edema (36%)

            Tremor (35%)

            Respiratory infections (34%)

            Anemia (33%)

            Hypertension (28%)

            Vomiting (25%)

            Hypomagnesemia (24%)

            Insomnia (24%)

            Hypophosphatemia (23%)

            Serious infections (22%)

            Headache (22%)

            Hyperkalemia (20%)

            Increased blood creatinine (19%)

            Urinary tract infections (16%)

            Fatigue (16%)

            Leukopenia (16%)

            Hyperlipidemia (16%)

            Hyperglycemia (16%)

            1-10% (Astagraf XL)

            Cytomegalovirus infection (10%)

            Bacterial infections (8%)

            Gastroenteritis (7%)

            Polyomavirus infections (3%)

            1-10% (Envarsus XR)

            Urinary tract infections (9-10%)

            Nasopharyngitis (9%)

            Headache (9%)

            Serious infections (8%)

            Bacterial infections (7%)

            Upper respiratory tract infection (7%)

            Peripheral edema (7%)

            Hypertension (4%)

            Fungal infections (4%)

            Gastrointestinal infections (2%)

            Cytomegalovirus infections (2%)

            BK virus (2%)

            Postmarketing Reports

            Blood and lymphatic system disorders: Agranulocytosis, disseminated intravascular coagulation, hemolytic uremic syndrome, febrile neutropenia, pancytopenia, pure red cell aplasia, coagulopathy, thrombotic thrombocytopenic purpura, prolonged activated partial thromboplastin time, decreased blood fibrinogen

            Cardiac disorders: Cardiac arrest, myocardial infarction, ventricular fibrillation, congestive cardiac failure, hypertrophic cardiomyopathy, pericardial effusion, angina pectoris, supraventricular extrasystoles, supraventricular tachycardia, bradycardia, Torsade de Pointes, QT prolongation

            Ear disorders: Hearing loss

            Eye disorders: Blindness, optic neuropathy, optic atrophy, photophobia

            Gastrointestinal disorders: Gastrointestinal hemorrhage, gastrointestinal perforation, pancreatitis, peritonitis, stomach ulcer, intestinal obstruction, ascites, colitis, ileus, impaired gastric emptying, dysphagia

            Hepatobiliary disorders: Hepatic failure, hepatic necrosis, cirrhosis, cholangitis, venoocclusive liver disease, bile duct stenosis, hepatic steatosis, jaundice

            Hypersensitivity reactions: Hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

            Immune system disorders: Graft versus host disease (acute and chronic)

            Investigations: Increased international normalized ratio

            Metabolism and nutrition disorders: Hypoproteinemia

            Musculoskeletal and connective tissue disorders: Rhabdomyolysis, myalgia, polyarthritis, pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS)

            Neoplasms: Lymphoma including EBV-associated lymphoproliferative disorder, hepatosplenic T-cell lymphoma, PTLD, leukemia, melanoma

            Nervous system disorders: Cerebral infarction, progressive multifocal leukoencephalopathy (PML) sometimes fatal, posterior reversible encephalopathy syndrome (PRES), coma, status epilepticus, quadriplegia, flaccid paralysis, hemiparesis, aphasia, syncope, carpal tunnel syndrome, nerve compression, mutism, dysarthria, somnolence

            Psychiatric disorders: Mental status changes

            Renal and urinary disorders: Hemorrhagic cystitis, hematuria, urinary retention, urinary incontinence

            Respiratory, thoracic and mediastinal disorders: Interstitial lung disease, pulmonary hypertension, lung infiltration, rhinitis allergic, hiccups

            Skin and subcutaneous tissue disorders: Hyperpigmentation, photosensitivity

            Vascular disorders: Hemorrhage

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            Warnings

            Black Box Warnings

            Serious infections and malignancies

            • Increased risk for developing serious infections and malignancies, including lymphoma and skin malignancies, with tacrolimus or other immunosuppressants that may lead to hospitalization or death

            Increased mortality in female liver transplant patients

            • Astagraf XL
            • Increased mortality in female transplant recipients was observed in clinical trial of liver transplantation; use of extended release formulation in liver transplantation is not recommended

            Experienced physician

            • Only healthcare providers experienced in immunosuppressive therapy and management of organ transplant patients should prescribe the drug; patients therapy should be managed in facilities equipped and staffed with laboratory and supportive medical resources; healthcare provider responsible for maintenance therapy should have complete information required for follow up of patient

            Contraindications

            Hypersensitivity to tacrolimus or any component of the formulation, including castor oil (Prograf)

            Cautions

            Hypersensitivity reactions, including anaphylaxis reported with injection formulation, which contains polyoxyl 60 hydrogenated castor oil (HCO-60), a castor oil derivative; limit IV use to patients unable to take orally; monitor patient for 30 min after initiation of infusion and then at frequent intervals; discontinue infusion if anaphylaxis occurs; transition patient from IV to oral dosing as soon as patient can tolerate oral administration

            Increased risk of infections and lymphoma, including latent virus activation (eg, BK virus-induced nephropathy)

            Patients receiving immunosuppressants are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections; these infections may lead to serious, including fatal, outcomes; serious viral infections reported include, cytomegalovirus infections; CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at higher risk of developing CMV viremia and CMV disease; monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection (see Black Box Warnings)

            Medication errors (eg, substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products) reported outside the U.S; which led to serious adverse reactions such as graft rejection, or other adverse reactions due to under-or over-exposure to tacrolimus; not interchangeable or substitutable for tacrolimus extended-release tablets, tacrolimus immediate-release capsules or tacrolimus for oral suspension; changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision

            Hypertension may occur; may treat with antihypertensives that are non-potassium-sparing diuretics; concurrent use of calcium channel blockers may require tacrolimus dosage adjustment

            Mild-to-severe hyperkalemia may occur; avoid use of potassium sparing diuretics

            Myocardial hypertrophy reported (reversible with dose reduction or discontinuation)

            QT prolongation reported; consider obtaining electrocardiograms and monitoring electrolytes periodically during treatment in patients with congestive heart failure, bradyarrhythmias, patients taking antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances, including hypokalemia, hypomagnesemia, or hypocalcemia

            Cases of pure red-cell aplasia reported; if this is diagnosed, consider discontinuing tacrolimus

            Gastrointestinal perforation; all reported cases were considered a complication of transplant surgery or accompanied by infection, diverticulum, or malignant neoplasm

            Increased risk of malignancy is related to intensity/duration of therapy; limit or avoid sun and ultraviolet light exposure; use appropriate sun protection; post-transplant lymphoproliferative disorder related to EBV infection reported in immunosuppressed organ transplant patients; risk highest in young children

            African-Americans may need to be titrated to higher dosages to achieve the target tacrolimus concentrations

            Graft rejection and other serious adverse effects have resulted from medication errors with extended release dosage form; patients and caregivers are advised to recognize appearance extended release tablets

            Monitor blood glucose; new onset of diabetes after transplants reported

            Acute and or chronic nephrotoxicity reported with therapy; monitor renal function; consider dosage reduction

            Neurotoxicity including risk of posterior reversible encephalopathy syndrome (PRES) reported; monitor for neurologic abnormalities; reduce dosage or discontinue

            Posttransplant diabetes mellitus

            • Risk of posttransplant diabetes mellitus, especially in black and Hispanic patients; may occur in patients without pretransplant history of diabetes mellitus
            • Insulin dependence may be reversible
            • Black patients may require higher doses in kidney transplant
            • Monitor blood glucose frequently
            • Discontinue cyclosporine 24 hours before starting tacrolimus
            • Combination immunosuppressant therapy

            Drug interactions overview

            • Use with strong CYP3A inhibitors and inducers: Adjust tacrolimus dose and monitor trough concentrations and for occurrence of adverse reactions, including QT prolongation
            • Not for use with sirolimus; associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT); the concomitant administration of sirolimus (2 mg per day) in heart transplant patients associated with increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus
            • Use caution with concurrent administration of nephrotoxic agents, consider dosage reduction in patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than recommended range; risk for nephrotoxicity may increase when drug is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (eg, aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors)
            • Avoid use of live vaccines during treatment with tacrolimus
            • Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment
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            Pregnancy & Lactation

            Pregnancy

            There is a pregnancy registry that monitors pregnancy outcomes in women exposed to drug during pregnancy; the transplantation pregnancy registry international (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants including tacrolimus; healthcare providers are encouraged to advise their patients to register by contacting the Transplantation Pregnancy Registry International at 1-877-955-6877 or https://www.transplantpregnancyregistry.org/

            Tacrolimus can cause fetal harm when administered to a pregnant woman; data from postmarketing surveillance and TPRI suggest that infants exposed to tacrolimus in utero are at a risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress; advise pregnant women of potential risk to fetus; administration of oral tacrolimus to pregnant rabbits and rats throughout the period of organogenesis was associated with maternal toxicity/lethality, and an increased incidence of abortion, malformation and embryofetal death at clinically relevant doses (0.5 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m2 basis)

            Risks during pregnancy are increased in organ transplant recipients; the risk of premature delivery following transplantation is increased; pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient; pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death; cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population; however, COP symptoms resolved postpartum and no long term effect on offsprings was reported

            Tacrolimus may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes); monitor maternal blood glucose levels regularly

            Therapy may exacerbate hypertension in pregnant women and increase pre-eclampsia; monitor and control blood pressure

            Renal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at time of delivery in infants of mothers taking drug

            There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to drug.

            Contraception

            • Therapy can cause fetal harm when administered to pregnant women; advise female and male patients of reproductive potential to speak to their healthcare provider on family planning options including appropriate contraception prior to starting treatment

            Infertility

            • Based on findings in animals, male and female fertility may be compromised by treatment

            Lactation

            Controlled lactation studies have not been conducted in humans; however tacrolimus has been reported to be present in human milk; effects of tacrolimus on breastfed infant, or on milk production have not been assessed

            Tacrolimus is excreted in rat milk and in peri-/postnatal rat studies, exposure to tacrolimus during postnatal period was associated with developmental toxicity in offspring at clinically relevant doses

            The developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for drug and any potential adverse effects on breastfed child from drug or from underlying maternal condition

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Calcineurin inhibitor; inhibits T-cell activation and proliferation, humoral immunity

            Macrolide antibiotic; potent immunosuppressant

            Absorption

            Bioavailability: 7-55% (children); 7-32% (adults)

            Peak plasma time: 0.5-6 hr

            Distribution

            Protein bound: 99%

            Vd: 0.5-4.7 L/kg (children); 0.55-2.47 L/kg (adults)

            Metabolism

            Metabolized in liver by CYP3A4

            Metabolites: 13-O-demethyl tacrolimus (major)

            P-gp substrate

            Elimination

            Half-life: 23-46 hr (immediate release); 34.5-41 hr (extended release)

            Excretion: Feces (94%); urine (<1%)

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            Administration

            IV Incompatibilities

            Y-site: Acyclovir, ganciclovir

            IV Compatibilities

            Solution: D5W, NS

            Additive: Cimetidine

            Y-site (partial list): Ampicillin, ampicillin-sulbactam, calcium gluconate, cefazolin, ciprofloxacin, dopamine, fluconazole, furosemide, heparin, lorazepam, metoclopramide, metronidazole, morphine sulfate, multivitamins, penicillin G potassium, potassium chloride, propranolol, sodium bicarbonate, trimethoprim-sulfamethoxazole, vancomycin

            IV Preparation

            Dilute with NS or D5W to 0.004-0.02 mg/mL

            Store diluted solutions in a polyvinyl chloride (PVC) container due to decreased stability and the potential for extraction of phthalates

            Visually inspect product for particulate matter and discoloration prior to administration, whenever solution and container permit

            Due to the chemical instability of tacrolimus in alkaline media, mix or co-infuse with solutions of pH ≥9

            IV Administration

            Administer by IV continuous infusion only (use infusion pump)

            In situations where more dilute solutions are utilized (eg, pediatric dosing.), utilize PVC-free tubing to minimize the potential for significant drug adsorption onto the tubing

            Oral Suspension Preparation

            Can cause fetal harm; follow applicable special handling and disposal procedures

            Calculate required dose; use the minimum whole number of packets that corresponds to the required morning or evening dose

            If morning or evening dose is not covered by the whole number of packets, use one additional 0.2 mg packet to round up the dose

            Do not use tubing, syringes and other equipment (cups) containing PVC to prepare or administer tacrolimus suspension; do not sprinkle on food

            Empty the entire contents of each packet into a glass cup; ensure packet is completely empty and add 1-2 tablespoons (15-30 mL) of room temperature drinking water to cup containing the granules

            Mix and administer the entire contents of the cup; granules will not completely dissolve; give immediately after preparation

            Pediatric patients

            • Draw up and dispense suspension via a non-PVC oral syringe
            • Rinse cup or syringe with the same quantity of water (15-30 mL) and ensure all of the medication is taken

            Oral Administration

            Administer the same time each day, 12 hr apart

            Do not eat too much grapefruit while taking tacrolimus

            Capsules and granules

            • Administer consistently with or without food
            • Do not open capsules

            Extended-release capsules or tablets

            • Take preferably on an empty stomach
            • Swallow whole; do not chew, divide, or crush

            Missed doses

            • Once daily extended-release: Take it as soon as possible within 14 hr (Astagraf XL) or 15 hr (Envarsus XR) after missing the dose; beyond the 14-hr or 15-hr time frame, wait until the usual scheduled time to take the next regular daily dose; do not double the next dose

            Storage

            Envarsus XR: Store at 25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)

            Astagraf XL: Store at 25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)

            Prograf

            • Capsules: Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)
            • Granules
              • Unit dose packets: Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)
            • Injection
              • Unused vials: Store at 5-25°C (41-77°F)
              • Diluted solutions: Discard after 24 hr
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            Images

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
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            • Compare formulary status to other drugs in the same class.
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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.