tacrolimus (Prograf, Astagraf XL, Hecoria, Envarsus XR)

Dosing and uses of Prograf, Astagraf XL (tacrolimus)

• Adult
• Pediatric

 

Adult dosage forms and strengths

capsule, immediate-release (Prograf, Hecoria, generics)

• 0.5mg
• 1mg
• 5mg

capsule, extended-release (Astagraf XL)

• 0.5mg
• 1mg
• 5mg

tablet, extended-release (Envarsus XR)

• 0.75mg
• 1mg
• 4mg

injectable solution

• 5mg/mL

 

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

Dosing considerations

• Administer initial dose no sooner than 6 hr after transplantation
• Dosage adjusted according to clinical response and trough tacrolimus concentration
• Trough level (months 1-3): 10-20 ng/mL
• Trough level (months >3): 5-15 ng/mL
• Monitor serum potassium

 

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

Dosing considerations

• Dosage adjusted according to clinical response and trough tacrolimus concentration
• Trough level (months 1-12): 5-20 ng/mL
• Monitor serum potassium

 

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

• Indicated for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations in combination with other immunosuppressants
• Not interchangeable or substitutable with other tacrolimus products
• Conversion from immediate-release tacrolimus
  • 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

Dosing considerations

• Dosage adjusted according to clinical response and observed tacrolimus whole-blood trough concentrations
• 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 (days 1-60): 5-17 ng/mL
• Trough level, Astragraf XL with basiliximab induction (months 3-12): 4-12 ng/mL
• Trough level, Astragraf XL without induction (days 1-60): 6-20 ng/mL
• Trough level, Astragraf XL without induction (months 3-12): 6-14 ng/mL
• Monitor serum potassium

 

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

• 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

 

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

 

Pediatric dosage forms and strengths

capsule, immediate-release

• 0.5mg
• 1mg
• 5mg

injectable solution

• 5mg/mL

 

Liver Transplant

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

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

PO (immediate-release): 0.15-0.2 mg/kg/day divided q12hr initially

Dosing considerations

• Use lower end of dosing range
• Dosage adjusted according to clinical response, tolerability, and observed whole-blood tacrolimus concentrations
• Trough level (months 1-12): 5-20 ng/mL
• Monitor serum potassium

 

Kidney, Liver, or Heart Transplantation (Orphan)

Granules for oral suspension: Orphan designation for prevention of rejection in kidney, liver, or heart transplant in pediatric patients

Sponsor

• Astellas Pharma Global Development, Inc; 1 Astellas Way; Northbrook, Illinois 60062

 

Prograf, Astagraf XL (tacrolimus) adverse (side) effects

>10% (selected)

Diarrhea (25-72%)

Headache (24-64%)

Insomnia (30-64%)

Abdominal pain (29-59%)

Tremor (15-56%)

Nephrotoxicity (36-52%)

Asthenia (11-52%)

Hypertension (38-50%)

Hypophosphatemia (49%)

Hypomagnesemia (16-48%)

Hyperglycemia (22-47%)

Hyperlipemia (10-31%)

Nausea (32-46%)

Increased serum creatinine (24-45%)

Hyperkalemia (13-45%)

Paresthesia (17-40%)

Constipation (23-35%)

Anorexia (34%)

Urinary tract infection (16-34%)

Increased blood urea nitrogen (BUN) (30%)

Vomiting (14-29%)

Hypokalemia (13-29%)

Dyspepsia (28%)

Dizziness (19%)

Edema (18%)

Oliguria (18%)

 

Warnings

Black box warnings

Should be prescribed only by physicians who have experience with immunosuppression in transplant recipients and can provide necessary follow-up and appropriate monitoring

Increased risk of fungal, viral, bacterial, and protozoal infections and lymphoma due to immunosuppression

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

 

Contraindications

Hypersensitivity to tacrolimus or castor oil (Prograf)

 

Cautions

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

Risk of posttransplant diabetes mellitus, especially in black and Hispanic patients

Black patients may require higher doses in kidney transplant

Discontinue cyclosporine 24 hours before starting tacrolimus

Combination immunosuppressant therapy

Hypertension may occur; may treat with antihypertensives that are non-potassium-sparing diuretics

Use caution with concurrent administration of nephrotoxic agents, calcium-channel blocking agents

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 in patients at high risk

Use with strong CYP3A inhibitors and inducers: Adjust tacrolimus dose and monitor trough concentrations and for occurrence of adverse reactions, including QT prolongation

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

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

 

Pregnancy and lactation

Pregnancy category: C

Lactation: Drug is excreted in breast milk; not recommended

 

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.

 

Pharmacology of Prograf, Astagraf XL (tacrolimus)

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%)

 

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

 

IV Administration

Administer by IV continuous infusion only (use infusion pump)

Tacrolimus is dispensed in 50-mL glass container with no overfilL

Use polyolefin administration sets, especially for low drug concentrations; polyvinyl chloride (PVC) sets may be used for concentrations >100 mg/mL, but significant absorption may occur with these sets at concentrations >50 mg/mL

 

Oral Administration

PO suspension of 0.5 mg/mL requires extemporaneous compounding by pharmacist

Immediate-release capsules: Administer consistently with or without food

Extended-release capsules or tablets: Take preferably on an empty stomach

Extended-release capsules or tablets: 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

Before dilution, store at 5-25°C (41-77°F)

Admixtures prepared in D5W or NS should be stored in polyolefin containers and glass bottles (PVC containers absorb significant amounts of drug)

Infusion through PVC tubing does not result in decreased concentrations; however, loss by absorption may be more important with lower concentrations