PROGRAF

Clinical safety rating: caution

Comprehensive clinical and safety monograph for PROGRAF (PROGRAF).

How it works

Calcineurin inhibitor; binds to FKBP-12, inhibits calcineurin, preventing dephosphorylation and nuclear translocation of NF-AT, thereby inhibiting T-cell activation and cytokine gene transcription.

What the body does with it

Metabolism	Primarily hepatic via CYP3A4 and CYP3A5; intestinal metabolism contributes. P-glycoprotein substrate.
Excretion	Primarily fecal (approximately 92%) with biliary excretion as the major route; renal excretion accounts for about 2.4% of the dose as unchanged drug and metabolites.
Half-life	Terminal elimination half-life is approximately 8.7 hours (range 4-41 hours) in healthy volunteers; in liver transplant patients, half-life is approximately 11.7 hours (range 3.9-56 hours); prolonged in patients with hepatic impairment.
Protein binding	99% bound primarily to albumin and alpha-1-acid glycoprotein; also binds to erythrocytes and lipoproteins.
Volume of Distribution	Volume of distribution is approximately 0.99 L/kg (range 0.6-1.9 L/kg) in healthy subjects; higher values indicate extensive tissue distribution and binding to erythrocytes.
Bioavailability	Oral bioavailability is approximately 17-25% (range 4-89%) in transplant patients, with high inter- and intra-subject variability; absorption is influenced by food.
Onset of Action	Oral: Onset of immunosuppression occurs within 1-2 hours after a single oral dose; IV: Immediate action upon administration.
Duration of Action	Duration of immunosuppressive effect persists for 12-24 hours; dosing is typically every 12 hours to maintain therapeutic levels.

Classification & Brands

Dosing & administration

Initial oral dose: 0.1-0.15 mg/kg/day divided into 2 doses (every 12 hours). IV dose: 0.03-0.05 mg/kg/day as continuous infusion. Adjunct with corticosteroids.

Dosage form	INJECTABLE
Renal impairment	No specific GFR-based dose adjustment required, but monitor renal function closely due to nephrotoxicity. For severe renal impairment (CrCl <30 mL/min), reduce dose by 25-50% and monitor levels.
Liver impairment	Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 25%. Child-Pugh C: reduce dose by 50% and titrate based on trough levels.
Pediatric use	Oral: 0.1-0.3 mg/kg/day divided every 12 hours. IV: 0.03-0.05 mg/kg/day continuous infusion. Monitor trough concentrations.
Geriatric use	Start at lower end of dosing range due to potential age-related decline in renal function. Monitor renal function and tacrolimus levels closely.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for PROGRAF (PROGRAF).

Breastfeeding	Excreted in breast milk; M/P ratio unknown. Weigh benefits of breastfeeding against potential risk of infant immunosuppression and renal toxicity. Consider avoiding or using alternative.
Teratogenic Risk	Pregnancy Category C. Risk in first trimester: increased risk of congenital malformations (animal studies); human data limited. Second and third trimester: potential for fetal growth restriction, prematurity, and neonatal toxicity (hyperkalemia, renal dysfunction). Use only if benefit outweighs risk.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

Increased risk of lymphomas and other malignancies, particularly skin cancer; increased susceptibility to infections. Only should be prescribed by physicians experienced in immunosuppressive therapy.

Side Effect Profile

Common Effects	Increased glucose level in blood Kidney damage Insomnia difficulty in sleeping Tremors High blood pressure Infection
Serious Effects

Absolute Contraindications

Hypersensitivity to tacrolimus or any component of the formulation, concomitant use with cyclosporine, and patients with or at risk for congenital long QT syndrome.

Clinical Precautions

Precautions

Nephrotoxicity, neurotoxicity (tremor, headache, seizures), hypertension, hyperkalemia, hyperglycemia, thrombotic microangiopathy, risk of BK virus infection, increased risk of EBV-associated post-transplant lymphoproliferative disorder.

Clinical Tips & Counseling

Drug interactions

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PROGRAF

Clinical safety rating: caution

Comprehensive clinical and safety monograph for PROGRAF (PROGRAF).

How it works

Calcineurin inhibitor; binds to FKBP-12, inhibits calcineurin, preventing dephosphorylation and nuclear translocation of NF-AT, thereby inhibiting T-cell activation and cytokine gene transcription.

What the body does with it

Metabolism	Primarily hepatic via CYP3A4 and CYP3A5; intestinal metabolism contributes. P-glycoprotein substrate.
Excretion	Primarily fecal (approximately 92%) with biliary excretion as the major route; renal excretion accounts for about 2.4% of the dose as unchanged drug and metabolites.
Half-life	Terminal elimination half-life is approximately 8.7 hours (range 4-41 hours) in healthy volunteers; in liver transplant patients, half-life is approximately 11.7 hours (range 3.9-56 hours); prolonged in patients with hepatic impairment.
Protein binding	99% bound primarily to albumin and alpha-1-acid glycoprotein; also binds to erythrocytes and lipoproteins.
Volume of Distribution	Volume of distribution is approximately 0.99 L/kg (range 0.6-1.9 L/kg) in healthy subjects; higher values indicate extensive tissue distribution and binding to erythrocytes.
Bioavailability	Oral bioavailability is approximately 17-25% (range 4-89%) in transplant patients, with high inter- and intra-subject variability; absorption is influenced by food.
Onset of Action	Oral: Onset of immunosuppression occurs within 1-2 hours after a single oral dose; IV: Immediate action upon administration.
Duration of Action	Duration of immunosuppressive effect persists for 12-24 hours; dosing is typically every 12 hours to maintain therapeutic levels.

Classification & Brands

Dosing & administration

Initial oral dose: 0.1-0.15 mg/kg/day divided into 2 doses (every 12 hours). IV dose: 0.03-0.05 mg/kg/day as continuous infusion. Adjunct with corticosteroids.

Dosage form	INJECTABLE
Renal impairment	No specific GFR-based dose adjustment required, but monitor renal function closely due to nephrotoxicity. For severe renal impairment (CrCl <30 mL/min), reduce dose by 25-50% and monitor levels.
Liver impairment	Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 25%. Child-Pugh C: reduce dose by 50% and titrate based on trough levels.
Pediatric use	Oral: 0.1-0.3 mg/kg/day divided every 12 hours. IV: 0.03-0.05 mg/kg/day continuous infusion. Monitor trough concentrations.
Geriatric use	Start at lower end of dosing range due to potential age-related decline in renal function. Monitor renal function and tacrolimus levels closely.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for PROGRAF (PROGRAF).

Breastfeeding	Excreted in breast milk; M/P ratio unknown. Weigh benefits of breastfeeding against potential risk of infant immunosuppression and renal toxicity. Consider avoiding or using alternative.
Teratogenic Risk	Pregnancy Category C. Risk in first trimester: increased risk of congenital malformations (animal studies); human data limited. Second and third trimester: potential for fetal growth restriction, prematurity, and neonatal toxicity (hyperkalemia, renal dysfunction). Use only if benefit outweighs risk.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

Increased risk of lymphomas and other malignancies, particularly skin cancer; increased susceptibility to infections. Only should be prescribed by physicians experienced in immunosuppressive therapy.

Side Effect Profile

Common Effects	Increased glucose level in blood Kidney damage Insomnia difficulty in sleeping Tremors High blood pressure Infection
Serious Effects

Absolute Contraindications

Hypersensitivity to tacrolimus or any component of the formulation, concomitant use with cyclosporine, and patients with or at risk for congenital long QT syndrome.