Tacrolimusdosage

Capsules must be taken whole.

Take consistently every morning at the same time on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal.

Avoid eating grapefruit or drinking grapefruit juice or alcohol.

African-American patients and patients with severe hepatic impairment may require dosing adjustments.

Frequent monitoring of trough concentrations is recommended.

For complete dosing information, see Full Prescribing Information. MMF = Mycophenolate mofetil Recommended ASTAGRAF XL Initial Dosage Patient Population Initial Oral Dosage Whole Blood Trough Concentration Range ADULT With basiliximab, MMF and steroids 0.15 to 0.2 mg/kg once daily prior to reperfusion or within 48 hours of completion of transplant

Month 1: 7‑15 ng/mL

Months 2-6: 5‑15 ng/mL

> 6 Months: 5‑10 ng/mL With MMF and steroids, without basiliximab induction

First dose (pre-operative): 0.1 mg/kg, within 12 hours prior to reperfusion

Subsequent doses (post-operative): 0.2 mg/kg once daily at least 4 hours after pre-operative dose and within 12 hours after reperfusion

Month 1: 10‑15 ng/mL

Months 2-6: 5‑15 ng/mL

> 6 Months: 5‑10 ng/mL PEDIATRIC With basiliximab, MMF and steroids 0.3 mg/kg once daily, administered within 24 hours following reperfusion

Month 1: 10‑20 ng/mL

> Month 1: 5‑15 ng/mL

2.1 Important

Administration Instructions

ASTAGRAF XL should not be used without the supervision by a physician with experience in immunosuppressive therapy.

ASTAGRAF XL (tacrolimus extended-release capsules) is not interchangeable or substitutable for tacrolimus extended-release tablets, tacrolimus immediate-release capsules or tacrolimus for oral suspension. Under or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision.

Advise patients to swallow ASTAGRAF XL capsules whole with liquid; patients must not chew, divide, or crush the capsules.

ASTAGRAF XL should be taken consistently every morning at the same time to ensure consistent and maximum possible drug exposure, on an empty stomach at least 1 hour before a meal, or at least 2 hours after a meal.

If a dose is missed, the dose may be taken up to 14 hours after the scheduled time (i.e., for a missed 8:00 AM dose, a dose may be taken by 10:00 PM). Beyond the 14-hour time frame, the patient should wait until the usual scheduled time the following morning to take the next regular daily dose. Instruct the patient not to double the next dose.

Advise patients to avoid eating grapefruit or drinking grapefruit juice or alcoholic beverages while taking ASTAGRAF XL.

Therapeutic drug monitoring is recommended for all patients receiving ASTAGRAF XL.

2.2 Dosage Recommendations for

Kidney Transplant Patients Table 1 includes the recommended starting ASTAGRAF XL dosages and whole blood trough concentration ranges; the observed trough concentrations are shown in another section of the Full Prescribing Information. Titrate the ASTAGRAF XL dosage based on clinical assessments of rejection and tolerability, and to achieve target trough concentration ranges. Table 1: Recommended Starting Daily Dosage Regimen of ASTAGRAF XL MMF = mycophenolate mofetil Recommended ASTAGRAF XL Initial Dosage * Patient Population Initial Oral Dosage Whole Blood Trough Concentration Range ADULT With basiliximab, MMF and steroids 0.15 to 0.2 mg/kg once daily prior to reperfusion or within 48 hours of completion of transplant

Month 1: 7-15 ng/mL

Months 2-6: 5-15 ng/mL

> 6 Months: 5-10 ng/mL With MMF and steroids, without basiliximab induction

First dose (pre-operative): 0.1 mg/kg, within 12 hours prior to reperfusion

Subsequent doses (post-operative): 0.2 mg/kg once daily at least 4 hours after pre-operative dose and within 12 hours after reperfusion

Month 1: 10-15 ng/mL

Months 2-6: 5-15 ng/mL

> 6 Months: 5-10 ng/mL PEDIATRIC With basiliximab, MMF and steroids 0.3 mg/kg once daily, administered within 24 hours following reperfusion.

Month 1: 10-20 ng/mL

> Month 1: 5-15 ng/mL

2.3 Dosage Modifications for

African-American Patients, Patients with Hepatic Impairment, and Drug Interactions African-American patients, compared to Caucasian patients, may need to be titrated to higher ASTAGRAF XL dosages to attain comparable trough concentrations. Patients with severe hepatic impairment (Child-Pugh ≥ 10) may require a lower starting dosage of ASTAGRAF XL, due to the reduced clearance and prolonged half-life. Dose adjustments of ASTAGRAF XL may be necessary when administered concomitantly with CYP3A inducers or CYP3A inhibitors or cannabidiol.

2.4 Therapeutic

Drug Monitoring Measure tacrolimus whole blood trough concentrations at least two times on separate days during the first week after initiation of dosing and after a change in dosage, after a change in co-administration of CYP3A4 inducers and/or inhibitors or cannabidiol, or after a change in renal or hepatic function. When interpreting measured concentrations, consider that the time to achieve tacrolimus steady state is approximately 7 days after initiating or changing the ASTAGRAF XL dose. Monitor tacrolimus whole blood trough concentrations using a validated assay [e.g., immunoassays or high performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS)]. The immunosuppressive activity of tacrolimus is mainly due to the parent drug rather than to its metabolites. Immunoassays may react with metabolites as well as the parent drug. Therefore, whole blood tacrolimus trough concentrations obtained with immunoassays may be numerically higher than concentrations obtained with an assay using HPLC/MS/MS. Comparison of the whole blood tacrolimus trough concentrations of patients to those described in the prescribing information and other published literature must be made with knowledge of the assay method(s) employed.