TOP

Astagraf XL（tacrolimus extended release capsules）

2015-11-20 10:26:00 来源: 作者: 【大中小】浏览:424次评论:0条

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ASTAGRAF XL ® safely and effectively. See full prescribing information for ASTAGRAF XL.

ASTAGRAF XL ® (tacrolimus extended-release capsules), for oral use
Initial U.S. Approval: 2013
WARNING: MALIGNANCIES; SERIOUS INFECTIONS; AND MORTALITY IN FEMALE LIVER TRANSPLANT RECIPIENTS
See full prescribing information for complete boxed warning

•: Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe ASTAGRAF XL (5.1)
•: Increased susceptibility to infection and the possible development of malignancies may result from immunosuppression (5.2, 5.3, 5.6, 5.7)
•: Use in liver transplantation is not recommended due to increased mortality rate in female liver transplant recipients (5.4)

INDICATIONS AND USAGE

ASTAGRAF XL is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in patients receiving a kidney transplant with mycophenolate mofetil (MMF) and corticosteroids, with or without basiliximab induction (1.1)

Limitations of use (1.2):

•: Not interchangeable with tacrolimus immediate-release capsules
•: Do not use simultaneously with cyclosporine

DOSAGE AND ADMINISTRATION

Recommended Initial Oral Dose and Observed Whole Blood Tacrolimus Trough Concentrations in Kidney Transplant Patients (2.1, 2.4)

* 10 th - 90 th percentile ( 14). † Give first dose prior to or within 48 hours after transplant completion; may delay therapy initiation until renal function has recovered ( 2.2). ‡ Give preoperative dose within 12 hours prior to reperfusion, and first post-operative dose within 12 hours after reperfusion but not less than 4 hours after pre-operative dose ( 2.1).
Treatment Regimen	Oral Dose	Observed Whole Blood Trough Concentrations*
With basiliximab induction†	0.15 mg/kg/day	Day 1 to 60: 5-17 ng/mL Month 3 to 12: 4-12 ng/mL
Without induction‡	Pre-operative: 0.1 mg/kg/day Post-operative: 0.2 mg/kg/day	Day 1 to 60: 6-20 ng/mL Month 3 to 12: 6-14 ng/mL

•: Take once daily in the morning, preferably on an empty stomach; do not take with an alcoholic beverage or grapefruit juice; do not chew, divide or crush capsules ( 2.4, 7)
•: Monitoring of whole blood tacrolimus trough concentrations is recommended ( 2.5)

DOSAGE FORMS AND STRENGTHS

•: Capsules: 0.5 mg, 1 mg, 5 mg ( 3)

CONTRAINDICATIONS

•: ASTAGRAF XL is contraindicated in patients with hypersensitivity to tacrolimus ( 4).

WARNINGS AND PRECAUTIONS

•: Medication errors have been reported including unintentional substitution between immediate-release tacrolimus and ASTAGRAF XL (extended-release) tacrolimus formulations ( 5.5)
•: New Onset Diabetes After Transplant: Monitor blood glucose ( 5.8)
•: Nephrotoxicity (acute and/or chronic): Monitor renal function; reduce the dose; use caution with other nephrotoxic drugs ( 5.9)
•: Neurotoxicity, Risk of Posterior Reversible Encephalopathy Syndrome (PRES): Monitor for neurologic abnormalities; reduce or discontinue immunosuppression ( 5.10)
•: Hyperkalemia: Monitor serum potassium levels; use caution with other agents that increase potassium ( 5.11)
•: Hypertension: May require antihypertensive therapy; monitor relevant drug-drug interactions ( 5.12)
•: Use with Sirolimus: Not recommended; increased risk of serious adverse reactions in liver and heart transplant recipients ( 5.13)
•: Use with Strong CYP3A Inhibitors and Inducers: Adjust tacrolimus dose and monitor trough concentrations and for occurrence of adverse reactions, including QT prolongation ( 5.14, 5.15, 7)
•: Immunizations: Avoid use of live vaccines ( 5.16)
•: Pure Red Cell Aplasia: Consider discontinuation ( 5.17)

ADVERSE REACTIONS

•: The most common adverse reactions ( ≥ 30%) are: diarrhea, constipation, nausea, peripheral edema, tremor and anemia ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

•: Mycophenolic Acid Products: Monitor for MPA-related adverse reactions and adjust MMF or MPA-dose as needed ( 7.1)
•: CYP3A Inhibitors: Increased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed with concomitant use ( 5.14, 7)
•: CYP3A Inducers: Decreased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed with concomitant use ( 5.14, 7)

USE IN SPECIFIC POPULATIONS

•: Pregnancy: Based on animal data may cause fetal harm ( 8.1)
•: Nursing Mothers: Discontinue drug or nursing ( 8.3)
•: Renal Impairment: If nephrotoxicity develops, reduce doses ( 2.2, 8.6)
•: Hepatic Impairment: Lower doses below the recommended starting dose may be required ( 2.3, 8.7)
•: Race: African-Americans may need higher doses ( 2.1, 8.8, 14)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 6/2015

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: MALIGNANCIES; SERIOUS INFECTIONS; AND MORTALITY IN FEMALE LIVER TRANSPLANT RECIPIENTS

1 INDICATIONS AND USAGE

1.1 Prophylaxis of Organ Rejection in Kidney Transplant

1.2 Limitations of Use

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Adult Kidney Transplant Recipients

2.2 Patients with Renal Impairment

2.3 Patients with Hepatic Impairment

2.4 Administration Instructions

2.5 Therapeutic Drug Monitoring

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Management of Immunosuppression

5.2 Lymphoma and Other Malignancies

5.3 Serious Infections

5.4 Liver Transplant Recipients

5.5 Medication Errors

5.6 Polyoma Virus Infections

5.7 Cytomegalovirus (CMV) Infections

5.8 New Onset Diabetes after Transplant

5.9 Nephrotoxicity

5.10 Neurotoxicity

5.11 Hyperkalemia

5.12 Hypertension

5.13 Use with Sirolimus

5.14 Use with CYP3A Inhibitors and Inducers

5.15 QT Prolongation

5.16 Immunizations

5.17 Pure Red Cell Aplasia

5.18 Gastrointestinal Perforation

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Mycophenolic Acid Products

7.2 Grapefruit Juice

7.3 Alcohol

7.4 Protease Inhibitors

7.5 Antifungal Agents

7.6 Calcium Channel Blockers

7.7 Antibacterials

7.8 Antimycobacterials

7.9 Anticonvulsants

7.10 St. John's Wort (Hypericum perforatum)

7.11 Gastric Acid Suppressors/Neutralizers

7.12 Other Drugs

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

8.8 Race

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*: Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

1.1 Prophylaxis of Organ Rejection in Kidney Transplant

ASTAGRAF XL is indicated for the prophylaxis of organ rejection in patients receiving a kidney transplant. It is recommended that ASTAGRAF XL be used concomitantly with mycophenolate mofetil (MMF) and corticosteroids, with or without basiliximab induction [see Clinical Studies (14)]. Therapeutic drug monitoring is recommended for all patients receiving ASTAGRAF XL [see Dosage and Administration (2.5)].

1.2 Limitations of Use

•: ASTAGRAF XL extended-release capsules are not interchangeable or substitutable with tacrolimus immediate-release capsules.
•: ASTAGRAF XL should not be used simultaneously with cyclosporine.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Adult Kidney Transplant Recipients

Initial dosage recommendations for adult patients after kidney transplantation are presented in Table 1. Dosing of ASTAGRAF XL should be titrated based on clinical assessments of rejection and tolerability, and to maintain trough concentration ranges as noted in Table 1. Frequent monitoring of tacrolimus trough concentrations is recommended in the early post-transplant period to ensure adequate drug exposure [see Dosage and Administration (2.5)].

ASTAGRAF XL extended-release capsules are not interchangeable or substitutable with tacrolimus immediate-release capsules.

With Basiliximab Induction

When used with basiliximab induction, MMF, and corticosteroids, the initial dose of ASTAGRAF XL should be administered prior to or within 48 hours of the completion of the transplant procedure, but may be delayed until renal function has recovered.

Without Induction

When used with MMF and corticosteroids, the pre-operative dose of ASTAGRAF XL should be given as one dose within 12 hours prior to reperfusion; the initial post-operative dose should be given not less than 4 hours after the pre-operative dose and within 12 hours after reperfusion.

Table 1. Recommended Initial Oral Dose and Observed Whole Blood Trough Concentrations in Kidney Transplant Patients
* 10th - 90th percentile; see also Clinical Studies ( 14) for description of immunosuppressive regimens.
Treatment Regimen	Oral Dose	Observed Whole Blood Trough Concentrations*
With basiliximab induction	0.15 mg/kg/day	Day 1 to 60: 5-17 ng/mL Month 3 to 12: 4-12 ng/mL
Without induction	Pre-operative: 0.1 mg/kg/day Post-operative: 0.2 mg/kg/day	Day 1 to 60: 6-20 ng/mL Month 3 to 12: 6-14 ng/mL

African-American kidney transplant patients may require higher doses of ASTAGRAF XL to attain comparable trough concentrations compared to Caucasian patients [see Clinical Pharmacology (12.3), Clinical Studies (14)].

2.2 Patients with Renal Impairment

In kidney transplant patients with post-operative oliguria, the initial dose of ASTAGRAF XL should be administered no sooner than 6 hours and within 48 hours of transplantation, but may be delayed until renal function shows evidence of recovery.

Frequent monitoring of renal function is recommended. ASTAGRAF XL dosage should be reduced if nephrotoxicity develops.