CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
`50708s053, 50709s045, 210115s005
`
` Prograf capsules, injection, oral suspension
`
`tacrolimus
`
`Trade Name:
`
`Astellas Pharma US, Inc.
`
`July 16, 2021
`
`For the prevention of rejection in lung transplantation
`
`Generic or Proper
`Name:
`
`Sponsor:
`
`
`
`
`Approval Date:
`
`
`Indication:
`
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`50708s053, 50709s045, 210115s005
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Officer/Employee List
`Multidiscipline Review(s)
`Product Quality Review(s)
`Clinical Microbiology / Virology Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`
`
`X
`X
`
`X
`
`
`X
`
`

`

`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`50708s053, 50709s045, 210115s005
`
`APPROVAL LETTER
`
`

`

`NDA 50708/S-053
`NDA 50709/S-045
`NDA 210115/S-005
`
`
`
`SUPPLEMENT APPROVAL
`
`
`Astellas Pharma US, Inc.
`1 Astellas Way
`Northbrook, IL 60062
`
`Attention: Mary Jo Pritza, MPH, PharmD
`
`
`Senior Director, Regulatory Affairs
`
`Dear Dr. Pritza:
`
`Please refer to your supplemental new drug applications (sNDA) dated December 15,
`2020, received December 15, 2020, and your amendments, submitted under section
`505(b)of the Federal Food, Drug, and Cosmetic Act (FDCA) for:
`
`
`NDA 50708/S-053: Prograf (tacrolimus) capsules
`NDA 50709/S-045: Prograf (tacrolimus) injection
`NDA 210115/S-005: Prograf Granules (tacrolimus) oral suspension
`
`
`These Prior Approval supplemental new drug applications provide updates to the USPI
`for Prograf (tacrolimus) use for the prevention of rejection in lung transplantation.
`
`APPROVAL & LABELING
`
`We have completed our review of these applications, as amended. They are approved,
`effective on the date of this letter, for use as recommended in the enclosed agreed-
`upon labeling.
`
`WAIVER OF ½ PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS
`
`Please note that we have previously granted a waiver of the requirements of 21 CFR
`201.57(d)(8) regarding the length of Highlights of Prescribing Information.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the
`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
`the FDA automated drug registration and listing system (eLIST), as described at
`FDA.gov.1 Content of labeling must be identical to the enclosed labeling (text for the
`
`1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
`
`Reference ID: 4827475
`
`

`

`NDA 50708/S-053
`NDA 50709/S-045
`NDA 210115/S-005
`Page 2
`
`
`Prescribing Information, Patient Package Insert, and Instructions for Use), with the
`addition of any labeling changes in pending “Changes Being Effected” (CBE)
`supplements, as well as annual reportable changes not included in the enclosed
`labeling.
`
`Information on submitting SPL files using eList may be found in the guidance for
`industry SPL Standard for Content of Labeling Technical Qs and As.2
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications that include labeling
`changes for these NDAs, including CBE supplements for which FDA has not yet issued
`an action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word
`format, that includes the changes approved in this supplemental application, as well as
`annual reportable changes. To facilitate review of your submission(s), provide a
`highlighted or marked-up copy that shows all changes, as well as a clean Microsoft
`Word version. The marked-up copy should provide appropriate annotations, including
`supplement number(s) and annual report date(s).
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for
`new active ingredients (which includes new salts and new fixed combinations), new
`indications, new dosage forms, new dosing regimens, or new routes of administration
`are required to contain an assessment of the safety and effectiveness of the product for
`the claimed indication in pediatric patients unless this requirement is waived, deferred,
`or inapplicable.
`
`Because this drug product for these indications have orphan drug designation, you are
`exempt from this requirement.
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and
`promotional labeling. For information about submitting promotional materials, see the
`final guidance for industry Providing Regulatory Submissions in Electronic and Non-
`Electronic Format-Promotional Labeling and Advertising Materials for Human
`Prescription Drugs.3
`
`
`2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
`Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`3 For the most recent version of a guidance, check the FDA guidance web page at
`https://www.fda.gov/media/128163/download.
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4827475
`
`

`

`NDA 50708/S-053
`NDA 50709/S-045
`NDA 210115/S-005
`Page 3
`
`
`
`You must submit final promotional materials and Prescribing Information, accompanied
`by a Form FDA 2253, at the time of initial dissemination or publication
`[21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at FDA.gov.4 Information and
`Instructions for completing the form can be found at FDA.gov.5
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`If you have any questions, call Susan Rhee, Regulatory Project Manager, at 301-796-
`2402.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Ozlem Belen, MD, MPH
`Deputy Director
`Division of Rheumatology and Transplant Medicine
`Office of Immunology and Inflammation
`Center for Drug Evaluation and Research
`
`
`ENCLOSURE(S):
`• Content of Labeling
`o Prescribing Information
`o Patient Package Insert
`Instructions for Use
`o
`
`
`
`
`
`
`
`4 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
`5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4827475
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`OZLEM A BELEN
`07/16/2021 03:43:11 PM
`
`Reference ID: 4827475
`
`

`

`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`50708s053, 50709s045, 210115s005
`
`LABELING
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not includeall the information needed to use
`PROGRAF* safely and effectively. See full prescribing information for
`PROGRAF.
`
`
`
`
`. .__|Initial Oral Dosage Whole Blood Trough
`
`PEDIATRIC
`
`WARNING: MALIGNANCIESand SERIOUS INFECTIONS
`Seefullprescribing informationfor complete boxed warning.
`0.15-0.2 mg/kg/day capsules|Month 1-12: 5-20 ng/mL
`Increased risk for developing serious infections and malignancies
`or 0.2 mg/kg/dayoral
`suspension, divided in two
`doses, every 12 hours
`
`Kidney Transplant
`
`0.3 mg/kg/day capsules or
`oral suspension, divided in
`two doses, every 12 hours
`
`Month 1-12: 5-20 ng/mL
`
`PROGRAF (tacrolimus) capsules, for oral use
`PROGRAF (tacrolimus)injection, for intravenous use
`PROGRAF Granules (tacrolimus for oral suspension)
`Initial U.S. Approval: 1994
`
`with PROGRAF or other immunosuppressants that maylead to
`
`—___________— RECENT MAJOR CHANGES
`Indications and Usage (1.1)
`Dosage and Administration (2.2, 2.3)
`Warnings and Precautions (5.11)
`
`7/2021
`7/2021
`12/2020
`
`
`
`, e yo hcdiedin|Week2 toMonth 12: 10-
`
`two doses, every 12 hours
`15 ng/mL
`MMF= Mycophenolate mofetil
`1.
`Patients with cystic fibrosis may require higher doses due to lower
`bioavailability.
`
`03 seghka/day” capsules or
`oral suspension, divided in
`two doses, every 12 hours
`
`Month 1-12: 5-20 ng/mL
`
`0.3 mg/kg/da’
`
`2
`
`ipsul
`
`Weeks 1-2: 10-20 ng/mL
`
`INDICATIONS AND USAGE
`PROGRAF is a calcineurin-inhibitor immunosuppressantindicated for the
`prophylaxis of organ rejection in adult and pediatric patients receiving
`allogeneic liver, kidney, heart, or lung transplants, in combination with other
`
`DOSAGE AND ADMINISTRATION
`
`ADULT
`
`Patient
`Population
`
`Initial Oral Dosage
`(formulation)
`
`Whole Blood Trough
`Concentration Range
`
`Kidney Transplant
`
`0.2 mg/kg/day capsules,
`divided in two doses, every
`12 hours
`
`0.1 mg/kg/day capsules,
`divided in two doses, every
`12 hours
`
`Month 1-3: 7-20 ng/mL
`Month 4-12: 5-15 ng/mL
`
`Month 1-12: 4-11 ng/mL
`
`12 hours
`
`2.
`
`Dose at 0.1 mg/kg/dayif antibody induction treatment is
`administered.
`
`e Intravenous (IV) use recommended for patients who cannottolerate oral
`formulations (capsules or suspension). (2.1, 2.2)
`Admunister capsules or suspension consistently with or without food. (2.1)
`Therapeutic drug monitoring is recommended. (2.1, 2.6)
`Avoid eating grapefruit or dnnking grapefruit juice. (2.1)
`See dosage adjustments for African-American patients (2.2). hepatic and
`renal impaired. (2.4, 2.5)
`e For complete dosing information, see the full prescribing information.
`
`—_—---___----_---—- CONTRAINDICATIONS
`e Hypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated
`castor oil). (4)
`
`WARNINGS AND PRECAUTIONS
`¢ Not Interchangeable with Extended-Release Tacrolimus Products -
`Medication Errors: Instruct patients or caregivers to recognize the
`appearance ofPROGRAF capsules. (5.3)
`e@ New Onset Diabetes After Transplant: Monitor blood glucose. (5.4)
`e Nephrotoxicity (acute and/or chronic): Reduce the dose; use caution with
`other nephrotoxic drugs. (5.5)
`e Neurotoxicity: Including risk of Posterior Reversible Encephalopathy
`Syndrome (PRES); monitor for neurologic abnormalities: reduce or
`discontinue PROGRAF.(5.6)
`e Hyperkalemia: Monitor serum potassium levels. Consider carefully before
`using with other agents also associated with hyperkalemia. (5.7)
`e Hypertension: May require antihypertensive therapy. Monitor relevant
`drug-druginteractions. (5.8)
`e Anaphylactic Reactions with IV formulation: Observe patients receiving
`PROGRAF injection for signs and symptoms of anaphylaxis. (5.9)
`e Not recommended for use with sirolimus: Not recommended in liver and
`heart transplant due to increased nsk of serious adverse reactions. (5.10)
`e@ Myocardial Hypertrophy: Consider dose reduction/discontinuation. (5.13)
`e Immunizations: Avoid live vaccines. (5.14)
`
`DOSAGE FORMS AND STRENGTHS
`© Capsules: 0.5 mg, 1 mg and 5 mg (3)
`e Injection: 5 mg/mL (3)
`0.1-0.15 mg/kg/day capsules,|Month 1-12: 5-20 ng/mL
`e For oral suspension: 0.2 mg, 1 mg unit-dose packets containing granules
`divided in two doses, every
`@
`12 hours
`
`0.075 mg/kg/day capsules,
`divided in two doses, every
`12 hours
`
`Month 1-3: 10-20 ng/mL
`Month > 4: 5-15 ng/mL
`
`0.075 mg/kg/day’capsules,
`divided in two doses, every
`
`Month 1-3: 10-15 ng/mL
`Month 4-12: 8-12 ng/mL
`
`Reference ID: 4827475
`
`

`

` Pure Red Cell Aplasia: Consider discontinuation of PROGRAF. (5.15)
`
` ------------------------------ ADVERSE REACTIONS -----------------------------
`The most common adverse reactions (≥ 15%) were abnormal renal function,
`hypertension, diabetes mellitus, fever, CMV infection, tremor, hyperglycemia,
`leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract
`infection, constipation, diarrhea, headache, abdominal pain, insomnia,
`paresthesia, peripheral edema, nausea, hyperkalemia, hypomagnesemia, and
`hyperlipemia. (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: Can increase MPA exposure after
`crossover from cyclosporine to PROGRAF; monitor for MPA-related
`adverse reactions and adjust MMF or MPA dose as needed. (7.1)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: MALIGNANCIES AND SERIOUS INFECTIONS 
`1 INDICATIONS AND USAGE 
`1.1 Prophylaxis of Organ Rejection in Kidney, Liver, Heart, or Lung
`Transplant 
`2 DOSAGE AND ADMINISTRATION 
`2.1 Important Administration Instructions 
`2.2 Dosage Recommendations for Adult Kidney, Liver, Heart, or Lung
`Transplant Patients - Capsules and Injection 
`2.3 Dosage Recommendations for Pediatric Kidney, Liver, Heart, or Lung
`Transplant Patients 
`2.4 Dosage Adjustment in Patients with Renal Impairment 
`2.5 Dosage Adjustment in Patients with Hepatic Impairment 
`2.6 Therapeutic Drug Monitoring 
`2.7 Preparation and Administration Instructions of PROGRAF Injection
`for Pharmacists 
`2.8 Preparation and Administration Instructions of PROGRAF Granules 
`3 DOSAGE FORMS AND STRENGTHS 
`4 CONTRAINDICATIONS 
`5 WARNINGS AND PRECAUTIONS 
`5.1 Lymphoma and Other Malignancies 
`5.2 Serious Infections 
`5.3 Not Interchangeable with Extended-Release Tacrolimus Products -
`Medication Errors 
`5.4 New Onset Diabetes After Transplant 
`5.5 Nephrotoxicity 
`5.6 Neurotoxicity 
`5.7 Hyperkalemia 
`5.8 Hypertension 
`5.9 Anaphylactic Reactions with PROGRAF Injection 
`5.10 Not Recommended for Use with Sirolimus 
`5.11 Interactions with CYP3A4 Inhibitors and Inducers 
`5.12 QT Prolongation 
`5.13 Myocardial Hypertrophy 
`5.14 Immunizations 
`5.15 Pure Red Cell Aplasia 
`6 ADVERSE REACTIONS 
`6.1 Clinical Studies Experience 
`6.2 Postmarketing Experience 
`7 DRUG INTERACTIONS 
`7.1 Mycophenolic Acid 
`7.2 Effects of Other Drugs on PROGRAF 
`8 USE IN SPECIFIC POPULATIONS 
`
`FULL PRESCRIBING INFORMATION
`
` Nelfinavir and Grapefruit Juice: Increased tacrolimus concentrations via
`CYP3A inhibition; avoid concomitant use. (7.2)
` CYP3A Inhibitors: Increased tacrolimus concentrations; monitor
`concentrations and adjust tacrolimus dose as needed. (5.11, 7.2)
` CYP3A4 Inducers: Decreased tacrolimus concentrations; monitor
`concentrations and adjust tacrolimus dose as needed. (5.11, 7.2)
`
` ----------------------- USE IN SPECIFIC POPULATIONS ----------------------
`Pregnancy: Can cause fetal harm. Advise pregnant women of the
`potential risk to the fetus. (8.1, 8.3)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling
`
`Revised: 07/2021
`
`
`
`8.1 Pregnancy 
`8.2 Lactation 
`8.3 Females and Males of Reproductive Potential 
`8.4 Pediatric Use 
`8.5 Geriatric Use 
`8.6 Renal Impairment 
`8.7 Hepatic Impairment 
`8.8 Race or Ethnicity 
`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 
`14.1 Kidney Transplantation 
`14.2 Liver Transplantation 
`14.3 Heart Transplantation 
`14.4 Lung Transplantation 
`15 REFERENCES 
`16 HOW SUPPLIED/STORAGE AND HANDLING 
`16.1 PROGRAF (tacrolimus) Capsules, USP 
`16.2 PROGRAF (tacrolimus) Injection 
`16.3 PROGRAF Granules (tacrolimus for oral suspension) 
`16.4 Handling and Disposal 
`17 PATIENT COUNSELING INFORMATION 
`17.1 Administration 
`17.2 Development of Lymphoma and Other Malignancies 
`17.3 Increased Risk of Infection 
`17.4 New Onset Diabetes After Transplant 
`17.5 Nephrotoxicity 
`17.6 Neurotoxicity 
`17.7 Hyperkalemia 
`17.8 Hypertension 
`17.9 Drug Interactions 
`17.10 Pregnancy, Lactation and Infertility 
`17.11 Myocardial Hypertrophy 
`17.12 Immunizations 
`
` 
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`
`
`
`
`
`WARNING: MALIGNANCIES and SERIOUS INFECTIONS
`Increased risk for developing serious infections and malignancies with PROGRAF or other
`immunosuppressants that may lead to hospitalization or death. (5.1, 5.2)
`
`Reference ID: 4827475
`
`

`

`1 INDICATIONS AND USAGE
`1.1 Prophylaxis of Organ Rejection in Kidney, Liver, Heart, or Lung Transplant
`PROGRAF® is indicated for the prophylaxis of organ rejection, in adult and pediatric patients receiving allogeneic kidney
`transplant [see Clinical Studies (14.1)], liver transplant [see Clinical Studies (14.2)], heart transplant [see Clinical Studies
`(14.3)], or lung transplant [see Clinical Studies (14.4)] in combination with other immunosuppressants.
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Important Administration Instructions
`PROGRAF should not be used without supervision by a physician with experience in immunosuppressive therapy.
`PROGRAF capsules and PROGRAF Granules are not interchangeable or substitutable for other tacrolimus extended-
`release products. This is because rate of absorption following the administration of an extended-release tacrolimus product
`is not equivalent to that of an immediate-release tacrolimus drug product. 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 [see Warnings and Precautions (5.3)].
`Intravenous Formulation - Administration Precautions due to Risk of Anaphylaxis
`Intravenous use is recommended for patients who cannot tolerate oral formulations, and conversion from intravenous to
`oral PROGRAF 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 [see Warnings and Precautions (5.9)].
`Patients receiving PROGRAF 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, the infusion should
`be stopped. An aqueous solution of epinephrine should be available at the bedside as well as a source of oxygen.
`Oral Formulations (Capsules and Oral Suspension)
`If patients are able to initiate oral therapy, the recommended starting doses should be initiated. PROGRAF Granules for
`oral suspension or PROGRAF capsules may be taken with or without food. However, since the presence of food affects
`the bioavailability of PROGRAF, if taken with food, it should be taken consistently the same way each time [see Clinical
`Pharmacology (12.3)].
`General Administration Instructions
`Patients should not eat grapefruit or drink grapefruit juice in combination with PROGRAF [see Drug Interactions (7.2)].
`PROGRAF should not be used simultaneously with cyclosporine. PROGRAF or cyclosporine should be discontinued at
`least 24 hours before initiating the other. In the presence of elevated PROGRAF or cyclosporine concentrations, dosing
`with the other drug usually should be further delayed.
`Therapeutic drug monitoring (TDM) is recommended for all patients receiving PROGRAF [see Dosage and
`Administration (2.6)].
`
`2.2 Dosage Recommendations for Adult Kidney, Liver, Heart, or Lung Transplant Patients - Capsules and
`Injection
`Capsules
`
`If patients are able to tolerate oral therapy, the recommended oral starting doses should be initiated. The initial dose of
`PROGRAF capsules should be administered no sooner than 6 hours after transplantation in the liver, heart, or lung
`transplant patients. In kidney transplant patients, the initial dose of PROGRAF capsules may be administered within 24
`hours of transplantation, but should be delayed until renal function has recovered.
`
`Reference ID: 4827475
`
`

`

`The initial oral PROGRAF capsule dosage recommendations for adult patients with kidney, liver, heart, or lung
`transplants and whole blood trough concentration range are shown in Table 1. Perform therapeutic drug monitoring
`(TDM) to ensure that patients are within the ranges listed in Table 1.
`
`Table 1. Summary of Initial Oral PROGRAF Capsules Dosage Recommendations and Whole Blood
`Trough Concentration Range in Adults
`
`Patient Population
`
`Kidney Transplant
` With Azathioprine
`
` With MMF/IL-2 receptor antagonist2
`
`Liver Transplant
` With corticosteroids only
`
`Heart Transplant
` With azathioprine or MMF
`
`Lung Transplant
` With azathioprine or MMF
`
`PROGRAF Capsules1 Initial Oral
`Dosage
`
`Whole Blood Trough
`Concentration Range
`
`0.2 mg/kg/day, divided in two doses,
`administered every 12 hours
`0.1 mg/kg/day, divided in two doses,
`administered every 12 hours
`
`Month 1-3: 7-20 ng/mL
`Month 4-12: 5-15 ng/mL
`Month 1-12: 4-11 ng/mL
`
`0.10-0.15 mg/kg/day, divided in two
`doses, administered every 12 hours
`
`Month 1-12: 5-20 ng/mL
`
`0.075 mg/kg/day, divided in two doses,
`administered every 12 hours
`
`Month 1-3: 10-20 ng/mL
`Month ≥ 4: 5-15 ng/mL
`
`0.075 mg/kg/day3, divided in two
`doses, administered every 12 hours
`1. African-American patients may require higher doses compared to Caucasians (see Table 2).
`2.
`In a second smaller trial, the initial dose of tacrolimus was 0.15-0.2 mg/kg/day and observed tacrolimus concentrations were 6-16 ng/mL.
`during month 1-3 and 5-12 ng/mL during month 4-12 [see Clinical Studies (14.1)].
`3. Patients with cystic fibrosis may require higher doses due to lower bioavailability [see Clinical Pharmacology (12.3)].
`
`Month 1-3: 10-15 ng/mL
`Month 4-12: 8-12 ng/mL
`
`Dosage should be titrated based on clinical assessments of rejection and tolerability. PROGRAF dosages lower than the
`recommended initial dosage may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is
`recommended early post-transplant.
`
`The data in kidney transplant patients indicate that the African-American patients required a higher dose to attain
`comparable trough concentrations compared to Caucasian patients (Table 2) [see Use in Specific Populations (8.8) and
`Clinical Pharmacology (12.3)].
`
`Table 2. Comparative Dose and Trough Concentrations Based on Race
`
`Time After
`Transplant
`
`Day 7
`Month 1
`Month 6
`Month 12
`
`Caucasian
`N = 114
`Trough Concentrations
`(ng/mL)
`12.0
`12.8
`11.8
`10.1
`
`Dose
`(mg/kg)
`0.18
`0.17
`0.14
`0.13
`
`African-American
`N = 56
`Trough Concentrations
`(ng/mL)
`10.9
`12.9
`11.5
`11.0
`
`Dose
`(mg/kg)
`0.23
`0.26
`0.24
`0.19
`
`In lung transplantation, cystic fibrosis patients may have a reduced bioavailability of orally administered tacrolimus
`resulting in the need for higher doses to achieve target tacrolimus trough concentrations. Monitor tacrolimus trough
`concentrations and adjust the dose accordingly.
`
`Intravenous Injection
`
`Reference ID: 4827475
`
`

`

`PROGRAF injection should be used only as a continuous intravenous infusion and should be discontinued as soon as the
`patient can tolerate oral administration. The first dose of PROGRAF capsules should be given 8-12 hours after
`discontinuing the intravenous infusion.
`
`The recommended starting dose of PROGRAF injection is 0.03-0.05 mg/kg/day in kidney or liver transplant, 0.01
`mg/kg/day in heart transplant, and 0.01-0.03 mg/kg/day in lung transplant, given as a continuous intravenous infusion.
`Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is
`recommended early post-transplantation.
`
`The whole blood trough concentration range described in Table 1 pertains to oral administration of PROGRAF only;
`while monitoring PROGRAF concentrations in patients receiving PROGRAF injection as a continuous intravenous
`infusion may have some utility, the observed concentrations will not represent comparable exposures to those estimated
`by the trough concentrations observed in patients on oral therapy.
`
`Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as PROGRAF injection.
`Therefore, monitoring for signs and symptoms of anaphylaxis is recommended [see Warnings and Precautions (5.9)].
`
`2.3 Dosage Recommendations for Pediatric Kidney, Liver, Heart, or Lung Transplant Patients
`Oral formulations (capsules or oral suspension)
`Pediatric patients, in general, need higher tacrolimus doses compared to adults: the higher dose requirements may
`decrease as the child grows older. Recommendations for the initial oral dosage for pediatric transplant patients and whole
`blood trough concentration range are shown in Table 3. Perform TDM to ensure that patients are within the ranges listed
`in Table 3.
`
`Table 3. Summary of Initial PROGRAF Capsule and PROGRAF Granules Dosage Recommendations
`and Whole Blood Trough Concentration Range in Children
`
`Patient Population
`
`Pediatric kidney transplant patients1
`
`Whole Blood Trough Concentration
`Range
`Month 1-12: 5-20 ng/mL
`
`Initial PROGRAF Capsule and
`PROGRAF Granules Dosing
`0.3 mg/kg/day capsules or oral
`suspension, divided in two doses,
`administered every 12 hours
`0.15-0.2 mg/kg/day capsules or 0.2
`mg/kg/day oral suspension,
`divided in two doses, administered
`every 12 hours
`0.3 mg/kg/day3 capsules or oral
`suspension, divided in two doses,
`administered every 12 hours
`0.3 mg/kg/day3,4 capsules or oral
`suspension, divided in two doses,
`administered every 12 hours
`1. See Clinical Pharmacology (12.3), PROGRAF Granules Pharmacokinetics in Pediatric Patients.
`2. See Clinical Studies (14.2), Liver Transplantation.
`3. Dose at 0.1 mg/kg/day if antibody induction treatment is administered.
`4. Patients with cystic fibrosis may require higher doses due to lower bioavailability [see Clinical Pharmacology (12.3)].
`
`Pediatric liver transplant patients2
`
`Month 1-12: 5-20 ng/mL
`
`Pediatric heart transplant patients1
`
`Month 1-12: 5-20 ng/mL
`
`Pediatric lung transplant patients
`
`Week 1-2: 10-20 ng/mL
`Week 2 to Month 12: 10-15 ng/mL
`
`In lung transplantation, cystic fibrosis patients may have a reduced bioavailability of orally administered tacrolimus
`resulting in the need for higher doses to achieve target tacrolimus trough concentrations. Monitor tacrolimus trough
`concentrations and adjust the dose accordingly.
`
`Reference ID: 4827475
`
`

`

`For conversion of pediatric patients from PROGRAF Granules to PROGRAF capsules or from PROGRAF capsules to
`PROGRAF Granules, the total daily dose should remain the same. Following conversion from one formulation to another
`formulation of tacrolimus, therapeutic drug monitoring is recommended [see Dosage and Administration (2.6)].
`
`Intravenous Injection
`
`If a patient is unable to receive an oral formulation, the patient may be started on PROGRAF injection. For pediatric liver
`transplant patients, the intravenous dose is 0.03-0.05 mg/kg/day.
`
`2.4 Dosage Adjustment in Patients with Renal Impairment
`Due to its potential for nephrotoxicity, consider dosing PROGRAF at the lower end of the therapeutic dosing range in
`patients who have received a liver, heart, or lung transplant, and have pre-existing renal impairment. Further reductions in
`dose below the targeted range may be required.
`
`In kidney transplant patients with post-operative oliguria, the initial dose of PROGRAF should be administered no sooner
`than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery
`[see Dosage and Administration (2.2), Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical
`Pharmacology (12.3)].
`
`2.5 Dosage Adjustment in Patients with Hepatic Impairment
`Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child-Pugh ≥ 10) may
`require lower doses of PROGRAF. Close monitoring of blood concentrations is warranted.
`
`The use of PROGRAF in liver transplant recipients experiencing post-transplant hepatic impairment may be associated
`with increased risk of developing renal insufficiency related to high whole blood concentrations of tacrolimus. These
`patients should be monitored closely, and dosage adjustments should be considered. Some evidence suggests that lower
`doses should be used in these patients [see Dosage and Administration (2.2), Warnings and Precautions (5.5), Use in
`Specific Populations (8.7), and Clinical Pharmacology (12.3)].
`
`2.6 Therapeutic Drug Monitoring
`Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered
`an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments, and compliance. Whole
`blood trough concentration range can be found in Table 1.
`
`Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or
`discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not a
`replacement for renal and liver function monitoring and tissue biopsies. Data from clinical trials show that tacrolimus
`whole blood concentrations were most variable during the first week post-transplantation.
`
`The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore,
`monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and
`efficacy failure.
`
`Methods commonly used for the assay of tacrolimus include high-performance liquid chromatography with tandem mass
`spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as parent
`compound. Therefore, assay results obtained with immunoassays may have a positive bias relative to results of
`HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published
`literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods
`and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes
`containing ethylene diamine tetraacetic acid (EDTA) anticoagulant. Heparin anticoagulation is not recommended because
`
`Reference ID: 4827475
`
`

`

`of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room
`temperature or in a refrigerator and assayed within 7 days; see assay instructions for specifics. If samples are to be kept
`longer, they should be deep frozen at -20°C. One study showed drug recovery > 90% for samples stored at -20°C for
`6 months, with reduced recovery observed after 6 months.
`
`2.7 Preparation and Administration Instructions of PROGRAF Injection for Pharmacists
`Tacrolimus can cause fetal harm. Follow applicable special handling and disposal procedures1 [see How Supplied/ Storage
`and Handling (16.4)].
`
`PROGRAF injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration
`between 0.004 mg/mL and 0.02 mg/mL prior to use. Diluted infusion solution should be stored in glass or polyethylene
`containers and should be discarded after 24 hours. The diluted infusion solution should not be stored in a polyvinyl
`chloride (PVC) container due to decreased stability and the potential for extraction of phthalates. In situations where more
`dilute solutions are utilized (e.g., pediatric dosing, etc.), PVC-free tubing should likewise be used to minimize the
`potential for significant drug adsorption onto the tubing.
`
`Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
`whenever solution and container permit.
`
`Due to the chemical instability of tacrolimus in alkaline media, PROGRAF injection should not be mixed or co-infused
`with solutions of pH 9 or greater (e.g., ganciclovir or acyclovir).
`
`2.8 Preparation and Administration Instructions of PROGRAF Granules
`Tacrolimus can cause fetal harm. Follow applicable special handling and disposal procedures1 [see How Supplied/ Storage
`and Handling (16.4)].
`
`The required dose for PROGRAF Granules is calculated based on the weight of the patient. Use the minimum whole
`number of packets that corresponds to the required morning or evening dose. If the 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 products. Do not sprinkle
`PROGRAF Granules on food. Prepare and administer PROGRAF Granules as follows:
`
` • To prepare the dose,