Tacrolimus (extended release): Difference between revisions

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* All of these patients reported risk factors for PRCA such as [[parvovirus B19 infection]], underlying disease, or concomitant medications associated with PRCA.
* All of these patients reported risk factors for PRCA such as [[parvovirus B19 infection]], underlying disease, or concomitant medications associated with PRCA.
* A mechanism for tacrolimus-induced PRCA has not been elucidated. If PRCA is diagnosed, consider discontinuation of TACROLIMUS (EXTENDED RELEASE).
* A mechanism for tacrolimus-induced PRCA has not been elucidated. If PRCA is diagnosed, consider discontinuation of TACROLIMUS (EXTENDED RELEASE).
|clinicalTrials=* Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.  
|clinicalTrials=* Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.  
* In addition, the clinical studies were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.
* In addition, the clinical studies were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.
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====Common Adverse Reactions====
====Common Adverse Reactions====
* The incidence of adverse reactions that occurred in ≥5% of ENVARSUS XR-treated patients compared to tacrolimus immediate-release product through one year of treatment in the conversion study is shown by treatment group in TABLE 3.
* The incidence of adverse reactions that occurred in ≥5% of ENVARSUS XR-treated patients compared to tacrolimus immediate-release product through one year of treatment in the conversion study is shown by treatment group in TABLE 3.
|postmarketing=* The following adverse reactions have been reported from marketing experience with tacrolimus in the U.S. and outside the U.S.  
|postmarketing=* The following adverse reactions have been reported from marketing experience with tacrolimus in the U.S. and outside the U.S.  
*  Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
*  Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
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* '''Skin and Subcutaneous Tissue Disorders''': [[Hyperpigmentation]], [[photosensitivity]].
* '''Skin and Subcutaneous Tissue Disorders''': [[Hyperpigmentation]], [[photosensitivity]].
|drugInteractions===== Mycophenolic Acid ====
|drugInteractions===== Mycophenolic Acid ====
* When ENVARSUS XR is prescribed with a given dose of [[mycophenolic acid]] (MPA) product, exposure to [[MPA]] is higher with ENVARSUS XR coadministration than with cyclosporine coadministration because cyclosporine interrupts the enterohepatic recirculation of [[MPA]] while tacrolimus does not.
* When ENVARSUS XR is prescribed with a given dose of [[mycophenolic acid]] (MPA) product, exposure to [[MPA]] is higher with ENVARSUS XR coadministration than with cyclosporine coadministration because cyclosporine interrupts the enterohepatic recirculation of [[MPA]] while tacrolimus does not.
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* In pregnant rats, tacrolimus at oral doses of 3.2 mg/kg (3.7 times the maximum clinical dose) was associated with maternal toxicity, an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability.
* In pregnant rats, tacrolimus at oral doses of 3.2 mg/kg (3.7 times the maximum clinical dose) was associated with maternal toxicity, an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability.
* Tacrolimus, given orally to pregnant rats after organogenesis and during lactation at 1.0 and 3.2 mg/kg (1.2 and 3.7 times the maximum recommended clinical dose, respectively) was associated with reduced pup weights and pup viability (3.2 mg/kg only); among the high dose pups that died early, an increased incidence of kidney [[hydronephrosis]] was observed.
* Tacrolimus, given orally to pregnant rats after organogenesis and during lactation at 1.0 and 3.2 mg/kg (1.2 and 3.7 times the maximum recommended clinical dose, respectively) was associated with reduced pup weights and pup viability (3.2 mg/kg only); among the high dose pups that died early, an increased incidence of kidney [[hydronephrosis]] was observed.
|useInNursing=* Tacrolimus is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from ENVARSUS XR, a decision should be made whether to discontinue nursing or to discontinue ENVARSUS XR, taking into account the importance of drug to the mother.
|useInNursing=* Tacrolimus is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from ENVARSUS XR, a decision should be made whether to discontinue nursing or to discontinue ENVARSUS XR, taking into account the importance of drug to the mother.
|useInPed=* The safety and effectiveness of ENVARSUS XR in pediatric patients have not been established.
|useInPed=* The safety and effectiveness of ENVARSUS XR in pediatric patients have not been established.
|useInGeri=* Clinical studies of ENVARSUS XR did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In the stable kidney transplant study, there were 17 patients 65 years of age and older, and no patients were over 75 years.
|useInGeri=* Clinical studies of ENVARSUS XR did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In the stable kidney transplant study, there were 17 patients 65 years of age and older, and no patients were over 75 years.
* Other reported clinical experience has not identified differences in responses between the elderly and younger patients.  
* Other reported clinical experience has not identified differences in responses between the elderly and younger patients.  
* In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
* In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
|useInRace=* African-American patients may need to be titrated to higher ENVARSUS XR dosages to attain comparable trough concentrations compared to Caucasian patients.
|useInRace=* African-American patients may need to be titrated to higher ENVARSUS XR dosages to attain comparable trough concentrations compared to Caucasian patients.
|useInRenalImpair=* The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy subjects with normal renal function.
|useInRenalImpair=* The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy subjects with normal renal function.
* However, due to its potential for nephrotoxicity, monitoring of renal function in patients with renal impairment is recommended; tacrolimus dosage should be reduced if indicated.
* However, due to its potential for nephrotoxicity, monitoring of renal function in patients with renal impairment is recommended; tacrolimus dosage should be reduced if indicated.
|useInHepaticImpair=* The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean [[Child-Pugh score]]: >10) compared to healthy subjects with normal hepatic function.
|useInHepaticImpair=* The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean [[Child-Pugh score]]: >10) compared to healthy subjects with normal hepatic function.
* With greater tacrolimus whole blood trough concentrations in patients with severe hepatic impairment, there is a greater risk of adverse reactions and dosage reduction is recommended.
* With greater tacrolimus whole blood trough concentrations in patients with severe hepatic impairment, there is a greater risk of adverse reactions and dosage reduction is recommended.
* For patients with moderate hepatic impairment, monitor tacrolimus whole blood trough concentrations.  
* For patients with moderate hepatic impairment, monitor tacrolimus whole blood trough concentrations.  
* For patients with mild hepatic impairment, no dosage adjustments are needed.
* For patients with mild hepatic impairment, no dosage adjustments are needed.
|administration=* Take TACROLIMUS (EXTENDED RELEASE) on an empty stomach at the same time of the day, preferably in the morning (to ensure consistent and maximum possible drug exposure).
|administration=* Take TACROLIMUS (EXTENDED RELEASE) on an empty stomach at the same time of the day, preferably in the morning (to ensure consistent and maximum possible drug exposure).
* Swallow TACROLIMUS (EXTENDED RELEASE) whole with fluid (preferably water); do not chew, divide, or crush the tablets.
* Swallow TACROLIMUS (EXTENDED RELEASE) whole with fluid (preferably water); do not chew, divide, or crush the tablets.
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* Avoid eating grapefruit or drinking grapefruit juice or alcoholic beverage while taking TACROLIMUS (EXTENDED RELEASE).
* Avoid eating grapefruit or drinking grapefruit juice or alcoholic beverage while taking TACROLIMUS (EXTENDED RELEASE).
* African-American patients, compared to Caucasian patients, may need to be titrated to higher TACROLIMUS (EXTENDED RELEASE) dosages to attain comparable trough concentrations.
* African-American patients, compared to Caucasian patients, may need to be titrated to higher TACROLIMUS (EXTENDED RELEASE) dosages to attain comparable trough concentrations.
|monitoring=* Measure tacrolimus whole blood trough concentrations at least two times on separate days during the first week after initiation of dosing and after any change in dosage, after a change in co-administration of CYP3A inducers and/or inhibitors, or after a change in renal or hepatic function.
|monitoring=* Measure tacrolimus whole blood trough concentrations at least two times on separate days during the first week after initiation of dosing and after any change in dosage, after a change in co-administration of CYP3A inducers and/or inhibitors, 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 TACROLIMUS (EXTENDED RELEASE) dose.
* When interpreting measured concentrations, consider that the time to achieve tacrolimus steady state is approximately 7 days after initiating or changing the TACROLIMUS (EXTENDED RELEASE) dose.
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* Therefore, whole blood tacrolimus trough concentrations obtained with immunoassays may be numerically higher than concentrations obtained with an assay using HPLC/MS/MS.
* 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.
* 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.
|overdose=* Postmarketing cases of overdose with tacrolimus have been reported. Overdosage adverse reactions included:
|overdose=* Postmarketing cases of overdose with tacrolimus have been reported. Overdosage adverse reactions included:
** Nervous system disorders ([[tremor]], [[headache]], [[confusional]] state, balance disorders, [[encephalopathy]], [[lethargy]] and [[somnolence]]).
** Nervous system disorders ([[tremor]], [[headache]], [[confusional]] state, balance disorders, [[encephalopathy]], [[lethargy]] and [[somnolence]]).
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* The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use.  
* The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use.  
* General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.
* General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.
|drugBox={{drugbox2
|drugBox={{drugbox2
| Verifiedfields = changed
| Verifiedfields = changed
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| routes_of_administration = Topical, oral, [[Intravenous|iv]]
| routes_of_administration = Topical, oral, [[Intravenous|iv]]
}}
}}
|mechAction=123
|mechAction=* Tacrolimus binds to an intracellular protein, FKBP-12.
|structure=123
* A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (an ubiquitous mammalian intracellular enzyme) is then formed and the phosphatase activity of calcineurin inhibited.
|PD=123
* Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT) and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB).
|PK=123
* Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony stimulating factor.
|nonClinToxic=123
* Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor-beta that can lead to immunosuppressive activity.
* The net result is the inhibition of T-lymphocyte activation and proliferation as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).
|PK=* Table 5 summarizes the pharmacokinetic (PK) parameters of tacrolimus following oral administration of once-daily ENVARSUS XR in healthy subjects and in kidney transplant patients, under fasted conditions.
* Whole blood tacrolimus concentrations in the pharmacokinetic studies were measured using validated HPLC/MS/MS assays.
 
* In adult kidney transplant patients ≥ 6 months post-transplant switched to ENVARSUS XR® XR at 67% to 80% of the daily dose of tacrolimus immediate-release capsules, the steady state tacrolimus exposures (AUC24) and tacrolimus trough concentrations (C24) were comparable to the AUC24 and C24 measured prior to the switch.
* However, the mean Cmax estimate was 30% lower and the median Tmax was more prolonged (6 hours versus 2 hours) following administration of ENVARSUS XR as compared to that of tacrolimus immediate-release capsules.
==== Absorption ====
* Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable.
* In healthy subjects, the oral bioavailability of ENVARSUS XR was approximately 50% higher as compared with both tacrolimus immediate-release and extended-release formulations at steady state.
* In healthy subjects who received single ENVARSUS XR doses ranging from 5 mg to 10 mg, the mean AUC and C24 of tacrolimus increased linearly and the elimination half-life did not change with increasing doses.
==== Food Effects ====
* The presence of a meal affects the absorption of tacrolimus; the rate and extent of absorption is greatest under fasted conditions.
* In 26 healthy subjects, administration of ENVARSUS XR following a high-fat breakfast reduced the systemic exposure (AUC) to tacrolimus by approximately 55% and the peak plasma concentration of tacrolimus (Cmax) by 22%, with no effect on the time to reach maximum plasma concentration (Tmax), compared to when ENVARSUS XR was administered under fasted conditions.
==== Chronopharmacokinetic Effect ====
* In 26 healthy subjects, administration of ENVARSUS XR tablets in the evening resulted in a 15% lower AUC0-inf, and a 20% lower C24, as compared to morning dosing.
==== Distribution ====
* The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL.
* Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes.
* The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration.
* In a U.S. trial in which tacrolimus was administered as immediate-release formulation, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).
==== Metabolism ====
* The desired pharmacological activity of tacrolimus is primarily due to the parent drug.
* Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system 3A (CYP3A).
* A metabolic pathway leading to the formation of 8 possible metabolites has been proposed.
* Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro.
* The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus.
* In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.
==== Excretion ====
* In a mass balance study of orally administered radiolabeled tacrolimus to 6 healthy subjects, the mean recovery of the radiolabel was 94.9 ± 30.7%.
* Fecal elimination accounted for 92.6 ± 30.7% and urinary elimination accounted for 2.3 ± 1.1% of the total radiolabel administered.
* The elimination half-life based on radioactivity was 31.9 ± 10.5 hours, whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations.
* The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and the mean clearance of tacrolimus was 0.172 ± 0.088 L/hr/kg.
* The elimination half-life of tacrolimus after oral administration of 2 mg ENVARSUS XR once-daily for 10 days was 31.0 ± 8.1 hours (mean ± SD) in 25 healthy subjects.
==== Specific Populations ====
* No dedicated pharmacokinetic studies in specific populations were conducted with ENVARSUS XR.
* '''Renal Impairment''':
:* Tacrolimus pharmacokinetics following a single administration of tacrolimus (administered as a continuous IV infusion) were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9±1.6 and 12.0±2.4 mg/dL, respectively) prior to their kidney transplant.
:* The mean clearance of tacrolimus in patients with renal dysfunction given IV tacrolimus was similar to that in healthy subjects given tacrolimus IV and in healthy subjects given oral tacrolimus immediate-release.
* '''Hepatic Impairment''':
:* Tacrolimus pharmacokinetics have been determined in 6 patients with mild hepatic impairment (mean Pugh score: 6.2) following single oral administration of tacrolimus immediate-release.
:* The mean clearance of tacrolimus in patients with mild hepatic impairment was not substantially different from that in healthy subjects.
:* Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic impairment (mean Pugh score: >10).
:* The mean clearance was substantially lower in patients with severe hepatic impairment.
* '''Race''':
:* The pharmacokinetics of tacrolimus was studied following single oral administration of tacrolimus immediate-release (5 mg) in 10 African-American, 12 Latino-American, and 12 Caucasian healthy subjects:
** The mean (±SD) tacrolimus Cmax in African-Americans (23.6±12.1 ng/mL) was lower than in Caucasians (40.2±12.6 ng/mL) and Latino-Americans (36.2±15.8 ng/mL).
** Mean AUC0-inf tended to be lower in African-Americans (203±115 ng•hr/mL) than Caucasians (344±186 ng•hr/mL) and Latino-Americans (274±150 ng•hr/mL).
** The mean (±SD) absolute oral bioavailability (F) in African-Americans (12±4.5%) and Latino-Americans (14±7.4%) was lower than in Caucasians (19±5.8%).
** There was no significant difference in mean terminal half-life among the three ethnic groups (range from approximately 25 to 30 hours).
* '''Gender''':
:* A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted. :* In a sub-group analysis from two combined Phase 3 studies in kidney transplant recipients performed with ENVARSUS XR over one year of treatment, no gender-dependent differences in tacrolimus systemic exposures were observed.
==== Drug Interaction Studies ====
* No drug-drug interaction studies were conducted specifically with ENVARSUS XR.
* Because tacrolimus is metabolized mainly by CYP3A enzymes, drugs or substances known to inhibit these enzymes and/or are known CYP3A substrates may increase tacrolimus whole blood concentrations.
* Drugs known to induce CYP3A enzymes may decrease tacrolimus whole blood concentrations.
|nonClinToxic===== Carcinogenesis, Mutagenesis, Impairment of Fertility ====
===== Carcinogenesis =====
* Carcinogenicity studies were conducted in male and female rats and mice.
* In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found.
* The highest dose used in the mouse was 3.0 mg/kg/day (0.84 times the AUC at the maximum clinical dose of 0.14 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.24 times the AUC at the maximum clinical dose of 0.14 mg/kg/day).
* A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03%-3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m2/day.
* In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting.
* However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study.
* Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment; 2.5-fold the human exposure in stable adult renal transplant patients converted from tacrolimus immediate-release product to ENVARSUS XR).
* No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment).
* The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown.
* The implications of these carcinogenicity studies are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system’s ability to inhibit unrelated carcinogenesis.
===== Mutagenesis =====
* No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.
===== Impairment of Fertility =====
* Tacrolimus given orally at 1.0 mg/kg (1.2 times the maximum clinical dose based on body surface area) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction.
* Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable pups.
* When given at 3.2 mg/kg (3.7 times the maximum clinical dose based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.
|clinicalStudies=123
|clinicalStudies=123
|howSupplied=123
|howSupplied=123

Revision as of 20:08, 28 February 2017

Tacrolimus (extended release)
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shivani Chaparala M.B.B.S [2]

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Black Box Warning

WARNING
See full prescribing information for complete Boxed Warning.
MALIGNANCIES AND SERIOUS INFECTIONS
  • INCREASED RISK FOR DEVELOPING SERIOUS INFECTIONS AND MALIGNANCIES WITH ENVARSUS XR OR OTHER IMMUNOSUPPRESSANTS THAT MAY LEAD TO HOSPITALIZATION OR DEATH.

Overview

Tacrolimus (extended release) is a calcineurin-inhibitor immunosuppressant that is FDA approved for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations in combination with other immunosuppressants. There is a Black Box Warning for this drug as shown here. Common adverse reactions include (incidence ≥10%): diarrhea and blood creatinine increased.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

  • ENVARSUS XR is indicated for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations, in combination with other immunosuppressants.

Extended-release tablets: 0.75 mg, 1 mg, 4 mg.

Administration Instructions

  • Take TACROLIMUS (EXTENDED RELEASE) on an empty stomach at the same time of the day, preferably in the morning (to ensure consistent and maximum possible drug exposure).
  • Swallow TACROLIMUS (EXTENDED RELEASE) whole with fluid (preferably water); do not chew, divide, or crush the tablets.
  • If a dose is missed, take it as soon as possible within 15 hours after missing the dose; beyond the 15-hour time frame, wait until the usual scheduled time to take the next regular daily dose. Do not double the next dose.
  • Avoid eating grapefruit or drinking grapefruit juice or alcoholic beverage while taking TACROLIMUS (EXTENDED RELEASE).
  • African-American patients, compared to Caucasian patients, may need to be titrated to higher TACROLIMUS (EXTENDED RELEASE) dosages to attain comparable trough concentrations.

Conversion from Tacrolimus Immediate-Release Formulations

  • To convert from a tacrolimus immediate-release product to TACROLIMUS (EXTENDED RELEASE), administer an TACROLIMUS (EXTENDED RELEASE) once daily dose that is 80% of the total daily dose of the tacrolimus immediate-release product.
  • Monitor tacrolimus whole blood trough concentrations and titrate TACROLIMUS (EXTENDED RELEASE) dosage to achieve target whole blood trough concentration ranges of 4 to 11 ng/mL.

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 any change in dosage, after a change in co-administration of CYP3A inducers and/or inhibitors, 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 TACROLIMUS (EXTENDED RELEASE) 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.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Tacrolimus (extended release) in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Tacrolimus (extended release) in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

The safety and effectiveness of TACROLIMUS (EXTENDED RELEASE) in pediatric patients have not been established.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Tacrolimus (extended release) in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Tacrolimus (extended release) in pediatric patients.

Contraindications

  • TACROLIMUS (EXTENDED RELEASE) is contraindicated in patients with known hypersensitivity to tacrolimus.

Warnings

WARNING
See full prescribing information for complete Boxed Warning.
MALIGNANCIES AND SERIOUS INFECTIONS
  • INCREASED RISK FOR DEVELOPING SERIOUS INFECTIONS AND MALIGNANCIES WITH ENVARSUS XR OR OTHER IMMUNOSUPPRESSANTS THAT MAY LEAD TO HOSPITALIZATION OR DEATH.

Lymphoma and Other Malignancies

  • Immunosuppressants, including TACROLIMUS (EXTENDED RELEASE), increase the risk of developing lymphomas and other malignancies, particularly of the skin.
  • The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.
  • Examine patients for skin changes and advise to avoid or limit exposure to sunlight and UV light.
  • Post-transplant lymphoproliferative disorder (PTLD), associated with Epstein-Barr Virus (EBV), has been reported in immunosuppressed organ transplant patients.
  • The risk of PTLD appears greatest in those individuals who are EBV seronegative. Monitor EBV serology during treatment.

Serious Infections

Graft Rejection and Other Serious Adverse Reactions due to Medication Errors

  • Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products were reported outside the U.S.
  • This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under- or over-exposure to tacrolimus.
  • TACROLIMUS (EXTENDED RELEASE) is not interchangeable or substitutable with tacrolimus immediate-release products or other tacrolimus extended-release products.
  • Instruct patients and caregivers to recognize the appearance of TACROLIMUS (EXTENDED RELEASE) tablet.

New Onset Diabetes After Transplant

  • TACROLIMUS (EXTENDED RELEASE) caused new onset diabetes after transplant (NODAT) in kidney transplant patients, which may be reversible in some patients.
  • African-American and Hispanic kidney transplant patients are at an increased risk.
  • Monitor blood glucose concentrations and treat appropriately.

Nephrotoxicity due to TACROLIMUS (EXTENDED RELEASE) and Drug Interactions

Neurotoxicity

  • TACROLIMUS (EXTENDED RELEASE) may cause a spectrum of neurotoxicities.
  • The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure, and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions.
  • As symptoms may be associated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of TACROLIMUS (EXTENDED RELEASE) if neurotoxicity occurs.

Hyperkalemia

Hypertension

  • Hypertension is a common adverse reaction of TACROLIMUS (EXTENDED RELEASE) therapy and may require antihypertensive therapy.
  • Some antihypertensive drugs can increase the risk for hyperkalemia.
  • Calcium-channel blocking agents may increase tacrolimus blood concentrations and require dosage reduction of TACROLIMUS (EXTENDED RELEASE).

Risk of Rejection with Strong CYP3A Inducers and Risk of Serious Adverse Reactions with Strong CYP3A Inhibitors

  • The concomitant use of strong CYP3A inducers may increase the metabolism of tacrolimus, leading to lower whole blood trough concentrations and greater risk of rejection.
  • In contrast, the concomitant use of strong CYP3A inhibitors may decrease the metabolism of tacrolimus, leading to higher whole blood trough concentrations and greater risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation).
  • Therefore, adjust TACROLIMUS (EXTENDED RELEASE) dose and monitor tacrolimus whole blood trough concentrations when coadministering TACROLIMUS (EXTENDED RELEASE) with strong CYP3A inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) or strong CYP3A inducers (e.g., rifampin, rifabutin).

QT Prolongation

Immunizations

Pure Red Cell Aplasia

  • Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus.
  • All of these patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA.
  • A mechanism for tacrolimus-induced PRCA has not been elucidated. If PRCA is diagnosed, consider discontinuation of TACROLIMUS (EXTENDED RELEASE).

Adverse Reactions

Clinical Trials Experience

  • Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
  • In addition, the clinical studies were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.
  • In an open label, randomized, multinational conversion study, stable kidney transplant patients on a tacrolimus immediate-release product and concomitant immunosuppressants were randomized to treatment with TACROLIMUS (EXTENDED RELEASE) (N=162) or to continued treatment on the tacrolimus immediate-release product (N=162) and treated for a duration of 12 months.
  • The proportion of patients who discontinued treatment due to adverse reactions was 7.4% and 1.2% in the ENVARSUS XR and tacrolimus immediate-release treatment groups, respectively, through 12 months of treatment.
  • The most common adverse reactions leading to discontinuation of study drug in the TACROLIMUS (EXTENDED RELEASE) treatment group was cardiac arrest (2 events).

Infections

  • The overall incidence of infections, serious infections, and infections with identified etiology reported in stable kidney transplant recipients treated with TACROLIMUS (EXTENDED RELEASE) or tacrolimus immediate-release product are shown in TABLE 1. Percentage of Stable Patients with Infections Through One Year Post- Treatment in the Conversion Study (a)
This image is provided by the U.S. National Library of Medicine.

(a) The stable kidney transplant study was not designed to support comparative claims of ENVARSUS XR compared to tacrolimus immediate-release product for the adverse reactions reported in this table.
(b) BK virus associated nephropathy (BKVAN) occurred in 1.2% (2/162) and 0.6% (1/162) in the ENVARSUS XR and tacrolimus immediate-release treatment groups, respectively.

New Onset Diabetes After Transplantation (NODAT)

  • New onset diabetes after transplantation (NODAT) was defined by the composite occurrence of fasting plasma glucose values ≥126 mg/dL, 2-hour postprandial plasma glucose of at least 200 mg/dL (in oral glucose tolerance test) on 2 or more consecutive occasions post baseline, insulin requirement for ≥31 days, an oral hypoglycemic agent use ≥31 days, or HbA1c ≥6.5% (at least 3 months after randomization) among kidney transplant patients with no medical history of diabetes.
  • The incidence of NODAT for the stable kidney transplant study through one year post-transplant is summarized in TABLE 2 below.

Common Adverse Reactions

  • The incidence of adverse reactions that occurred in ≥5% of ENVARSUS XR-treated patients compared to tacrolimus immediate-release product through one year of treatment in the conversion study is shown by treatment group in TABLE 3.

Postmarketing Experience

  • The following adverse reactions have been reported from marketing experience with tacrolimus in the U.S. and outside the U.S.
  • Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
  • Ear Disorders: Hearing loss including deafness.

Drug Interactions

Mycophenolic Acid

  • When ENVARSUS XR is prescribed with a given dose of mycophenolic acid (MPA) product, exposure to MPA is higher with ENVARSUS XR coadministration than with cyclosporine coadministration because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not.
  • Monitor for MPA associated adverse reactions and reduce the dose of concomitantly administered mycophenolic acid products as needed.

Effects of Other Drugs/Substances on ENVARSUS XR

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C

  • There are no adequate and well-controlled studies in pregnant women.
  • Tacrolimus is transferred across the placenta.
  • The use of tacrolimus during pregnancy in humans has been associated with neonatal hyperkalemia and renal dysfunction.
  • Tacrolimus given orally to pregnant rabbits at 0.7 times the maximum clinical dose and pregnant rats at 1.1 times the maximum clinical dose was associated with an increased incidence of fetal death in utero, fetal malformations (cardiovascular, skeletal, omphalocele, and gallbladder agenesis) and maternal toxicity.
  • ENVARSUS XR should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
  • In pregnant rabbits, tacrolimus at oral doses of 0.32 and 1.0 mg/kg (0.7 and 2.3 times the maximum clinical dose based on body surface area, respectively) was associated with maternal toxicity as well as an increased incidence of abortions.
  • At the 1 mg/kg dose, fetal rabbits showed an increased incidence of malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosis, interrupted ossification of vertebral arch, vertebral and rib malformations, omphalocele, and gallbladder agenesis) and developmental variations.
  • In pregnant rats, tacrolimus at oral doses of 3.2 mg/kg (3.7 times the maximum clinical dose) was associated with maternal toxicity, an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability.
  • Tacrolimus, given orally to pregnant rats after organogenesis and during lactation at 1.0 and 3.2 mg/kg (1.2 and 3.7 times the maximum recommended clinical dose, respectively) was associated with reduced pup weights and pup viability (3.2 mg/kg only); among the high dose pups that died early, an increased incidence of kidney hydronephrosis was observed.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tacrolimus (extended release) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Tacrolimus (extended release) during labor and delivery.

Nursing Mothers

  • Tacrolimus is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from ENVARSUS XR, a decision should be made whether to discontinue nursing or to discontinue ENVARSUS XR, taking into account the importance of drug to the mother.

Pediatric Use

  • The safety and effectiveness of ENVARSUS XR in pediatric patients have not been established.

Geriatic Use

  • Clinical studies of ENVARSUS XR did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In the stable kidney transplant study, there were 17 patients 65 years of age and older, and no patients were over 75 years.
  • Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
  • In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Gender

There is no FDA guidance on the use of Tacrolimus (extended release) with respect to specific gender populations.

Race

  • African-American patients may need to be titrated to higher ENVARSUS XR dosages to attain comparable trough concentrations compared to Caucasian patients.

Renal Impairment

  • The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy subjects with normal renal function.
  • However, due to its potential for nephrotoxicity, monitoring of renal function in patients with renal impairment is recommended; tacrolimus dosage should be reduced if indicated.

Hepatic Impairment

  • The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: >10) compared to healthy subjects with normal hepatic function.
  • With greater tacrolimus whole blood trough concentrations in patients with severe hepatic impairment, there is a greater risk of adverse reactions and dosage reduction is recommended.
  • For patients with moderate hepatic impairment, monitor tacrolimus whole blood trough concentrations.
  • For patients with mild hepatic impairment, no dosage adjustments are needed.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Tacrolimus (extended release) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Tacrolimus (extended release) in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Take TACROLIMUS (EXTENDED RELEASE) on an empty stomach at the same time of the day, preferably in the morning (to ensure consistent and maximum possible drug exposure).
  • Swallow TACROLIMUS (EXTENDED RELEASE) whole with fluid (preferably water); do not chew, divide, or crush the tablets.
  • If a dose is missed, take it as soon as possible within 15 hours after missing the dose; beyond the 15-hour time frame, wait until the usual scheduled time to take the next regular daily dose. Do not double the next dose.
  • Avoid eating grapefruit or drinking grapefruit juice or alcoholic beverage while taking TACROLIMUS (EXTENDED RELEASE).
  • African-American patients, compared to Caucasian patients, may need to be titrated to higher TACROLIMUS (EXTENDED RELEASE) dosages to attain comparable trough concentrations.

Monitoring

  • Measure tacrolimus whole blood trough concentrations at least two times on separate days during the first week after initiation of dosing and after any change in dosage, after a change in co-administration of CYP3A inducers and/or inhibitors, 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 TACROLIMUS (EXTENDED RELEASE) 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.

IV Compatibility

There is limited information regarding the compatibility of Tacrolimus (extended release) and IV administrations.

Overdosage

  • Postmarketing cases of overdose with tacrolimus have been reported. Overdosage adverse reactions included:
  • Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion.
  • The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use.
  • General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

Pharmacology

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Tacrolimus (extended release)
Systematic (IUPAC) name
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Identifiers
CAS number 104987-11-3
ATC code D11AH01
L04AD02 (WHO)
PubChem 6473866
DrugBank DB00864
Chemical data
Formula Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox 
Mol. mass 804.018 g/mol
Pharmacokinetic data
Bioavailability 24% (5–67%), less after eating food rich in fat
Protein binding ≥98.8%
Metabolism Hepatic CYP3A4, CYP3A5
Half life 11.3 h for transplant patients (range 3.5–40.6 h)
Excretion Mostly faecal
Therapeutic considerations
Pregnancy cat.

C(AU) C(US)

Legal status

Template:Unicode Prescription only

Routes Topical, oral, iv

Mechanism of Action

  • Tacrolimus binds to an intracellular protein, FKBP-12.
  • A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (an ubiquitous mammalian intracellular enzyme) is then formed and the phosphatase activity of calcineurin inhibited.
  • Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT) and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB).
  • Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony stimulating factor.
  • Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor-beta that can lead to immunosuppressive activity.
  • The net result is the inhibition of T-lymphocyte activation and proliferation as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

Structure

There is limited information regarding Tacrolimus (extended release) Structure in the drug label.

Pharmacodynamics

There is limited information regarding Tacrolimus (extended release) Pharmacodynamics in the drug label.

Pharmacokinetics

  • Table 5 summarizes the pharmacokinetic (PK) parameters of tacrolimus following oral administration of once-daily ENVARSUS XR in healthy subjects and in kidney transplant patients, under fasted conditions.
  • Whole blood tacrolimus concentrations in the pharmacokinetic studies were measured using validated HPLC/MS/MS assays.
  • In adult kidney transplant patients ≥ 6 months post-transplant switched to ENVARSUS XR® XR at 67% to 80% of the daily dose of tacrolimus immediate-release capsules, the steady state tacrolimus exposures (AUC24) and tacrolimus trough concentrations (C24) were comparable to the AUC24 and C24 measured prior to the switch.
  • However, the mean Cmax estimate was 30% lower and the median Tmax was more prolonged (6 hours versus 2 hours) following administration of ENVARSUS XR as compared to that of tacrolimus immediate-release capsules.

Absorption

  • Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable.
  • In healthy subjects, the oral bioavailability of ENVARSUS XR was approximately 50% higher as compared with both tacrolimus immediate-release and extended-release formulations at steady state.
  • In healthy subjects who received single ENVARSUS XR doses ranging from 5 mg to 10 mg, the mean AUC and C24 of tacrolimus increased linearly and the elimination half-life did not change with increasing doses.

Food Effects

  • The presence of a meal affects the absorption of tacrolimus; the rate and extent of absorption is greatest under fasted conditions.
  • In 26 healthy subjects, administration of ENVARSUS XR following a high-fat breakfast reduced the systemic exposure (AUC) to tacrolimus by approximately 55% and the peak plasma concentration of tacrolimus (Cmax) by 22%, with no effect on the time to reach maximum plasma concentration (Tmax), compared to when ENVARSUS XR was administered under fasted conditions.

Chronopharmacokinetic Effect

  • In 26 healthy subjects, administration of ENVARSUS XR tablets in the evening resulted in a 15% lower AUC0-inf, and a 20% lower C24, as compared to morning dosing.

Distribution

  • The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL.
  • Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes.
  • The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration.
  • In a U.S. trial in which tacrolimus was administered as immediate-release formulation, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).

Metabolism

  • The desired pharmacological activity of tacrolimus is primarily due to the parent drug.
  • Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system 3A (CYP3A).
  • A metabolic pathway leading to the formation of 8 possible metabolites has been proposed.
  • Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro.
  • The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus.
  • In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

Excretion

  • In a mass balance study of orally administered radiolabeled tacrolimus to 6 healthy subjects, the mean recovery of the radiolabel was 94.9 ± 30.7%.
  • Fecal elimination accounted for 92.6 ± 30.7% and urinary elimination accounted for 2.3 ± 1.1% of the total radiolabel administered.
  • The elimination half-life based on radioactivity was 31.9 ± 10.5 hours, whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations.
  • The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and the mean clearance of tacrolimus was 0.172 ± 0.088 L/hr/kg.
  • The elimination half-life of tacrolimus after oral administration of 2 mg ENVARSUS XR once-daily for 10 days was 31.0 ± 8.1 hours (mean ± SD) in 25 healthy subjects.

Specific Populations

  • No dedicated pharmacokinetic studies in specific populations were conducted with ENVARSUS XR.
  • Renal Impairment:
  • Tacrolimus pharmacokinetics following a single administration of tacrolimus (administered as a continuous IV infusion) were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9±1.6 and 12.0±2.4 mg/dL, respectively) prior to their kidney transplant.
  • The mean clearance of tacrolimus in patients with renal dysfunction given IV tacrolimus was similar to that in healthy subjects given tacrolimus IV and in healthy subjects given oral tacrolimus immediate-release.
  • Hepatic Impairment:
  • Tacrolimus pharmacokinetics have been determined in 6 patients with mild hepatic impairment (mean Pugh score: 6.2) following single oral administration of tacrolimus immediate-release.
  • The mean clearance of tacrolimus in patients with mild hepatic impairment was not substantially different from that in healthy subjects.
  • Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic impairment (mean Pugh score: >10).
  • The mean clearance was substantially lower in patients with severe hepatic impairment.
  • Race:
  • The pharmacokinetics of tacrolimus was studied following single oral administration of tacrolimus immediate-release (5 mg) in 10 African-American, 12 Latino-American, and 12 Caucasian healthy subjects:
    • The mean (±SD) tacrolimus Cmax in African-Americans (23.6±12.1 ng/mL) was lower than in Caucasians (40.2±12.6 ng/mL) and Latino-Americans (36.2±15.8 ng/mL).
    • Mean AUC0-inf tended to be lower in African-Americans (203±115 ng•hr/mL) than Caucasians (344±186 ng•hr/mL) and Latino-Americans (274±150 ng•hr/mL).
    • The mean (±SD) absolute oral bioavailability (F) in African-Americans (12±4.5%) and Latino-Americans (14±7.4%) was lower than in Caucasians (19±5.8%).
    • There was no significant difference in mean terminal half-life among the three ethnic groups (range from approximately 25 to 30 hours).
  • Gender:
  • A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted. :* In a sub-group analysis from two combined Phase 3 studies in kidney transplant recipients performed with ENVARSUS XR over one year of treatment, no gender-dependent differences in tacrolimus systemic exposures were observed.

Drug Interaction Studies

  • No drug-drug interaction studies were conducted specifically with ENVARSUS XR.
  • Because tacrolimus is metabolized mainly by CYP3A enzymes, drugs or substances known to inhibit these enzymes and/or are known CYP3A substrates may increase tacrolimus whole blood concentrations.
  • Drugs known to induce CYP3A enzymes may decrease tacrolimus whole blood concentrations.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
  • Carcinogenicity studies were conducted in male and female rats and mice.
  • In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found.
  • The highest dose used in the mouse was 3.0 mg/kg/day (0.84 times the AUC at the maximum clinical dose of 0.14 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.24 times the AUC at the maximum clinical dose of 0.14 mg/kg/day).
  • A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03%-3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m2/day.
  • In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting.
  • However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study.
  • Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment; 2.5-fold the human exposure in stable adult renal transplant patients converted from tacrolimus immediate-release product to ENVARSUS XR).
  • No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment).
  • The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown.
  • The implications of these carcinogenicity studies are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system’s ability to inhibit unrelated carcinogenesis.
Mutagenesis
  • No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.
Impairment of Fertility
  • Tacrolimus given orally at 1.0 mg/kg (1.2 times the maximum clinical dose based on body surface area) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction.
  • Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable pups.
  • When given at 3.2 mg/kg (3.7 times the maximum clinical dose based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

Clinical Studies

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How Supplied

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Storage

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Patient Counseling Information

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Precautions with Alcohol

Alcohol-Tacrolimus (extended release) interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

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Look-Alike Drug Names

There is limited information regarding Tacrolimus (extended release) Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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