Envarsus XR (Page 5 of 9)

8.2 Lactation

Risk Summary

Controlled lactation studies have not been conducted in humans; however tacrolimus has been reported to be present in human milk. The effects of tacrolimus on the breastfed infant, or on milk production have not been assessed. Tacrolimus is excreted in rat milk and in peri-/postnatal rat studies, exposure to tacrolimus during the postnatal period was associated with developmental toxicity in the offspring at clinically relevant doses [see Pregnancy (8.1), Nonclinical Toxicology (13.1)].

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for ENVARSUS XR and any potential adverse effects on the breastfed child from ENVARSUS XR or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Contraception

ENVARSUS XR can cause fetal harm when administered to pregnant women. Advise female and male patients of reproductive potential to speak with their healthcare provider on family planning options including appropriate contraception prior to starting treatment with ENVARSUS XR [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1)].

Infertility

Based on findings in animals, male and female fertility may be compromised by treatment with ENVARSUS XR [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

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

8.5 Geriatric 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 Studies 1, 2 and 3, there were 37 patients 65 years of age and older, and no patients were over 75 years [see Clinical Studies (14)]. 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.

8.6 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 [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

8.7 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 [see Clinical Pharmacology (12.3)]. 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 [see Dosage and Administration (2.4)]. For patients with moderate hepatic impairment, monitor tacrolimus whole blood trough concentrations. For patients with mild hepatic impairment, no dosage adjustments are needed.

8.8 Race

African-American patients may need to be titrated to higher ENVARSUS XR dosages to attain comparable trough concentrations compared to Caucasian patients. The pharmacokinetics of ENVARSUS XR were evaluated in a study of 46 stable African-American kidney transplant recipients converted from tacrolimus immediate-release to ENVARSUS XR and indicated that an 80% conversion factor is appropriate for African-American patients [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

African-American and Hispanic kidney transplant patients are at an increased risk for new onset diabetes after transplant. Monitor blood glucose concentrations and treat appropriately [see Warnings and Precautions (5.4)].

10 OVERDOSAGE

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)
• gastrointestinal disturbances (nausea, vomiting, and diarrhea)
• abnormal renal function (increased blood urea nitrogen and elevated serum creatinine)
• urticaria
• hypertension
• peripheral edema, and
• infections (one fatal postmarketing case of bilateral pneumopathy and CMV infection was attributed to tacrolimus extended-release capsules overdose).

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.

11 DESCRIPTION

Tacrolimus is the active ingredient in ENVARSUS XR. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as [3S -[3R *[E (1S *,3S *,4S *)],4S *,5R *,8S *,9E ,12R *,14R *,15S *,16R *,18S *,19S *,26aR *]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclo-hexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c ][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate.

The chemical structure of tacrolimus is:

Tacrolimus has an empirical formula of C₄₄ H₆₉ NO₁₂ •H₂ O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform.

ENVARSUS XR is available for oral administration as extended-release tablets containing the equivalent of 0.75 mg, 1 mg, or 4 mg of anhydrous tacrolimus USP. Inactive ingredients include hypromellose USP, lactose monohydrate NF, polyethylene glycol NF, poloxamer NF, magnesium stearate NF, tartaric acid NF, butylated hydroxytoluene NF, and dimethicone NF.

12 CLINICAL PHARMACOLOGY

12.1 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).

12.3 Pharmacokinetics

Table 9 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.

Table 9. Pharmacokinetic Parameters of ENVARSUS XR by Study Day in Healthy Subjects and Kidney Transplant Patients Under Fasted Conditions

a) Healthy adult subjects (administered mg/day dose); Adult de novo kidney transplant patients (group average of administered mg/day dose); Adult kidney ≥ 6 months post-transplant (group average of administered mg/day dose of ENVARSUS XR, following conversion to 67% to 80% of the daily tacrolimus immediate -release capsules dose) b) Day of ENVARSUS XR dosing and PK profiling c) Arithmetic means ± S.D. d) Median [range] e) “De novo ” refers to immunosuppression starting at the time of transplantation f) Starting ENVARSUS XR dose = 0.14 mg/kg/day g) Starting ENVARSUS XR dose = 0.17 mg/kg/day. De novo kidney transplant patients who received ENVARSUS XR starting dose of 0.17 mg/kg/day achieved higher than recommended target tacrolimus trough concentrations, as high as 57 ng/mL during the first 1 to 2 weeks post-transplant. h) Tacrolimus trough concentration before the next dose i) After 7 days of stable dosing with ENVARSUS XR j) AUC0-24 –to- C24 correlation coefficient (r) at steady state was 0.80 or higher k) Conversion to ENVARSUS XR at a mean dose of 80% of the total daily dose of tacrolimus immediate-release resulted in equivalent exposure with a 30% reduction in Cmax .
Population	ENVARSUSXR Dose	Dayb	Pharmacokinetic Parameters of ENVARSUS XR
			Cmax c (ng/mL)	Tmax d (hr)	AUC24 c (ng•hr/mL)	C24 h (ng/mL)
Healthy Subjectsa (n=19)	2 mg2 mg	Day 1Day 10	11.9 ± 3.88.3 ± 2.9	14.0 [6 — 28]8.0 [1.0-12.0]	50 ± 14140 ± 50	1.8 ± 0.64.6 ± 1.7
Adult Kidneya De novo e (n=21)	11.8 mg f 10 mg 9.5 mg	Day 1Day 7Day 14	11.8 ± 7.225.1 ± 16.327.1 ± 13.4	8.0 [4-24]6.0 [2-12]4.0 [1-8]	138 ± 80335 ± 129371 ± 104	5.2 ± 2.79.9 ± 4.411.4 ± 4.1j
Adult Kidneya De novo (n=10)	15.5 mg g 11.4 mg 11.1 mg	Day 1Day 14Day 28	33.6 ± 21.831.1 ± 14.635.9± 18.7	6.0 [4-24]4.0 [1-18]4.0 [1-14]	377 ± 257376 ± 140396 ± 150	11.0 ± 6.19.1 ± 3.010.5 ± 3.2
Adult Kidneya (≥ 6 months post-transplant) (n=47)	5.3 mg	Day 7i	13.5 ± 4.8	6.0 [1 — 16]	216 ± 63	7.0 ± 2.3 j
Adult African-American Kidneyk (≥ 6 months post-transplant) (n=46)	7.8 mg	Day 7i	18.4 ± 7.2	5.0 [1 — 16]	272 ± 97	7.8 ± 2.9 j

In de novo adult kidney transplant patients, the administration of ENVARSUS XR once daily at a starting dose of 0.14 mg/kg/day results in a tacrolimus systemic exposure (AUC₂₄ ) on Day 1 post-transplant that is up to 10% lower than that of tacrolimus immediate-release capsules twice daily administered at a starting dose of 0.1 mg/kg/day, while similar tacrolimus trough concentrations (C₂₄ ) are achieved. As steady state is achieved (typically within 7 days of stable ENVARSUS XR dosing), the AUC₂₄ of ENVARSUS XR is approximately 15% higher than that of tacrolimus immediate-release capsules, at comparable trough concentrations (C₂₄ ).

In adult kidney transplant patients ≥ 6 months post-transplant switched to ENVARSUS 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 C_max estimate was 30% lower and the median T_max 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 de novo kidney transplant patients, the median time to achieve maximum blood concentrations (C_max ) of ENVARSUS XR was approximately 6 to 10 hours (T_max ) on day 1 post-transplant; the median T_max at steady state was 4 to 6 hours. In healthy subjects, the oral bioavailability of ENVARSUS XR was approximately 50% higher as compared with both tacrolimus immediate-release and extended-release capsule 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 (C_max ) by 22%, with no effect on the time to reach maximum plasma concentration (T_max ), compared to when ENVARSUS XR was administered under fasted conditions. ENVARSUS XR tablets should be taken preferably on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal.

Chronopharmacokinetic Effect

In 26 healthy subjects, administration of ENVARSUS XR tablets in the evening resulted in a 15% lower AUC_0-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

Patients With 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 [see Use In Specific Populations (8.6)].

Patients With 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 [see Dosage and Administration (2.3) and Use in Specific Populations (8.7)].

Racial or Ethnic Groups

The pharmacokinetics of ENVARSUS XR were evaluated in a study of 46 stable African American kidney transplant recipients converted from tacrolimus immediate-release to ENVARSUS XR. Approximately 80% of the African American patients were carriers of the active, wild type CYP3A5^* 1 allele. Regardless of genotype status, the PK results demonstrated similar exposure, lower C_max , prolonged T_max , and increased bioavailability compared to tacrolimus immediate-release [see Dosage and Administration (2.3) and Use in Specific Populations (8.8)].

Male and Female Patients

A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted. In a sub-group analysis from the two combined Phase 3 studies in kidney transplant recipients (Study 1 and Study 3) performed with ENVARSUS XR over one year of treatment, no gender-dependent differences in tacrolimus systemic exposures were observed.

Drug Interaction Studies

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 [see Warnings and Precautions (5.9) and Drug Interactions (7.2)].

Voriconazole: Co-administration of ENVARSUS XR with voriconazole following 400 mg BID of voriconazole resulted in a tacrolimus mean AUC_inf increase by 2.62 fold and C_max by 2.03 fold.