Astagraf XL

Name: Astagraf XL

Uses For Astagraf XL

Tacrolimus is used together with other medicines to prevent the body from rejecting a transplanted organ (eg, kidney, liver, or heart). This medicine may be used with steroids, azathioprine (Imuran®), basiliximab (Simulect®), or mycophenolate mofetil (Cellcept®). Tacrolimus belongs to a group of medicines known as immunosuppressive agents.

When a patient receives an organ transplant, the body's white blood cells will try to get rid of (reject) the transplanted organ. Tacrolimus works by suppressing the immune system to prevent the white blood cells from trying to get rid of the transplanted organ.

Tacrolimus is a very strong medicine. It can cause side effects that can be very serious, such as kidney problems. It may also decrease the body's ability to fight infections. You and your doctor should talk about the benefits of this medicine as well as the risks of using it.

This medicine is available only with your doctor's prescription.

What are some other side effects of Astagraf XL?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Dizziness.
  • Headache.
  • Belly pain or heartburn.
  • Upset stomach or throwing up.
  • Loose stools (diarrhea).
  • Hard stools (constipation).
  • Not hungry.
  • Not able to sleep.
  • Back pain.
  • Joint pain.
  • Nose or throat irritation.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

How do I store and/or throw out Astagraf XL?

  • Store at room temperature.
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time Astagraf XL is refilled. If you have any questions about this medicine, please talk with the doctor, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Astagraf XL or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Astagraf XL. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Drug Interactions

Mycophenolic Acid

When Astagraf XL is prescribed with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher with Astagraf XL 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 on Astagraf XL

Table 6 displays the effects of other drugs on Astagraf XL.

Table 6: Effects of Other Drugs/Substances on Astagraf XLa
a   Astagraf XL dosage adjustment recommendation based on observed effect of coadministered drug on tacrolimus exposures [see Clinical Pharmacology (12.3)], literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status
b   High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor
c   Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate)

Drug/Substance Class or Name

Drug Interaction Effect

Recommendations

Grapefruit or grapefruit juiceb

May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.7, 5.10, 5.11)]

Avoid grapefruit or grapefruit juice

Alcohol

May increase the rate of tacrolimus release and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation ) [see Warnings and Precautions (5.7, 5.10, 5.11)]

Avoid alcoholic beverages

Strong CYP3A Inducersc:

    Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John’s Wort

May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see Warnings and Precautions (5.10)]

Increase Astagraf XL dose and monitor tacrolimus whole blood trough concentrations [see Dosage and Administration (2.3, 2.4) and Clinical Pharmacology (12.3)]

Strong CYP3A Inhibitorsc:

    Protease inhibitors (e.g, nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, schisandra sphenanthera extracts

May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.7, 5.10, 5.11)]

Reduce Astagraf XL dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations [see Dosage and Administration (2.3, 2.4) and Clinical Pharmacology (12.3)]

Mild or Moderate CYP3A Inhibitors:

    Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole

May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.7, 5.10, 5.11)]

Monitor tacrolimus whole blood trough concentrations and reduce ASTAGRAF XL dose if needed [see Dosage and Administration (2.3, 2.4) and Clinical Pharmacology (12.3)]

Other drugs, such as:

    Magnesium and aluminum hydroxide antacids

    Metoclopramide

May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.7, 5.10, 5.11)]

Monitor tacrolimus whole blood trough concentrations and reduce ASTAGRAF XL dose if needed [see Dosage and Administration (2.3, 2.4) and Clinical Pharmacology (12.3)]

Mild or Moderate CYP3A Inducers

    Methylprednisolone, prednisone

May decrease tacrolimus concentrations

Monitor tacrolimus whole blood trough concentrations and adjust ASTAGRAF XL dose if needed [see Dosage and Administration (2.3, 2.4)]

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) • urticarial • hypertension • peripheral edema, and • infections [one fatal postmarketing case of bilateral pneumopathy and CMV infection was attributed to tacrolimus (extended-release) 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.

Clinical Studies

Astagraf XL with Basiliximab Induction

Study 1 was a 12-month, randomized, open-label trial of Astagraf XL (N=214) compared to active-control of tacrolimus (PROGRAF) immediate-release (N=212), conducted primarily in the U.S. in patients who were a recipient of a primary or retransplanted non-HLA-identical living or deceased donor kidney transplant. All patients received basiliximab induction and concomitant MMF and corticosteroids. The study population was 17 to 77 years of age, the mean age was 48 years; 64% were male and 36% were female; 73% were Caucasian, 22% were African-American, 2% were Asian, and 3% were categorized as other races. Living donors provided 49% of the organs and 51% of patients received a kidney transplant from a deceased donor with a mean cold ischemia time of 19 hours. The most frequent diseases leading to transplantation were balanced between the groups and included nephrosclerosis/hypertensive nephropathy, diabetic nephropathy, glomerulonephritis, and polycystic kidney disease. In the study, 97% of patients had no previous transplant and 3% had a previous transplant.

Study Medication
Astagraf XL or Control [PROGRAF (tacrolimus) capsules]
The initial dose of Astagraf XL was administered prior to reperfusion or within 48 hours after completion of the transplant procedure. The protocol defined initial post-operative daily doses were 0.15 to 0.20 mg per kg given as a single dose in the morning for Astagraf XL and 0.075 to 0.10 mg per kg twice daily for control. The ASTAGRAF XL and control dosage was then adjusted on the basis of safety and efficacy and a target whole blood tacrolimus trough concentration range of 7 to 16 ng/mL for the first 90 days post-transplant and 5 to 15 ng/mL thereafter.

The average recorded starting tacrolimus daily dose, given any time up to day 2 post-transplant, was higher for Astagraf XL than for control (0.14 mg per kg per day versus 0.10 mg per kg per day). Thereafter, to achieve comparable mean tacrolimus trough concentrations, on average, 15% higher total mean daily doses of tacrolimus were required for Astagraf XL than for control.

Tacrolimus whole blood trough concentrations were monitored on Days 3, 7, 10, 14, 21, then Months 1, 2, 4, 6, 8, 10, and 12. Table 8 shows the tacrolimus whole blood trough concentrations measured at protocol-specified time points for Astagraf XL. Approximately 80% of Astagraf XL-treated patients maintained tacrolimus whole trough blood concentrations between 5 to 17 ng/mL during months 1 through 2 and between 4 to 12 ng/mL from months 3 through 12.

Table 8: Observed Tacrolimus Whole Blood Trough Concentrations in Astagraf XL-Treated Kidney Transplant Patients in Study 1
* Immunoassay was used in most laboratories

Scheduled Visit

Tacrolimus Whole Blood Trough Concentrations (ng/mL)*

Median (10th to 90th Percentile)

Day 3

9.6 (4.9 to 20.2)

Day 7

9.1 (4.4 to 16.8)

Day 14

10.0 (5.7 to 16.9)

Month 1

10.5 (5.6 to 17.1)

Month 2

9.4 (6.1 to 14.2)

Month 6

7.7 (4.4 to 11.5)

Month 12

7.2 (3.8 to 10.4)

African-American patients required higher Astagraf XL dosages to attain similar trough concentrations as Caucasian patients (see Table 9).

Table 9: Astagraf XL Dosages and Mean Whole Blood Trough Concentrations in African-American and Caucasian Kidney Transplant Patients in Study 1

Time After Transplant

Caucasian Patients

n=160

African-American Patients

n=41

Dose

(mg/kg)

Mean Trough

Concentration

(ng/mL)

Dose

(mg/kg)

Mean Trough

Concentration

(ng/mL)

Day 7

0.14

10.65

0.14

7.78

Month 1

0.14

11.11

0.17

10.92

Month 6

0.10

7.95

0.13

8.42

Month 12

0.09

7.53

0.12

7.33

MMF
The initial dose of MMF was 1 gram administered orally or intravenously prior to or within 48 hours of completion of the transplant procedure. Subsequent MMF was administered orally 1 gram twice daily or up to 1.5 grams twice daily in African-American patients. Dose-equivalent three times daily or four times daily dosing was permitted if MMF tolerability was a concern.

The MMF dosages administered by time period in Astagraf XL-treated patients are shown in Table 10. The MMF dosage was reduced to less than 2 grams per day by month 12 in 56% of Astagraf XL-treated patients. Approximately 57% of the MMF dose reductions were because of adverse reactions in the Astagraf XL group [see Adverse Reactions (6.1)].

Table 10: Proportion of Patients Who Received 2 grams (or less than or more than 2 grams) of MMF by Time Period in Astagraf XL-treated Patients in Study 1
a   Time-averaged MMF dosage is the total MMF dosage per day divided by the duration of treatment. A time-averaged MMF dosage of 2 grams per day means that the MMF dosage was not reduced in those patients during the time period.

Time period

(Days)

Patients on MMF

Time-averaged MMF dosagea

N

Less than

2 grams per day

2 grams per

day

Greater than

2 grams per day

1-30

211

30%

64%

6%

31-90

208

38%

57%

5%

91-180

205

49%

48%

3%

181-365

201

51%

47%

3%

Basiliximab Induction
All patients were administered 2 doses of basiliximab induction therapy (20 mg intravenously) with the first dose on day 0 before skin closure and the second dose between days 3 and 5.

Steroids
All patients were administered an intravenous bolus of 500 to 1000 mg of methylprednisolone (or an equivalent steroid dose) on day 0 followed by oral administration of 200 mg methylprednisolone (or an equivalent dose of steroid) on day 1 and subsequent tapering to achieve a targeted mean prednisone dose of 5 to 10 mg/day after the first 3 months.

Efficacy Results
The efficacy failure rate, defined as the percentage of patients with biopsy-proven acute rejection (BPAR), graft failure, death, and/or lost to follow at 12 months, is shown in Table 11 for the intent-to-treat population, as well as the rates of the individual events.

Table 11: Incidence of BPAR, Graft Loss, Death or Lost to Follow-up at 12 Months in Kidney Transplant Patients in Study 1
a   95% confidence interval calculated using normal approximation

Astagraf XL + MMF,

steroids, basiliximab induction
(N=214)

PROGRAF + MMF,

steroids, basiliximab

induction
(N=212)

Efficacy Failure

30 (14.0%)

32 (15.1%)

Treatment Difference (95% CIa)

-1.1% (-7.8%, +5.6%)

Efficacy Failure Endpoints

    Biopsy Proven Acute Rejection

22 (10.3%)

16 (7.5%)

    Graft Loss

5 (2.3%)

9 (4.2%)

    Death

3 (1.4%)

9 (4.2%)

    Lost to follow-up

3 (1.4%)

4 (1.9%)

Glomerular Filtration Rate
The estimated mean glomerular filtration rates, using the Modification of Diet in Renal Disease (MDRD) formula, by treatment group at Month 12 in the intent-to-treat population is shown in Table 12.

Table 12: Estimated Glomerular Filtration Rate (mL/min/1.73m2) by MDRD Formula at 12 Months Post-Transplant in Study 1
a   Last observation carried forward (LOCF); patients who died, lost the graft or were lost to follow-up are imputed as zeroes
b   Results from analysis of covariance model with Month 1 Baseline as a covariate

Astagraf XL + MMF,

steroids, basiliximab

induction

(n=201)

PROGRAF + MMF,
steroids, basiliximab

induction

(n=202)

Month 1 Baseline Mean (SD)

Month 12 LOCFa

  Mean (Standard deviation)

  Mean Difference XL minus

    PROGRAF (tacrolimus

    immediate-release)b

56 (20)

 

58 (21)

 

+2.3 (-1.2, +5.8)

56 (21)

 

56 (23)

Clinical Study of Astagraf XL without Induction

Study 2 was a 12-month, randomized, double-blind trial of Astagraf XL (N = 331) compared to active control of tacrolimus (PROGRAF) immediate-release (N=336) in non-U.S. patients who received a primary or retransplanted non-HLA-identical living or deceased donor kidney transplant. This trial was designed to remain double-blind until the last patient enrolled had completed 24 weeks on study treatment. Patients with a high immunologic risk defined as a panel reactive antibody (PRA) grade > 50% in the previous 6 months and/or with a previous graft survival of less than 12 months due to immunologic reasons were excluded, as were patients of donor kidneys with cold ischemia time > 30 hours, or donor kidneys from a non heart-beating donor. The patient treatment assignments remained blinded for 12 months for 96% of the patients participating in the trial.

All patients received concomitant MMF and corticosteroids without induction. The population was 18 to 65 years of age; the mean age was 48 years; 63% of the study population was male; 82% were Caucasian, 5% were African-American, 2% were Asian, and 11% were categorized as other races. Living donors provided 27% of the organs and 73% of patients received a kidney transplant from a deceased donor with a mean cold ischemia time of 17 hours. The most frequent diseases leading to transplantation were balanced between the groups and included nephrosclerosis/hypertensive nephropathy, diabetic nephropathy, glomerulonephritis, and polycystic kidney disease.

Study Medication
Astagraf XL or Control [PROGRAF (tacrolimus) capsules]
The protocol specified initial pre-operative dose for both Astagraf XL and control was 0.1 mg per kg given orally in one dose within 12 hours prior to reperfusion, given at any time of the day. The initial post-operative tacrolimus daily dose (0.2 mg per kg per day) was given orally in one dose, preferably in the morning for Astagraf XL, and was given as 0.1 mg/kg twice daily for control. Subsequent doses of Astagraf XL and control were adjusted on the basis of clinical evidence of efficacy, occurrence of adverse events and according to whole blood tacrolimus trough concentration target ranges of 10 to 15 ng/mL for the first 28 days post-transplant, 5 to 15 ng/mL from Day 29 to Day 168, 5 to 10 ng/mL thereafter.

The actual tacrolimus doses on day 0 (0.1 mg per kg per day pre-operative) and day 1 (0.2 mg per kg per day post-operative) were comparable between Astagraf XL and control. Thereafter, to achieve comparable mean tacrolimus trough concentrations, on average, 25% higher total mean daily doses of tacrolimus were required for Astagraf XL than for control.

Tacrolimus whole blood trough concentrations were monitored on Days 1, 3, 7, 14 then Months 1, 2, 3, 6, 11, 12, and then every 3 months.

Table 13 shows the tacrolimus whole blood trough concentrations measured at protocol-specified time points for Astagraf XL. Approximately 80% of Astagraf XL-treated patients maintained tacrolimus whole trough blood concentrations between 6 to 20 ng/mL during months 1 through 2 and between 6 to 14 ng/mL from months 3 through 12.

Table 13: Observed Tacrolimus Whole Blood Trough Concentrations for Astagraf XL Kidney Transplant Patients Evaluated in Study 2
* Immunoassay was used in most laboratories

Scheduled Visit

Tacrolimus Whole Blood Trough Concentrations (ng/mL)*

[Median (10th to 90th Percentile)]

Day 3

13.8 (6.5 to 25.5)

Day 7

10.1 (5.5 to 17.3)

Day 14

10.8 (6.7 to 17.9)

Month 1

12.0 (7.5 to 17.6)

Month 2

11.1 (6.6 to 17.3)

Month 6

9.2 (5.7 to 13.5)

Month 12

8.0 (5.1 to 13.8)

MMF
The initial dose of MMF was 1 gram orally twice daily starting pre-operatively and given for the first 14 days of the study. Thereafter the MMF dose was reduced to 0.5 grams twice daily to be maintained throughout the study.

The MMF dosages administered by time period in Astagraf XL-treated patients are shown in Table 14. The MMF dosage was reduced to 0.5 grams twice daily starting after day 14 in the majority of patients.

Table 14: Distribution (%) of Astagraf XL-treated Patients, by Average Daily Dosage of MMF received by Time Period in Study 2
a   Time-averaged MMF dosage is the total MMF dosage per day divided by the duration of treatment. A time-averaged MMF dosage of 2 grams per day means that the MMF dosage was not reduced in those patients during the time period.
b   One patient had a time-averaged dose during the first and last period of > 2 gm/day.

Time period

(Days)

Patients on

MMF

Time-averaged MMF dosagea,b

N

Less than 1 gram

per day

1 gram to less than
2 grams per day

2 grams per

day

1-30

331

1%

78%

21%

31-90

303

8%

87%

6%

91-180

281

12%

85%

3%

181-365

258

15%

83%

2%

Steroids
An intravenous (IV) bolus of up to 1000 mg methylprednisolone (or equivalent) was administered perioperatively (Day 0) with a second IV bolus of 125 mg being administered 1 day after reperfusion (Day 1). On Day 2, oral prednisone was started at 20 mg per day. Thereafter the dose of oral prednisone (or equivalent) was tapered to a dose of 0 to 5 mg/day.

No Antibody Induction
Antibody induction therapy was not allowed.

Efficacy Results
The efficacy failure rate, defined as the percentage of patients with biopsy-proven acute rejection (BPAR), graft failure, death, and/or lost to follow at 12 months, is shown in Table 15 for the intent-to-treat population, as well as the rates of the individual events. About 1% of randomized patients were not transplanted and were not included in the ITT analysis.

Table 15: Incidence of BPAR, Graft Loss, Death or Lost to Follow-up at 12 Months in Kidney Transplant Patients in Study 2
a   95% confidence interval calculated using normal approximation

Astagraf XL + MMF
and steroids

(N=331)

PROGRAF + MMF
and steroids

(N=336)

Efficacy Failure

93 (28.1%)

78 (23.2%)

    Treatment Difference (95% CIa)

+4.9% (-1.7%, +11.5%)

Efficacy Failure Endpoints

    Biopsy Proven Acute Rejection

68 (20.5%)

54 (16.1%)

    Graft loss

28 (8.5%)

24 (7.1%)

    Death

10 (3%)

8 (2.4%)

    Lost to follow-up

4 (1.2%)

7 (2.1%)

Glomerular Filtration Rate
The estimated mean glomerular filtration rates, using the Modification of Diet in Renal Disease (MDRD) formula, by treatment group at Month 12 in the intent-to-treat population in Study 2 is shown in Table 16.

Table 16: Estimated Glomerular Filtration Rate (mL/min/1.73m2) by MDRD Formula at 12 Months Post-Kidney Transplant in Study 2
a   Last observation carried forward (LOCF); patients who died, lost the graft or were lost to follow-up are imputed as zeroes
b   Results from analysis of covariance model with Month 1 Baseline as a covariate.

Astagraf XL + MMF

and steroids

(N=287)

PROGRAF + MMF
and steroids

(N=300)

Month 1 Baseline Mean (SD)

Month 12 LOCFa

   Mean (Standard deviation)

   Mean Difference XL minus

   PROGRAF (tacrolimus immediate-

   release)b

51 (19)

 

52 (20)

 

-1.8 (-4.6, +0.8)

52 (20)

 

55 (19)

 

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL – 1 mg bottle label

NDC 0469-0677-73

Astagraf XL®
(tacrolimus extended-release capsules)

1 mg

ONCE-DAILY

Swallow capsule whole.
Do not cut, crush, or chew capsule.

30 Capsules

(web3)