ASTAGRAF XL (tacrolimus 0.5 mg) Dailymed

1 Indications And Usage

ASTAGRAF XL^® is indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants in adult and pediatric patients who can swallow capsules intact [see Use in Specific Populations (8.4) and Clinical Studies (14.1), (14.2)].


ASTAGRAF XL is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants in adult and pediatric patients who can swallow capsules intact. (1, 8.4, 14.1, 14.2)

2 Dosage And Administration

• •Capsules must be taken whole. (2.1)
• •Take consistently every morning at the same time on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal. (2.1)
• •Avoid eating grapefruit or drinking grapefruit juice or alcohol. (2.1)
• •African-American patients and patients with severe hepatic impairment may require dosing adjustments. (2.3)
• •Frequent monitoring of trough concentrations is recommended. (2.4)
• •For complete dosing information, see Full Prescribing Information.

Month 1: 7‑15 ng/mL

Months 2-6: 5‑15 ng/mL

> 6 Months: 5‑10 ng/mLFirst dose (pre-operative): 0.1 mg/kg, within 12 hours prior to reperfusion

Subsequent doses (post-operative): 0.2 mg/kg once daily at least 4 hours after pre-operative dose and within 12 hours after reperfusionMonth 1: 10‑15 ng/mL

Months 2-6: 5‑15 ng/mL

> 6 Months: 5‑10 ng/mLMonth 1: 10‑20 ng/mL

> Month 1: 5‑15 ng/mL

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MMF = Mycophenolate mofetil
Recommended ASTAGRAF XL Initial Dosage
Patient Population	Initial Oral Dosage	Whole Blood Trough Concentration Range
ADULT
With basiliximab, MMF and steroids	0.15 to 0.2 mg/kg once daily prior to reperfusion or within 48 hours of completion of transplant
With MMF and steroids, without basiliximab induction
PEDIATRIC
With basiliximab, MMF and steroids	0.3 mg/kg once daily, administered within 24 hours following reperfusion

2.1 Important Administration Instructions

• • ASTAGRAF XL should not be used without the supervision by a physician with experience in immunosuppressive therapy.
• •ASTAGRAF XL (tacrolimus extended-release capsules) is not interchangeable or substitutable for tacrolimus extended-release tablets, tacrolimus immediate-release capsules or tacrolimus for oral suspension. Under or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision [see Warnings and Precautions (5.4)].
• •Advise patients to swallow ASTAGRAF XL capsules whole with liquid; patients must not chew, divide, or crush the capsules.
• •ASTAGRAF XL should be taken consistently every morning at the same time to ensure consistent and maximum possible drug exposure, on an empty stomach at least 1 hour before a meal, or at least 2 hours after a meal [see Clinical Pharmacology (12.3)].
• •If a dose is missed, the dose may be taken up to 14 hours after the scheduled time (i.e., for a missed 8:00 AM dose, a dose may be taken by 10:00 PM). Beyond the 14-hour time frame, the patient should wait until the usual scheduled time the following morning to take the next regular daily dose. Instruct the patient not to double the next dose.
• •Advise patients to avoid eating grapefruit or drinking grapefruit juice or alcoholic beverages while taking ASTAGRAF XL [see Drug Interactions (7.2)].
• •Therapeutic drug monitoring is recommended for all patients receiving ASTAGRAF XL [see Dosage and Administration (2.4)].

2.2 Dosage Recommendations for Kidney Transplant Patients

Table 1 includes the recommended starting ASTAGRAF XL dosages and whole blood trough concentration ranges; the observed trough concentrations are shown in another section of the Full Prescribing Information [see Clinical Studies (14)]. Titrate the ASTAGRAF XL dosage based on clinical assessments of rejection and tolerability, and to achieve target trough concentration ranges [see Dosage and Administration (2.4) and Warnings and Precautions (5.6, 5.7, 5.10, 5.11)].

Table 1: Recommended Starting Daily Dosage Regimen of ASTAGRAF XL

MMF = mycophenolate mofetil
Recommended ASTAGRAF XL Initial Dosage*
Patient Population	Initial Oral Dosage	Whole Blood Trough Concentration Range
ADULT
With basiliximab, MMF and steroids	0.15 to 0.2 mg/kg once daily prior to reperfusion or within 48 hours of completion of transplant	•    Month 1: 7-15 ng/mL    •    Months 2-6: 5-15 ng/mL    •    > 6 Months: 5-10 ng/mL
With MMF and steroids, without basiliximab induction	•    First dose (pre-operative): 0.1 mg/kg, within 12 hours prior to reperfusion    •    Subsequent doses (post-operative): 0.2 mg/kg once daily at least 4 hours after pre-operative dose and within 12 hours after reperfusion	•    Month 1: 10-15 ng/mL    •    Months 2-6: 5-15 ng/mL    •    > 6 Months: 5-10 ng/mL
PEDIATRIC
With basiliximab, MMF and steroids	0.3 mg/kg once daily, administered within 24 hours following reperfusion.	•    Month 1: 10-20 ng/mL    •    > Month 1: 5-15 ng/mL

2.3 Dosage Modifications for African-American Patients, Patients with Hepatic Impairment, and Drug Interactions

African-American patients, compared to Caucasian patients, may need to be titrated to higher ASTAGRAF XL dosages to attain comparable trough concentrations [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

Patients with severe hepatic impairment (Child-Pugh ≥ 10) may require a lower starting dosage of ASTAGRAF XL, due to the reduced clearance and prolonged half-life [see Clinical Pharmacology (12.3)].

Dose adjustments of ASTAGRAF XL may be necessary when administered concomitantly with CYP3A inducers or CYP3A inhibitors or cannabidiol [see Warnings and Precautions (5.10, 5.15) and Drug Interactions (7.2, 7.3)].

2.4 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 a change in dosage, after a change in co-administration of CYP3A4 inducers and/or inhibitors or cannabidiol [see Drug Interactions (7.2, 7.3 )], 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 ASTAGRAF XL 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.

• •Not Interchangeable with Other Tacrolimus Products-Medication Errors: Instruct patients or caregivers to recognize the appearance of ASTAGRAF XL capsules. (5.4)
• •New onset diabetes after transplant: Monitor blood glucose. (5.5)
• •Nephrotoxicity (acute and/or chronic): May occur due to ASTAGRAF XL, drug interactions, concomitant nephrotoxic drugs. Monitor renal function; consider dosage reduction. (5.6)
• •Neurotoxicity: Including risk of posterior reversible encephalopathy syndrome (PRES), monitor for neurologic abnormalities; reduce dosage or discontinue ASTAGRAF XL. (5.7)
• •Hyperkalemia: Risk may be increased with other agents associated with hyperkalemia; monitor serum potassium levels. (5.8)
• •Hypertension: May require antihypertensive therapy; monitor relevant drug interactions. (5.9)
• •QT prolongation: Consider obtaining electrocardiograms and monitoring electrolytes in patients at high risk. (5.11)
• •Immunizations: Avoid live vaccines. (5.12)
• •Pure red cell aplasia: Consider discontinuation of ASTAGRAF XL. (5.13)
• •Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: May occur, especially in patients with infections and certain concomitant medications. (5.14)

5.1 Lymphoma and Other Malignancies

Immunosuppressants, including ASTAGRAF XL, 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 by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor.

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 patients who are EBV seronegative, a population which includes many young children. Monitor EBV serology during treatment.

5.2 Serious Infections

Immunosuppressants, including ASTAGRAF XL, increase the risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Serious viral infections reported include:

• •Polyomavirus-associated nephropathy (especially due to BK virus infection)
• •JC virus-associated progressive multifocal leukoencephalopathy (PML)
• •Cytomegalovirus (CMV) infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at highest risk of CMV viremia and CMV disease.

Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection [see Adverse Reactions (6.1, 6.2)].

5.3 Increased Mortality in Female Liver Transplant Patients

In a clinical trial of 471 liver transplant patients randomized to ASTAGRAF XL or tacrolimus immediate-release product, mortality at 12 months was 10% higher among the 76 female patients (18%) treated with ASTAGRAF XL compared to the 64 female patients (8%) treated with tacrolimus immediate-release product. ASTAGRAF XL is not approved for the prophylaxis of organ rejection in patients who received a liver transplant.

5.4 Not Interchangeable with Other Tacrolimus Products - Medication Errors

Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and ASTAGRAF XL (tacrolimus extended-release capsules) 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. ASTAGRAF XL is not interchangeable or substitutable for tacrolimus extended-release tablets, tacrolimus immediate-release capsules or tacrolimus for oral suspension. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision. Instruct patients and caregivers to recognize the appearance of ASTAGRAF XL capsules [see Dosage Forms and Strengths (3)] and to confirm with the healthcare provider if a different product is dispensed or if dosing instructions have changed.

5.5 New Onset Diabetes After Transplant

ASTAGRAF XL 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 [see Adverse Reactions (6.1) and Use in Specific Populations (8.8)].

5.6 Nephrotoxicity due to ASTAGRAF XL and Drug Interactions

ASTAGRAF XL, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy and tubular-interstitial effects. Acute renal impairment associated with tacrolimus toxicity can result in high serum creatinine, hyperkalemia, decreased secretion of urea and hyperuricemia, and is usually reversible. In patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range, consider dosage reduction or temporary interruption of tacrolimus administration.

The risk for nephrotoxicity may increase when ASTAGRAF XL is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors). When tacrolimus is used concurrently with other known nephrotoxic drugs, monitor renal function and tacrolimus blood concentrations, and adjust dose of both tacrolimus and/or concomitant medications during concurrent use [ see Adverse Reactions (6.1, 6.2) and Drug Interactions (7.2)].

5.7 Neurotoxicity

ASTAGRAF XL 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 [see Adverse Reactions (6.1, 6.2)]. 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 ASTAGRAF XL if neurotoxicity occurs.

5.8 Hyperkalemia

Mild to severe hyperkalemia, which may require treatment, has been reported with tacrolimus including ASTAGRAF XL. Concomitant use of agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) may increase the risk for hyperkalemia [see Adverse Reactions (6.1)]. Monitor serum potassium levels periodically during treatment.

5.9 Hypertension

Hypertension is a common adverse reaction of ASTAGRAF XL therapy and may require antihypertensive therapy [see Adverse Reactions (6.1)]. Some antihypertensive drugs can increase the risk for hyperkalemia [see Warnings and Precautions (5.8)]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and require dosage reduction of ASTAGRAF XL [see Drug Interactions (7.2)].

5.10 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) [see Warnings and Precautions (5.7, 5.11)]. Therefore, adjust ASTAGRAF XL dose and monitor tacrolimus whole blood trough concentrations when co-administering ASTAGRAF XL with strong CYP3A inhibitors (e.g., including, but not limited to, telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) or strong CYP3A inducers (e.g., including, but not limited to, rifampin, rifabutin) [see Dosage and Administration (2.4) and Drug Interactions (7.2)]. A rapid, sharp rise in tacrolimus levels has been reported after co-administration with a strong CYP3A4 inhibitor, clarithromycin, despite an initial reduction of tacrolimus dose. Early and frequent monitoring of tacrolimus whole blood trough levels is recommended [see Drug Interactions ( 7.2 )].

5.11 QT Prolongation

ASTAGRAF XL may prolong the QT/QTc interval and cause Torsades de pointes. Avoid ASTAGRAF XL in patients with congenital long QT syndrome. Consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment in patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other products that lead to QT prolongation, and those with electrolyte disturbances (e.g., hypokalemia, hypocalcemia, or hypomagnesemia).

When co-administering ASTAGRAF XL with other substrates and/or inhibitors of CYP3A, especially those that also have the potential to prolong the QT interval, a reduction in ASTAGRAF XL dosage, monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended [see Dosage and Administration (2.4) and Drug Interactions (7.2)].

5.12 Immunizations

Whenever possible, administer the complete complement of vaccines before transplantation and treatment with ASTAGRAF XL.

Avoid the use of live attenuated vaccines during treatment with ASTAGRAF XL (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines).

Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with ASTAGRAF XL.

5.13 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 ASTAGRAF XL.

5.

Cases of thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients treated with ASTAGRAF XL TMA may have a multifactorial etiology. Risk factors for TMA that can occur in transplant patients include, for example, severe infections, graft-versus-host disease (GVHD), Human Leukocyte Antigen (HLA) mismatch, the use of calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. These risk factors may, either alone or combined, contribute to the risk of TMA.

In patients with signs and symptoms of TMA, consider tacrolimus as a risk factor. Concurrent use of tacrolimus and mTOR inhibitors may contribute to the risk of TMA.

5.

When cannabidiol and ASTAGRAF XL are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of ASTAGRAF XL should be considered as needed when ASTAGRAF XL is co-administered with cannabidiol [see Dosage and Administration (2.4) and Drug Interactions (7.3)].

6 Adverse Reactions

The following clinically significant adverse drug reactions are discussed in greater detail in other sections of labeling:

• •Lymphoma and Other Malignancies [see Warnings and Precautions (5.1)]
• •Serious Infections [see Warnings and Precautions (5.2)]
• •Increased Mortality in Female Liver Transplant Patients [see Warnings and Precautions (5.3)]
• •New Onset Diabetes after Transplant [see Warnings and Precautions (5.5)]
• •Nephrotoxicity due to ASTAGRAF XL and Drug Interactions [see Warnings and Precautions (5.6)]
• •Neurotoxicity [see Warnings and Precautions (5.7)]
• •Hyperkalemia [see Warnings and Precautions (5.8)]
• •Hypertension [see Warnings and Precautions (5.9)]
• •QT Prolongation [see Warnings and Precautions (5.11)]
• •Pure Red Cell Aplasia [see Warnings and Precautions (5.13)]
• •Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura [see Warnings and Precautions (5.14)]

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

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

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.

Kidney transplant patients were treated with ASTAGRAF XL (N=214) or tacrolimus immediate-release product (N=212) and concomitant immunosuppressants (median duration of exposure of 12 months) in a randomized, open-label, active-controlled trial of mostly U.S. patients (Study 1) [see Clinical Studies (14.1)]. The types of adverse reactions seen in Study 1 were similar to the adverse reactions seen in Study 2 [non-U.S. trial in kidney transplant patients treated with ASTAGRAF XL (N=331) or tacrolimus immediate-release product (N=336) and concomitant immunosuppressants] [see Clinical Studies (14.2)].

In Study 1, the proportion of patients who discontinued treatment due to adverse reactions was 9% and 11% in the ASTAGRAF XL and tacrolimus immediate-release treatment groups, respectively, through 12 months of treatment. The most common adverse reactions leading to discontinuation in ASTAGRAF XL-treated patients were related to infections or renal/urinary disorders.

Infections The overall incidence of infections, serious infections, and infections with identified etiology reported in patients treated with the ASTAGRAF XL or tacrolimus immediate-release product in Study 1 are shown in Table 2.

Table 2: Percentage of Patients with Infections in Study 1^a Through One Year Post-Kidney Transplant

a   Study 1 was not designed to support comparative claims of ASTAGRAF XL compared to tacrolimus immediate-release product for the adverse reactions reported in this table.
	ASTAGRAF XL, MMF, steroids, basiliximab induction N=214	Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=212
All Infections	69%	69%
Respiratory Infections	34%	31%
Urinary Tract Infections	16%	25%
Cytomegalovirus Infections	10%	11%
Bacterial Infections	8%	12%
Gastroenteritis	7%	3%
Polyomavirus Infections	3%	5%
Serious Infections	22%	23%

New Onset Diabetes After Transplant (NODAT) The incidence of new onset diabetes after transplantation (defined by the composite occurrence of ≥ 2 fasting plasma glucose values that were > 126 mg/dL at ≥ 30 days apart, insulin use for ≥ 30 consecutive days, oral hypoglycemic use for ≥ 30 consecutive days, and/or HbA_1C ≥ 6.5%) is summarized in Table 3 below for Study 1 through one year post-transplant [see Warnings and Precautions (5.5)].

Table 3: Percentage of Patients with NODAT Through One Year Post-Kidney Transplant in Study 1^a

	ASTAGRAF XL, MMF, steroids, basiliximab induction N=162	Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=151
a   Study 1 was not designed to support comparative claims of ASTAGRAF XL compared to tacrolimus immediate-release product for the adverse reactions reported in this table.
Composite NODAT	36%	35%
≥ 2 Fasting Plasma Glucose Values      ≥ 126 mg/dL ≥ 30 days apart	26%	23%
HbA1C ≥ 6.5%	19%	22%
Oral hypoglycemic use ≥ 30 consecutive days	14%	9%
Insulin use ≥ 30 consecutive days	6%	8%

Hyperkalemia In Study 1 [see Clinical Studies (14.1)], 73 of 214 (34.1%) patients on ASTAGRAF XL had a serum potassium level greater than 5.4 up to 6.4 mEq/L, and 8 out of 214 (3.7%) patients had a serum potassium level greater than 6.4 mEq/L [see Warnings and Precautions (5.8)].

Common Adverse Reactions The most common (≥ 30%) adverse reactions observed with ASTAGRAF XL in Study 1 were: diarrhea, constipation, nausea, peripheral edema, tremor, and anemia. The incidence of adverse reactions that occurred in ≥ 15% of ASTAGRAF XL-treated patients compared to tacrolimus immediate-release product through one year of treatment in Study 1 is shown by treatment groups in Table 4.

Table 4: Adverse Reactions (≥ 15%) in Kidney Transplant Patients Through One Year Post-Transplant in Study 1^a

	ASTAGRAF XL, MMF, steroids, basiliximab induction N=214	Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=212
a   Study 1 was not designed to support comparative claims of ASTAGRAF XL compared to tacrolimus immediate-release for the adverse reactions reported in this table.
Diarrhea	45%	44%
Constipation	40%	32%
Nausea	36%	35%
Peripheral Edema	36%	34%
Tremor	35%	34%
Anemia	33%	29%
Hypertension	28%	30%
Vomiting	25%	25%
Hypomagnesemia	24%	27%
Insomnia	24%	28%
Hypophosphatemia	23%	28%
Headache	22%	24%
Hyperkalemia	20%	23%
Increased Blood Creatinine	19%	23%
Fatigue	16%	10%
Leukopenia	16%	16%
Hyperlipidemia	16%	17%
Hyperglycemia	16%	18%

Less Frequently Reported Adverse Reactions (< 15% in ASTAGRAF XL-treated patients) by System Organ Class

The following adverse reactions were reported in clinical studies of kidney transplant patients who were treated with ASTAGRAF XL, MMF, and steroids (Studies 1 and 2):

• •Blood and Lymphatic System Disorders: Hemolytic anemia, leukocytosis, neutropenia, thrombocytopenia, thrombotic microangiopathy
• •Cardiac Disorders: Atrial fibrillation, atrial flutter, tachycardia
• •Ear Disorders: Tinnitus
• •Eye Disorders: Vision blurred, conjunctivitis
• •Gastrointestinal Disorders: Abdominal distension, abdominal pain, aphthous stomatitis, dyspepsia, esophagitis, flatulence, gastritis, gastroesophageal reflux disease
• •General Disorders and Administration Site Conditions: Anasarca, asthenia, edema, pyrexia
• •Hepatobiliary Disorders: Abnormal hepatic function, cholestasis, hepatitis (acute and chronic), hepatotoxicity
• •Infections and Infestations: Condyloma acuminatum, tinea versicolor
• •Injury: Fall
• •Investigations: Increased blood lactate dehydrogenase, increased blood urea, increased hepatic enzyme
• •Metabolism and Nutrition Disorders: Anorexia, hyperphosphatemia, hyperuricemia, hypokalemia, hyponatremia, metabolic acidosis
• •Musculoskeletal and Connective Tissue Disorders: Arthralgia, osteopenia, osteoporosis
• •Neoplasms: Kaposi’s sarcoma
• •Nervous System Disorders: Convulsion, dizziness, hypoesthesia, neurotoxicity, paresthesia, peripheral neuropathy
• •Psychiatric Disorders: Agitation, anxiety, confusional state, depression, hallucination, mood swings, nightmare
• •Renal and Urinary Disorders: Anuria, oliguria, proteinuria, renal failure, renal tubular necrosis, toxic nephropathy
• •Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, dyspnea, pulmonary edema, productive cough
• •Skin and Subcutaneous Tissue Disorders: Acne, alopecia, dermatitis, hyperhidrosis, hypotrichosis, pruritus, rash
• •Vascular Disorders: Deep vein thrombosis, flushing

Pediatrics

De Novo Pediatric Transplant Patients

A study was conducted in 44 de novo pediatric transplant patients (including 25 kidney transplant patients; 13 randomized to ASTAGRAF XL and 12 randomized to Prograf), who were started on 0.3 mg/kg daily of tacrolimus product, given once daily for ASTAGRAF XL and divided into two doses for Prograf. Two kidney transplant patients on Prograf discontinued the study (withdrawn consent, sapovirus enteritis). Thirteen (13) pediatric kidney transplant patients completed 52 weeks on ASTAGRAF XL. The most common adverse reactions were diarrhea [7/13 (54%)], increased blood creatinine [6/13 (46%)], hypertension [3/13 (23%)], cough [4/13 (31%)], and upper respiratory tract infection [4/13 (31%)].

Stable Pediatric Transplant Patients

Another study was conducted in 81 stable pediatric allograft recipients (including 48 kidney transplant patients) 5 to 16 years of age converted 1:1 (mg:mg) from Prograf to ASTAGRAF XL. Seventy-six (76) pediatric patients completed at least one year of ASTAGRAF XL-based treatment. Treatment-related adverse reactions were reported in 35%, including 13% serious adverse reactions. The most frequent adverse reactions by system organ class were infections (55.7%), followed by gastrointestinal disorders (27.8%), skin and subcutaneous tissue disorders (21.5%), respiratory, thoracic and mediastinal disorders (20.3% each). The most common adverse reactions were diarrhea (13.9%), headache (13.9%) and cough (11.4%).

6.2 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. These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to ASTAGRAF XL:

• •Blood and Lymphatic System Disorders: Agranulocytosis, disseminated intravascular coagulation, hemolytic uremic syndrome, febrile neutropenia, pancytopenia, pure red cell aplasia [see Warnings and Precautions (5.13)], coagulopathy, thrombotic thrombocytopenic purpura, prolonged activated partial thromboplastin time, decreased blood fibrinogen
• •Cardiac Disorders: Cardiac arrest, myocardial infarction, ventricular fibrillation, congestive cardiac failure, hypertrophic cardiomyopathy, pericardial effusion, angina pectoris, supraventricular extrasystoles, supraventricular tachycardia, bradycardia, Torsades de pointes, QT prolongation
• •Ear Disorders: Hearing loss
• •Eye Disorders: Blindness, optic neuropathy, optic atrophy, photophobia
• •Gastrointestinal Disorders: Gastrointestinal hemorrhage, gastrointestinal perforation, pancreatitis, peritonitis, stomach ulcer, intestinal obstruction, ascites, colitis, ileus, impaired gastric emptying, dysphagia
• •Hepatobiliary Disorders: Hepatic failure, hepatic necrosis, cirrhosis, cholangitis, venoocclusive liver disease, bile duct stenosis, hepatic steatosis, jaundice
• •Hypersensitivity Reactions: Hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
• •Immune System Disorders: Graft versus host disease (acute and chronic)
• •Investigations: Increased international normalized ratio
• •Metabolism and Nutrition Disorders: Hypoproteinemia
• •Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, myalgia, polyarthritis, pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS)
• •Neoplasms: Lymphoma including EBV-associated lymphoproliferative disorder, hepatosplenic T-cell lymphoma, PTLD [see Warnings and Precautions (5.1)], leukemia, melanoma
• •Nervous System Disorders: Cerebral infarction, progressive multifocal leukoencephalopathy (PML) sometimes fatal [see Warnings and Precautions (5.2)], posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions (5.7)], coma, status epilepticus, quadriplegia, flaccid paralysis, hemiparesis, aphasia, syncope, carpal tunnel syndrome, nerve compression, mutism, dysarthria, somnolence
• •Psychiatric Disorders: Mental status changes
• •Renal and Urinary Disorders: Hemorrhagic cystitis, hematuria, urinary retention, urinary incontinence
• •Respiratory, Thoracic and Mediastinal Disorders: Interstitial lung disease, pulmonary hypertension, lung infiltration, rhinitis allergic, hiccups
• •Skin and Subcutaneous Tissue Disorders: Hyperpigmentation, photosensitivity
• •Vascular Disorders: Hemorrhage