February 6, 2016
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Astagraf XL

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Astagraf XL

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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.

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. Monitor EBV serology during treatment.

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), and
  • 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].

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.

Graft Rejection And Other Serious Adverse Reactions Due To 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 with tacrolimus immediate-release products or tacrolimus extended-release products. Instruct patients and caregivers to recognize the appearance of ASTAGRAF XL capsules [see Dosage Forms and Strengths].

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 and Use In Specific Populations].

Nephrotoxicity Due To ASTAGRAF XL And Drug Interactions

ASTAGRAF XL, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity. Consider dosage reduction in patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range.

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) [see DRUG INTERACTIONS]. Monitor renal function and consider dosage reduction if nephrotoxicity occurs.

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]. 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.

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]. Monitor serum potassium levels periodically during treatment.

Hypertension

Hypertension is a common adverse reaction of ASTAGRAF XL therapy and may require antihypertensive therapy [see ADVERSE REACTIONS]. Some antihypertensive drugs can increase the risk for hyperkalemia [see Hyperkalemia]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and require dosage reduction of ASTAGRAF XL [see DRUG INTERACTIONS].

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 QT Prolongation]. Therefore, adjust ASTAGRAF XL dose and monitor tacrolimus whole blood trough concentrations when coadministering ASTAGRAF XL with strong CYP3A inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) or strong CYP3A inducers (e.g., rifampin, rifabutin) [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

QT Prolongation

ASTAGRAF XL may prolong the QT/QTc interval and cause Torsade 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 coadministering 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 DRUG INTERACTIONS].

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.

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.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Administration

Advise patients to:

  • Inspect their ASTAGRAF XL medicine when they receive a new prescription and before taking it. If the appearance of the capsule is not the same as usual, or if dosage instructions have changed, advise patients to contact their healthcare provider as soon as possible to make sure that they have the right medicine. Other tacrolimus products cannot be substituted for ASTAGRAF XL [see WARNINGS AND PRECAUTIONS].
  • Take ASTAGRAF XL at the same time every day to achieve consistent blood concentrations.
  • Take ASTAGRAF XL in the morning, preferably at least 1 hour before or at least 2 hours after breakfast to achieve maximum possible blood concentrations of the drug.
  • Swallow capsule whole with liquid. Do not chew, divide or crush capsule.
  • Avoid alcoholic beverage, grapefruit and grapefruit juice while on ASTAGRAF XL [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].
  • Take a missed dose of ASTAGRAF XL as soon as possible but not more than 14 hours after the scheduled time (i.e., for a missed 8 AM dose, take by 10 PM). Beyond the 14-hour timeframe, instruct the patient to wait until the usual scheduled time the following morning to take the next scheduled dose. Do not take 2 doses at the same time.
Development of Lymphoma and Other Malignancies

Inform patients that they are at an increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and use a sunscreen with a high protection factor [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

Increased Risk of Infection

Inform patients that they are at an increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

New Onset Diabetes After Transplant

Inform patients that ASTAGRAF XL can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst or hunger [see WARNINGS AND PRECAUTIONS].

Nephrotoxicity

Inform patients that ASTAGRAF XL can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team [see WARNINGS AND PRECAUTIONS].

Neurotoxicity

Inform patients that they are at risk of developing adverse neurologic reactions including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, delirium, or tremors [see WARNINGS AND PRECAUTIONS].

Hyperkalemia

Inform patients that ASTAGRAF XL can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia [see WARNINGS AND PRECAUTIONS].

Hypertension

Inform patients that ASTAGRAF XL can cause high blood pressure which may require treatment with anti-hypertensive therapy [see WARNINGS AND PRECAUTIONS].

Drug Interactions

Instruct patients to tell their healthcare providers when they start or stop taking any concomitant medications, including prescription and non-prescription medicines, herbal and dietary supplements. Some medications could alter tacrolimus concentrations in the blood and thus may require the adjustment of the dosage of ASTAGRAF XL [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

Immunizations

Inform patients that ASTAGRAF XL can interfere with the usual response to immunizations and that they should avoid live vaccines [see WARNINGS AND PRECAUTIONS].

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 mg/kg/day (0.49 times the AUC at the maximum clinical dose of 0.2 mg/kg/day) and in the rat was 5 mg/kg/day (0.14 times the AUC at the maximum clinical dose of 0.2 mg/kg/day) [see BOXED WARNING, WARNINGS AND PRECAUTIONS].

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; 2.4-fold the human exposure in stable adult renal transplant patients > 6 months post transplant). 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 mg/kg (0.8 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 (2.6 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.

Use In Specific Populations

Pregnancy

Pregnancy Category 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 0.5 times the maximum clinical dose and pregnant rats at 0.8 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. ASTAGRAF XL 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 (0.5 and 1.6 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 arteriosus, 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 (2.6 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 (0.8 and 2.6 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.

Nursing Mothers

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

Pediatric Use

The safety and effectiveness of ASTAGRAF XL in pediatric patients less than 16 years of age have not been established.

Geriatric Use

Clinical studies of ASTAGRAF XL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In Studies 1 and 2, 29 patients were 65 years of age and older, and 3 patients were 75 years of age and over [see Clinical Studies]. 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.

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 and CLINICAL PHARMACOLOGY].

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]. 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]. For patients with moderate hepatic impairment, monitor tacrolimus whole blood trough concentrations. For patients with mild hepatic impairment, no dosage adjustments are needed.

Race

African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY, and Clinical Studies].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 12/28/2015

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Precautions

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