November 29, 2015
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Astagraf XL

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The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended approval of tolvaptan (Jinarc, Otuska) to slow progression of cyst developmen"...

Astagraf XL



Included as part of the PRECAUTIONS section.


Management Of Immunosuppression

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe ASTAGRAF XL. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physicians responsible for maintenance therapy should have complete information requisite for the follow-up of the patients [see BOXED WARNING].

Lymphoma And Other Malignancies

Patients receiving immunosuppressants, including ASTAGRAF XL, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see BOXED WARNING]. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children.

Serious Infections

Patients receiving immunosuppressants, including ASTAGRAF XL, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see BOXED WARNING]. These infections may lead to serious, including fatal, outcomes. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution.

Liver Transplant Recipients

In a clinical trial of 471 liver transplant recipients randomized to ASTAGRAF XL or Prograf, 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 Prograf. Use of ASTAGRAF XL in liver transplantation is not recommended [see BOXED WARNING].

Medication Errors

ASTAGRAF XL extended-release capsules are not interchangeable or substitutable with tacrolimus immediate-release capsules. Medication and dispensing errors, including inadvertent or unintentional substitution between twice daily immediate-release and ASTAGRAF XL (once daily extended-release) tacrolimus formulations have been observed in postmarketing surveillance of ASTAGRAF XL in countries where it is approved and marketed. This has led to serious adverse events, including graft rejection, or other adverse reactions, which could be a consequence of either under- or over-exposure to tacrolimus [see HOW SUPPLIED].

Note that ASTAGRAF XL is supplied in short, square bottles as well as in blister cartons containing 5 blister cards of 10 capsules on each card, and contains the statement “ONCE DAILY” on its label.

Polyoma Virus Infections

Patients receiving immunosuppressants, including ASTAGRAF XL, are at increased risk for opportunistic infections, including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes fatal, outcomes. These include polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus-associated progressive multifocal leukoencephalopathy (PML), which have been observed in patients receiving ASTAGRAF XL [see ADVERSE REACTIONS]. PVAN is associated with serious outcomes, including deteriorating renal function and kidney graft loss. Patient monitoring may help detect patients at risk for PVAN.

Cases of PML have been reported in patients treated with ASTAGRAF XL. PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.

Reductions in immunosuppression should be considered for patients who develop evidence of PVAN or PML. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.

Cytomegalovirus (CMV) Infections

Patients receiving immunosuppressants, including ASTAGRAF XL, are at increased risk of developing CMV viremia and CMV disease. The risk of CMV disease is highest among transplant recipients seronegative for CMV at the time of transplant who receive a graft from a CMV seropositive donor. Therapeutic approaches to limiting CMV disease exist and should be routinely provided. Patient monitoring may help detect patients at risk for CMV disease. Consideration should be given to reducing the amount of immunosuppression in patients who develop CMV viremia and/or CMV disease.

New Onset Diabetes After Transplant

ASTAGRAF XL was shown to cause new onset diabetes mellitus in clinical trials of kidney transplant patients [see ADVERSE REACTIONS]. New onset diabetes after transplantation may be reversible in some patients. Black and Hispanic kidney transplant patients are at an increased risk [see Use In Specific Populations]. Blood glucose concentrations should be monitored frequently in patients using ASTAGRAF XL.


ASTAGRAF XL, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity, particularly when used in high doses. Acute nephrotoxicity is most often related to vasoconstriction of the afferent renal arteriole, is characterized by increasing serum creatinine, hyperkalemia, and/or a decrease in urine output, and is typically reversible. Chronic calcineurin-inhibitor nephrotoxicity is associated with increased serum creatinine, decreased kidney graft life, and characteristic histologic changes observed on renal biopsy; the changes associated with chronic calcineurin-inhibitor nephrotoxicity are typically progressive. Patients with impaired renal function should be monitored closely, as the dosage of ASTAGRAF XL may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to another immunosuppressive therapy.

Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering ASTAGRAF XL with drugs that may be associated with renal dysfunction. These include, but are not limited to, aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors (e.g., tenofovir) and protease inhibitors (e.g., ritonavir, indinavir). Similarly, care should be exercised when administering with CYP3A inhibitors such as antifungal drugs (e.g., ketoconazole), calcium channel blockers (e.g., diltiazem, verapamil), and macrolide antibiotics (e.g., clarithromycin, erythromycin, troleandomycin), which will result in increased tacrolimus whole blood concentrations due to inhibition of tacrolimus metabolism [see DRUG INTERACTIONS].


ASTAGRAF XL may cause a spectrum of neurotoxicities, particularly when used in high doses. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, and coma. Patients treated with tacrolimus have been reported to develop PRES. Symptoms indicating PRES include headache, altered mental status, seizures, visual disturbances and hypertension. Diagnosis may be confirmed by radiological procedure. If PRES is suspected or diagnosed, blood pressure control should be maintained and immediate reduction of immunosuppression is advised. This syndrome is characterized by reversal of symptoms upon reduction or discontinuation of immunosuppression.

Coma and delirium, in the absence of PRES, have also been associated with high plasma concentrations of tacrolimus. Seizures have occurred in patients receiving tacrolimus [see ADVERSE REACTIONS]. Other less severe neurotoxicities, include tremors, paresthesias, headache, and other changes in motor function, mental status, and sensory function have also been reported [see ADVERSE REACTIONS]. Tremor and headache have been associated with high whole-blood concentrations of tacrolimus and may respond to dosage adjustment.


Hyperkalemia has been reported with ASTAGRAF XL use. Serum potassium levels should be monitored. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during ASTAGRAF XL therapy [see ADVERSE REACTIONS].


Hypertension is a common adverse effect of ASTAGRAF XL therapy and may require antihypertensive therapy [see ADVERSE REACTIONS]. The control of blood pressure can be accomplished with any of the common antihypertensive agents, though careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers). Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of ASTAGRAF XL [see DRUG INTERACTIONS].

Use With Sirolimus

The use of ASTAGRAF XL with sirolimus is not recommended in kidney transplant patients. Use of sirolimus with tacrolimus in studies of de novo liver transplant recipients was associated with an excess mortality, graft loss and hepatic artery thrombosis (HAT). Use of sirolimus with tacrolimus in heart transplant patients was associated with an increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus.

Use With CYP3A Inhibitors And Inducers

When coadministering ASTAGRAF XL with strong CYP3A-inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong CYP3A inducers (e.g., rifampin, rifabutin), adjustments in the dosing regimen of ASTAGRAF XL and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended [see DRUG INTERACTIONS].

QT Prolongation

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

When coadministering ASTAGRAF XL with other substrates and/or inhibitors of CYP3A that also have the potential to prolong the QT interval, a reduction in ASTAGRAF XL dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Use of tacrolimus with amiodarone has been reported to result in increased tacrolimus whole blood concentrations with or without concurrent QT prolongation [see DRUG INTERACTIONS].


The use of live vaccines should be avoided during treatment with ASTAGRAF XL; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

Pure Red Cell Aplasia

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

Gastrointestinal Perforation

Gastrointestinal perforation has been reported in patients treated with tacrolimus; all reported cases were considered to be a complication of transplant surgery or accompanied by infection, diverticulum, or malignant neoplasm. As gastrointestinal perforation may be serious or life-threatening, appropriate medical/surgical management should be instituted promptly [see ADVERSE REACTIONS].

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide)


Advise patients to:

  • Inspect your ASTAGRAF XL medicine when you 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, speak to your doctor or pharmacist as soon as possible to make sure that you have the right medicine.
  • Take ASTAGRAF XL at the same time everyday 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.
  • Not take ASTAGRAF XL with an alcoholic beverage [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS]
  • Take a missed dose of ASTAGRAF XL as soon as the patient remembers but not more than 14 hours after the scheduled time (i.e. for a missed 8AM dose, take by 10PM). Beyond the 14-hour timeframe, the patient should 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 they are at 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, WARNINGS AND PRECAUTIONS].

Increased Risk Of Infection

Inform patients they are at 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, 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].


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].


Inform patients that they are at risk of developing adverse neurologic effects 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].


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].


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

Drug Interactions

Instruct patients to tell their health care 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, DRUG INTERACTIONS].

Pregnant Women And Nursing Mothers

Instruct patients to tell their healthcare provider if they plan to become pregnant or breast-feed their infant [see Use In Specific Populations]


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

Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.49 times the AUC at the maximum clinical dose of 0.2 mg/kg/day) and in the rat was 5.0 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.

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.

Tacrolimus given orally at 1.0 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 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 the drug, taking into account the importance of drug to the mother.

Pediatric Use

The safety and efficacy of ASTAGRAF XL in pediatric kidney transplant patients < 16 years of age has not been established.

Geriatric Use

Clinical studies of ASTAGRAF XL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, 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, frequent monitoring of renal function is recommended; tacrolimus dosage should be reduced if indicated [see WARNINGS AND PRECAUTIONS, 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. Frequent monitoring of tacrolimus trough concentrations is warranted in patients with hepatic impairment [see CLINICAL PHARMACOLOGY].


The data from ASTAGRAF XL administration in kidney transplant patients indicate that African-American patients may require higher doses to attain comparable trough concentrations compared to Caucasian patients [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY, Clinical Studies].

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

Last reviewed on RxList: 3/18/2014


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