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WARNING
MALIGNANCIES AND SERIOUS INFECTIONS IN TRANSPLANT PATIENTS; and INCREASED MORTALITY IN FEMALE LIVER TRANSPLANT PATIENTS
ASTAGRAF XL, a calcineurin-inhibitor immunosuppressant, is available for oral administration as hard gelatin capsules (tacrolimus extended-release capsules) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include ethylcellulose NF, hypromellose USP, magnesium stearate NF and lactose monohydrate NF. The ingredients are directly proportional across all capsule strengths. The capsule shell contains gelatin NF, titanium dioxide USP, ferric oxide NF, and sodium lauryl sulfate.
Tacrolimus is the active ingredient in ASTAGRAF XL. Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as [3S – [3R*[E(1S*, 3S*, 4S*)], 4S*, 5R*, 8S*, 9E, 12R*, 14R*, 15S*, 16R*, 18S*, 19S*, 26aR*]] – 5, 6, 8, 11, 12, 13, 14, 15, 16, 17, 18, 19, 24, 25, 26, 26a – hexadecahydro – 5, 19 – dihydroxy – 3 – [2 – (4 – hydroxy – 3 – methoxycyclo – hexyl) – 1 – methylethenyl] – 14, 16 – dimethoxy – 4, 10, 12, 18 – tetramethyl – 8 – (2 – propenyl) – 15, 19 – epoxy – 3H – pyrido[2, 1 – c][1, 4]oxaazacyclotricosine – 1, 7, 20, 21(4H, 23H) – tetrone, monohydrate.
The chemical structure of tacrolimus is:
 |
Tacrolimus has an empirical formula of C44H69NO12•H2O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform.
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 and Clinical Studies].
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]. Titrate the ASTAGRAF XL dosage based on clinical assessments of rejection and tolerability, and to achieve target trough concentration ranges [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
Table 1: Recommended Starting Daily Dosage Regimen of ASTAGRAF XL
| 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. |
|
| MMF = mycophenolate mofetil | ||
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 and Clinical Studies].
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].
Dose adjustments of ASTAGRAF XL may be necessary when administered concomitantly with CYP3A inducers or CYP3A inhibitors or cannabidiol [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
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], 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.
ASTAGRAF XL (tacrolimus) extended-release capsules are supplied in short, square bottles (see Table 19).
Table 19: Strengths of ASTAGRAF XL
| 0.5 mg | Oblong capsule with a light yellow cap and orange body. Capsule is branded with red “647” on capsule body and “0.5 mg” on the capsule cap. The bottle packaging is branded with a brown stripe.
|
| 1 mg | Oblong capsule with a white cap and orange body. Capsule is branded with red “677” on capsule body and “1 mg” on the capsule cap. The bottle packaging is branded with a blue stripe.
|
| 5 mg | Oblong capsule with a grayish-red cap and orange body. Capsule is branded with red “687” on capsule body and “5 mg” on the capsule cap. The bottle packaging is branded with an orange stripe.
|
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062. Revised: Aug 2023
The following clinically significant adverse drug reactions are discussed in greater detail in other sections of labeling:
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]. 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].
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.
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 1a Through One Year Post-Kidney Transplant
| 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% |
| 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. | ||
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 HbA1C ≥ 6.5%) is summarized in Table 3 below for Study 1 through one year post-transplant [see WARNINGS AND PRECAUTIONS].
Table 3: Percentage of Patients with NODAT Through One Year Post-Kidney Transplant in Study 1a
| ASTAGRAF XL, MMF, steroids, basiliximab induction N=162 |
Tacrolimus immediate - release product, MMF, steroids, basiliximab induction N=151 |
|
| 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% |
| 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. | ||
In Study 1 [see Clinical Studies], 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].
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 1a
| ASTAGRAF XL, MMF, steroids, basiliximab induction N=214 |
Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=212 |
|
| 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% |
| 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. | ||
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):
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%)].
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%).
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:
When ASTAGRAF XL is prescribed with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher with ASTAGRAF XL co-administration than with cyclosporine co-administration with MPA, 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.
Table 5 displays the effects of other drugs on ASTAGRAF XL.
Table 5: Effects of Other Drugs/Substances on ASTAGRAF XLa
| 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]. | 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]. | 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 ]. | Increase ASTAGRAF XL dose and monitor tacrolimus whole blood trough concentrations [see DOSAGE AND ADMINISTRATION 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, letermovir, Schisandra sphenanthera extracts | May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation). A rapid, sharp rise in tacrolimus levels may occur early, despite an immediate reduction of tacrolimus dose [see WARNINGS AND PRECAUTIONS]. | 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 and CLINICAL PHARMACOLOGY]. Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1-3 days and continue monitoring as necessary [see WARNINGS AND PRECAUTIONS]. |
| Mild or Moderate CYP3A Inhibitors: Clotrimazole, antibiotics (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]. | Monitor tacrolimus whole blood trough concentrations and reduce ASTAGRAF XL dose if needed [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. |
| 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]. | Monitor tacrolimus whole blood trough concentrations and reduce ASTAGRAF XL dose if needed [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. |
| Mild or Moderate CYP3A Inducers Methylprednisolone, prednisone | May decrease tacrolimus whole blood trough concentrations. | Monitor tacrolimus whole blood trough concentrations and adjust ASTAGRAF XL dose if needed [see DOSAGE AND ADMINISTRATION]. |
| Caspofungin | May decrease tacrolimus whole blood trough concentrations. | Monitor tacrolimus whole blood trough concentrations and adjust ASTAGRAF XL dose if needed [see DOSAGE AND ADMINISTRATION]. |
| a ASTAGRAF XL dosage adjustment recommendation based on observed effect of co-administered drug on tacrolimus exposures [see CLINICAL PHARMACOLOGY], 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). |
||
The pharmacokinetics of tacrolimus may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. Close monitoring and potential dose adjustment of ASTAGRAF XL is warranted to ensure continued efficacy and safety [see DOSAGE AND ADMINISTRATION].
The blood levels of tacrolimus may increase upon concomitant use with cannabidiol. 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 and WARNINGS AND PRECAUTIONS].
Included as part of the PRECAUTIONS section.
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.
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:
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].
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.
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] and to confirm with the healthcare provider if a different product is dispensed or if dosing instructions have changed.
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].
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 and DRUG INTERACTIONS].
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.
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 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 WARNINGS AND PRECAUTIONS]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and require dosage reduction of ASTAGRAF XL [see DRUG INTERACTIONS].
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]. 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 and DRUG INTERACTIONS]. 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].
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 and DRUG INTERACTIONS].
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.
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.
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.
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 and DRUG INTERACTIONS].
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Advise patients or caregivers to:
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 using a broad spectrum sunscreen with a high protection factor [see WARNINGS AND PRECAUTIONS].
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 such as fever, sweats or chills, cough or flu-like symptoms, muscle aches, or warm, red, painful areas of the skin [see BOXED WARNING and WARNINGS AND PRECAUTIONS].
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 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].
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 anti-hypertensive therapy [see WARNINGS AND PRECAUTIONS]. Advise patients to monitor their blood pressure.
Inform patients that ASTAGRAF XL can cause blood clotting problems. The risk of this occurring increases when patients take ASTAGRAF XL and sirolimus or everolimus concomitantly, or when patients develop certain infections. Advise them to seek medical attention promptly if they develop fever, petequiae or bruises, fatigue, confusion, jaundice, oliguria [see WARNINGS AND PRECAUTIONS].
Instruct patients to tell their healthcare providers when they start or stop taking any medicines, including prescription and nonprescription 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. Advise patients to avoid grapefruit, grapefruit juice and alcoholic beverages [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Inform women of childbearing potential that ASTAGRAF XL can harm the fetus. Instruct male and female patients to discuss with their healthcare provider family planning options including appropriate contraception. Also, discuss with pregnant patients the risks and benefits of breastfeeding their infant [see Use In Specific Populations].
Encourage female transplant patients who become pregnant and male patients who have fathered a pregnancy, exposed to immunosuppressants including tacrolimus, to enroll in the voluntary Transplantation Pregnancy Registry International. To enroll or register, patients can call the toll free number 1-877-955-6877 or https://www.transplantpregnancyregistry.org/ [see Use In Specific Populations].
Based on animal studies, ASTAGRAF XL may affect fertility in males and females [see Nonclinical Toxicology].
Inform patients that ASTAGRAF XL can interfere with the usual response to immunizations and that they should avoid live vaccines [see WARNINGS AND PRECAUTIONS].
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 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 kidney 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 subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day [1.6 times the maximum recommended clinical dose (0.2 mg/kg/day) on a mg/m² basis] or 3 mg/kg/day (2.4 times the maximum recommended clinical dose) resulted in a dose-related decrease in sperm count.
Tacrolimus administered orally at 1.0 mg/kg (0.8 times the maximum clinical dose) 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- and post-implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (2.6 times the maximum clinical dose range 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.
There is a pregnancy registry that monitors pregnancy outcomes in women exposed to ASTAGRAF XL during pregnancy. The Transplantation Pregnancy Registry International (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants including tacrolimus. Healthcare providers are encouraged to advise their patients to register by contacting the Transplantation Pregnancy Registry International at 1-877-955-6877 or https://www.transplantpregnancyregistry.org/.
Tacrolimus can cause fetal harm when administered to a pregnant woman. Data from postmarketing surveillance and TPRI suggest that infants exposed to tacrolimus in utero are at a risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress [see Human Data]. Advise pregnant women of the potential risk to the fetus.
Administration of oral tacrolimus to pregnant rabbits and rats throughout the period of organogenesis was associated with maternal toxicity/lethality, and an increased incidence of abortion, malformation and embryofetal death at clinically relevant doses [0.5 the maximum recommended clinical dose (0.2 mg/kg/day), on a mg/m² basis]. Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 the maximum recommended clinical dose, on a mg/m² basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 times the maximum recommended clinical dose, on a mg/m² basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data].
The background risk of major birth defects and miscarriage in the indicated population is unknown.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Disease-Associated Maternal And/Or Embryo-Fetal Risk
Risks during pregnancy are increased in organ transplant recipients. The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death.
Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no longÂterm effects on the offspring were reported.
Maternal Adverse Reactions
ASTAGRAF XL may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see WARNINGS AND PRECAUTIONS].
ASTAGRAF XL may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [see WARNINGS AND PRECAUTIONS].
Fetal/Neonatal Adverse Reactions
Renal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in infants of mothers taking ASTAGRAF XL.
Labor Or Delivery
There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to ASTAGRAF XL.
Human Data
There are no adequate and well-controlled studies on the effects of tacrolimus in human pregnancy.
Safety data from the TPRI and postmarketing surveillance suggest infants exposed to tacrolimus in utero have an increased risk for miscarriage, pre-term delivery (< 37 weeks), low birth weight (< 2500 g), birth defects/congenital anomalies and fetal distress.
TPRI reported 450 and 241 total pregnancies in kidney and liver transplant recipients exposed to tacrolimus, respectively. The TPRI pregnancy outcomes are summarized in Table 6. In the table below, the number of recipients exposed to tacrolimus concomitantly with mycophenolic acid (MPA) products during the preconception and first trimester periods is high (27% and 29% for kidney and liver transplant recipients, respectively). Because MPA products may also cause birth defects, the birth defect rate may be confounded and this should be taken into consideration when reviewing the data, particularly for birth defects. Birth defects observed include cardiac malformations, craniofacial malformations, renal/urogenital disorders, skeletal abnormalities, neurological abnormalities and multiple malformations.
Table 6: TPRI-Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus
| Kidney | Liver | |
| Pregnancy Outcomes1 | 462 | 253 |
| Miscarriage | 24.5% | 25% |
| Live births | 331 | 180 |
| Pre-term delivery (< 37 weeks) | 49% | 42% |
| Low birth weight (< 2500 g) | 42% | 30% |
| Birth defects | 8%2 | 5% |
| 1Includes multiple births and terminations. 2Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects. |
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Additional information reported by TPRI in pregnant transplant patients receiving tacrolimus included diabetes during pregnancy in 9% of kidney recipients and 13% of liver recipients and hypertension during pregnancy in 53% of kidney recipients and 16.2% of liver recipients.
Animal Data
Administration of oral tacrolimus to pregnant rabbits throughout organogenesis produced maternal toxicity and abortion at 0.32 mg/kg (0.5 times the maximum recommended clinical dose [0.2 mg/kg/day], on a mg/m² basis). At 1 mg/kg (1.6 times the maximum recommended clinical dose), embryofetal lethality and fetal malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, omphalocele, gallbladder agenesis, skeletal anomalies) were observed. Administration of 3.2 mg/kg oral tacrolimus (2.6 times the maximum recommended clinical dose) to pregnant rats throughout organogenesis produced maternal toxicity/lethality, embryofetal lethality and decreased fetal body weight in the offspring of C-sectioned dams; and decreased pup viability and interventricular septal defect in offspring of dams that delivered.
In a peri-/postnatal development study, oral administration of tacrolimus to pregnant rats during late gestation (after organogenesis) and throughout lactation produced maternal toxicity, effects on parturition, and reduced pup viability at 3.2 mg/kg (2.6 times the maximum recommended clinical dose); among these pups that died early, an increased incidence of kidney hydronephrosis was observed. Reduced pup weight was observed at 1.0 mg/kg (0.8 times the maximum recommended clinical dose).
Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, embryofetal loss and reduced pup viability at 3.2 mg/kg (2.6 times the maximum recommended clinical dose range). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died. Effects on parturition (incomplete delivery of nonviable pups) were observed at 1 mg/kg (0.8 times the maximum recommended clinical dose) [see Nonclinical Toxicology].
Controlled lactation studies have not been conducted in humans; however, tacrolimus has been reported to be present in human milk. The effects of tacrolimus on the breastfed infant, or on milk production, have not been assessed. Tacrolimus is excreted in rat milk and in peri-/postnatal rat studies; exposure to tacrolimus during the postnatal period was associated with developmental toxicity in the offspring at clinically relevant doses [see Pregnancy and Nonclinical Toxicology].
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ASTAGRAF XL and any potential adverse effects on the breastfed child from ASTAGRAF XL or from the underlying maternal condition.
ASTAGRAF XL can cause fetal harm when administered to pregnant women. Advise female and male patients of reproductive potential to speak to their healthcare provider on family planning options including appropriate contraception prior to starting treatment with ASTAGRAF XL [see Use In Specific Populations and Nonclinical Toxicology].
Based on findings in animals, male and female fertility may be compromised by treatment with ASTAGRAF XL [see Nonclinical Toxicology].
The safety and effectiveness of ASTAGRAF XL in de novo pediatric kidney transplant patients have been established. Use of ASTAGRAF XL in pediatric kidney transplant patients is based on adequate and well-controlled studies of ASTAGRAF XL in adult kidney transplant patients [see Clinical Studies] and supported by pharmacokinetic and safety data of ASTAGRAF XL in pediatric transplant patients 4 years of age and older who are able to swallow capsules intact and Prograf (tacrolimus) capsules in adult and pediatric transplant patients [see CLINICAL PHARMACOLOGY].
A pharmacokinetic and safety study included 25 de novo pediatric kidney transplant patients, 4 to 15 years of age, randomized to Prograf (N=12) or ASTAGRAF XL (N=13). Tacrolimus exposures for the two drug products were comparable on Days 7 and 28 [see CLINICAL PHARMACOLOGY]. Among the 13 pediatric kidney transplant patients who completed 52 weeks on ASTAGRAF XL, there were no graft loss, deaths or episodes of biopsy-proven acute rejection [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS].
Another pharmacokinetic and safety study included 48 stable pediatric kidney transplant patients, 5 to 16 years of age, who were converted from a Prograf-based regimen to ASTAGRAF XL. Tacrolimus systemic exposures for the two drug products were comparable [see CLINICAL PHARMACOLOGY]. Acute rejections were reported in 2/48 kidney pediatric patients that responded to subsequent treatment. There were no graft failures or deaths following use of ASTAGRAF XL during the 54-week follow up [see ADVERSE REACTIONS].
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.
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].
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.
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].
African-American and Hispanic patients are at increased risk for new onset diabetes after transplant. Monitor blood glucose concentrations and treat appropriately [see WARNINGS AND PRECAUTIONS].
Postmarketing cases of overdose with tacrolimus have been reported. Overdosage adverse reactions included:
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.
ASTAGRAF XL is contraindicated in patients with known hypersensitivity to tacrolimus [see ADVERSE REACTIONS].
Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian intracellular enzyme) is then formed and the phosphatase activity of calcineurin is inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB).
Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony-stimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor-beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).
Table 7 summarizes the pharmacokinetic (PK) parameters of tacrolimus following oral administration of ASTAGRAF XL in healthy subjects and in kidney transplant patients. Whole blood tacrolimus concentrations in these PK studies were measured using validated HPLC/MS/MS assays.
Table 7: Pharmacokinetic Parameters of ASTAGRAF XL (Given Once Daily) in Healthy Subjects and in Kidney Transplant Patients (Under Fasted Conditions)
| Population | ASTAGRAF XL Dosea | Dayb | PK Parameters of ASTAGRAF XL | |||
| Cmaxc (ng/mL) | Tmax d (hr) | AUC24c (ng»hr/mL) | C24f (ng/mL) | |||
| Healthy Subjects (N=24) | 4 mg | Day 1 | 6.2 ± 2.1 | 2.0 [1.0-5.0] |
74 ± 22 | 2.3 ± 0.8 |
| 4 mg | Day 10 | 11.6 ± 3.4 | 2.0 [1.0-3.0] |
155 ± 46 | 4.7 ± 1.5 | |
| Adult Kidney De novoe (N=17) | 0.20 mg/kg | Day 1 | 26.0 ± 13.7 | 3.0 [2-24] |
372 ± 202 | 12.1 ± 7.2 |
| 0.19 mg/kg | Day 3 | 31.0 ± 13.9 | 2.0 [0.5-2.0] |
437 ± 175 | 13.5 ± 5.6 | |
| 0.18 mg/kg | Day 7 | 32.2 ± 10.2 | 2.0 [1-6] |
405 ± 117 | 11.4 ± 4.0 | |
| 0.18 mg/kg | Day 14 | 32.7 ± 9.0 | 2.0 [1-4] |
412 ± 109 | 11.2 ± 3.9 | |
| Adult Kidney (6 months or greater posttransplant) (N=60) | 5.2 mg/dayg | Day 14g | 16.1 ± 5.3 | 2.0 [1.0 - 6.0] |
222 ± 64 | 6.7 ± 1.9h |
| a Healthy adult subjects (actual administered dose of ASTAGRAF XL); adult de novo kidney transplant patients (actual group mean dose of ASTAGRAF XL). b Day of ASTAGRAF XL treatment and PK profiling. cArithmetic means ± S.D. d Median [range]. e“De novo” refers to immunosuppression starting at the time of transplantation; data from PK substudy of Study 2. f Tacrolimus trough concentration before the next dose. g Same daily dose of ASTAGRAF XL for 14-day period. h Correlation coefficient of AUC24 to Cmin r = 0.88. |
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In de novo adult kidney transplant patients, the tacrolimus systemic exposure, as assessed by AUC24, for ASTAGRAF XL 0.2 mg/kg once daily on Day 1 post-transplant was 18% (Ratio [SD]: 0.822 [1.647]) lower when compared with Prograf (tacrolimus immediate-release) 0.2 mg/kg/day given twice daily. By Day 3 post-transplant, the AUC24 was similar between the two formulations. On Day 14 (steady state), the AUC24 for ASTAGRAF XL was 21% (Ratio [SD]: 1.207 [1.326]) higher than that of Prograf (tacrolimus immediate-release), at comparable trough concentrations (C24).
Due to intersubject variability in tacrolimus PK, individualization of dosing regimen is necessary for optimal therapy [see DOSAGE AND ADMINISTRATION].
Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus PK.
In healthy subjects, the administration of escalating ASTAGRAF XL doses ranging from 1.5 mg to 10 mg resulted in dose-proportional increases in tacrolimus AUC and C24h, and no change in elimination half-life.
Food Effects
The presence of a meal affects the absorption of tacrolimus; the rate and extent of absorption is greatest under fasted conditions. In 24 healthy subjects, administration of ASTAGRAF XL immediately following a high-fat meal (150 protein calories, 250 carbohydrate calories, and 500 to 600 fat calories) reduced the Cmax, AUCt, and AUCinf of tacrolimus by approximately 25% compared with fasting values. Food delayed the median Tmax from 2 hours in the fasted state to 4 hours in the fed state; however, the terminal half-life remained 36 hours regardless of dosing conditions. The time when a meal is consumed also affected tacrolimus bioavailability. In 24 healthy subjects, when ASTAGRAF XL was administered 1.5 hours after consumption of a high-fat breakfast, tacrolimus exposure was decreased approximately 35%. Administration of ASTAGRAF XL 1 hour prior to a high-fat breakfast reduced tacrolimus exposure by 10%. ASTAGRAF XL capsules should be taken, preferably on an empty stomach, at least 1 hour before a meal or at least 2 hours after a meal.
Chronopharmacokinetic Effect
In 23 healthy subjects, a diurnal effect on the absorption of tacrolimus was observed. Evening dosing of ASTAGRAF XL reduced AUCinf by 35% relative to morning dosing. ASTAGRAF XL capsules should be taken consistently at the same time every morning.
The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5Â50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S. trial in which tacrolimus was administered as tacrolimus immediate-release, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).
Metabolism
The desired pharmacological activity of tacrolimus is primarily due to the parent drug. Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A4 and CYP3A5). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.
Excretion
In a mass balance study of orally-administered radiolabeled tacrolimus to 6 healthy subjects, the mean recovery of the radiolabel was 94.9 ± 30.7%. Fecal elimination accounted for 92.6 ± 30.7% and urinary elimination accounted for 2.3 ± 1.1% of the total radiolabel administered. The elimination half-life based on radioactivity was 31.9 ± 10.5 hours, whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and the mean clearance of tacrolimus was 0.172 ± 0.088 L/hr/kg.
The elimination half-life of tacrolimus after oral administration of 4 mg ASTAGRAF XL daily for 10 days was 38 ± 3 hours in 24 healthy subjects.
De Novo Pediatric Transplant Patients
A PK study to compare ASTAGRAF XL to Prograf capsules was conducted in 44 de novo pediatric transplant patients, including 25 pediatric de novo kidney transplant patients, 4 to 15 years of age (mean age of 10.6 years). These patients were administered a starting daily dose of 0.3 mg/kg/day of Prograf capsules divided into two daily doses or ASTAGRAF XL once daily. Overall, the tacrolimus PK parameters AUC24 and C24 are comparable among Prograf and ASTAGRAF XL on Days 7 and 28 (Table 8).
Table 8: Tacrolimus Pharmacokinetic Parameters Following Daily Doses of Prograf Capsules orASTAGRAF XL in Pediatric De Novo Kidney Transplant Patients 4 to 15 Years of Age
| Study Visita | Mean ± SD (Range) PK Parameters for Prograf Capsules and ASTAGRAF XL | ||
| PK Parameters | Prograf Capsulesb (N=10) |
ASTAGRAF XL (N=10) |
|
| Day 1 | AUC24 (ng•hr/mL) |
280.4 ± 164.4 (145.0 - 688.4) |
211.4 ± 128.2 (76.9 - 459.8) |
| Cmax (ng/mL) |
23.1 ± 14.4 (8.2 - 55.7) |
17.7 ± 11.1 (5.0 - 44.9) |
|
| C24 (ng/mL)c |
8.5 ± 5.4 (3.2 - 16.7) |
6.7 ± 4.3 (2.0 - 16.5) |
|
| Tmax (hr)d |
2.0 (0.9 - 4.0) |
2.0 (1.0 - 12.0) |
|
| Day 7 | AUC24 (ng•hr/mL) |
347.2 ± 124.2 (153.7 - 561.8) |
350.6 ± 92.7 (149.0 - 493.0) |
| Cmax (ng/mL) |
28.7 ± 14.6 (10.5 - 49.0) |
37.7 ± 13.9 (15.1 - 62.6) |
|
| C24 (ng/mL)c |
9.6 ± 2.8 (5.9 - 16.0) |
8.4 ± 2.7 (4.3 - 14.4) |
|
| Tmax (hr)d |
1.0 (1.0 - 2.3) |
1.0 (1.0 - 2.0) |
|
| Day 28 | AUC24 (ng-hr/mL) |
323.6 ± 114.5 (234.5 - 614.0) |
322.4 ± 78.1 (240.3 - 516.4) |
| Cmax (ng/mL) |
28.5 ± 17.1 (17.5 - 70.1) |
24.7 ± 4.8 (14.2 - 32.5) |
|
| C24 (ng/mL)c |
9.8 ± 3.1 (5.4 - 16.0) |
9.2 ± 3.0 (5.1 - 15.9) |
|
| Tmax (hr)d |
1.0 (1.0 - 4.0) |
1.5 (1.0 - 4.0) |
|
| a Study Visit Day on which PK profiles were collected following administration of Prograf capsules or ASTAGRAF XL. b PK estimates following the morning Prograf capsules dose are reported for Tmax and Cmax. c Observed whole blood tacrolimus trough levels at 12 hours following the evening dose of Prograf capsules or 24 hours after the morning dose of ASTAGRAF XL. d Tmax -Reported as median (range). |
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Another PK study to compare ASTAGRAF XL to Prograf capsules was conducted in 81 stable pediatric transplant patients, including 48 pediatric kidney transplant patients, 5 to 16 years of age (mean age of 11.0 years). Pediatric kidney transplant patients who had been administered Prograf for at least 3 months prior to treatment were converted on a 1:1 (mg:mg) basis from Prograf, given in two divided doses, to ASTAGRAF XL once-daily. Overall, the tacrolimus AUC24, Cmax, and C24 are comparable upon conversion from Prograf to ASTAGRAF XL on a 1:1 (mg:mg) basis in stable pediatric kidney transplant patients (Table 9).
Table 9: Tacrolimus Pharmacokinetic Parameters at Steady State Following 1:1 (mg:mg) Total Daily Dose Conversion from Prograf Capsules to ASTAGRAF XL in Stable Pediatric Kidney Transplant Patients 5 to 16 Years of Age
| Organ Transplant Population | Mean ± SD (Range) PK Parameters for Prograf Capsules and ASTAGRAF XL | ||
| PK Parameters | Prograf Capsules | ASTAGRAF XL | |
| Pediatric Kidney (N=45) | AUC24 (ng•hr/mL) | 188.8 ± 53.5 (102.3 - 406.8) |
173.2 ± 44.6 (80.9 - 262.5) |
| Cmax (ng/mL) | 14.9 ± 5.8 (4.9 - 34.4) |
12.5 ± 4.5 (5.4 - 24.4) |
|
| C24a (ng/mL) | 5.6 ± 1.9 (2.9 - 13.8) |
5.1 ± 1.4 (2.0 - 8.4) |
|
| a Observed whole blood tacrolimus trough levels at 12 hours following the evening dose of Prograf capsules and at 24 hours after the morning dose of ASTAGRAF XL once daily under steady-state conditions. | |||
Tacrolimus pharmacokinetics following a single administration of tacrolimus immediate-release injection (administered as a continuous IV infusion) were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9 ± 1.6 and 12.0 ± 2.4 mg/dL, respectively) prior to their kidney transplant. The mean clearance of tacrolimus in patients with renal dysfunction given tacrolimus IV was similar to that in healthy subjects given tacrolimus IV and in healthy subjects given oral tacrolimus immediate-release [see Use In Specific Populations].
Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic impairment (mean Child-Pugh score: 6.2) following single oral administration of tacrolimus immediate-release. The mean clearance of tacrolimus in patients with mild hepatic impairment was not substantially different from that in healthy subjects. Tacrolimus pharmacokinetics were studied in six patients with severe hepatic impairment (mean Child-Pugh score: > 10). The mean clearance was substantially lower in patients with severe hepatic impairment [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].
The pharmacokinetics of tacrolimus was studied following single oral administration of tacrolimus immediate-release (5 mg) in 10 African-American, 12 Latino-American, and 12 Caucasian healthy subjects [see DOSAGE AND ADMINISTRATION, Use In Specific Populations and Clinical Studies]:
A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted; however, there was no difference in total mg daily dosages between male and female patients receiving ASTAGRAF XL in the kidney transplant trials. A retrospective comparison of pharmacokinetics in healthy subjects, and in kidney transplant patients indicated no gender-based differences.
Because tacrolimus is metabolized mainly by CYP3A enzymes, drugs or substances known to inhibit these enzymes and/or are known CYP3A substrates may increase tacrolimus whole blood concentrations. Drugs known to induce CYP3A enzymes may decrease tacrolimus whole blood concentrations [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Figures 1 and 2 summarize the PK data from drug interaction studies of ASTAGRAF XL or tacrolimus immediate-release capsules. These studies assessed the effect of co-administered drugs on tacrolimus PK in healthy subjects. Dosing adjustments, when using drugs that inhibit or increase CYP3A enzymes, may be necessary [see DRUG INTERACTIONS].
Figure 1: Effect of Co-administered Drugs on the Pharmacokinetics of Tacrolimus (when Given as ASTAGRAF XL)
 |
Figure 2: Effect of Co-administered Drugs on the Pharmacokinetics of Tacrolimus (when Given as Immediate-Release Tacrolimus)
 |
Caspofungin (see complete prescribing information for CANCIDAS): Caspofungin reduced the blood AUC0-12 of tacrolimus by approximately 20%, peak blood concentration (Cmax) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone [see DRUG INTERACTIONS]. The mechanism of interaction has not been confirmed.
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 mycophenolate mofetil (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.
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, and 21, then Months 1, 2, 4, 6, 8, 10, and 12. Table 10 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 10: Observed Tacrolimus Whole Blood Trough Concentrations in ASTAGRAF XL-Treated Kidney Transplant Patients in Study 1
| Scheduled Visit | Tacrolimus Whole Blood Trough Concentrations (ng/mL)1 [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) |
| 1 Immunoassay was used in most laboratories. | |
African-American patients required higher ASTAGRAF XL dosages to attain similar trough concentrations as Caucasian patients (see Table 11).
Table 11: 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 |
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| 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 |
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 12. 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].
Table 12: 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
| 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% |
| 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. | ||||
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.
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.
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 13 for the intent-to-treat population, as well as the rates of the individual events.
Table 13: Incidence of BPAR, Graft Loss, Death or Lost to Follow-up at 12 Months in Kidney Transplant Patients in Study 1
| 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%) |
| a 95% confidence interval calculated using normal approximation. | ||
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 14.
Table 14: Estimated Glomerular Filtration Rate (mL/min/1.73m²) by MDRD Formula at 12 Months Post-Transplant in Study 1
| ASTAGRAF XL + MMF, steroids, basiliximab induction (N=201) |
Prograf + MMF, steroids, basiliximab induction (N=202) |
|
| Month 1 Baseline Mean (SD) | 56 (20) | 56 (21) |
| Month 12 LOCFa | ||
| Mean (Standard deviation) Mean Difference XL minus | 58 (21) | 56 (23) |
| Prograf (tacrolimus immediate-release)b | +2.3 (-1.2, +5.8) | |
| 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. |
||
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.
ASTAGRAF XL Or Control [Prograf (tacrolimus) capsules]
The protocol-specified initial preoperative 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 preoperative) and day 1 (0.2 mg per kg per day postÂoperative) 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 15 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 15: Observed Tacrolimus Whole Blood Trough Concentrations for ASTAGRAF XL Kidney Transplant Patients Evaluated in Study 2
| Scheduled Visit | Tacrolimus Whole Blood Trough Concentrations (ng/mL)1 [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) |
| 1 Immunoassay was used in most laboratories. | |
MMF
The initial dose of MMF was 1 gram orally twice daily starting preoperatively 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 16. The MMF dosage was reduced to 0.5 grams twice daily starting after day 14 in the majority of patients.
Table 16: Distribution (%) of ASTAGRAF XL-Treated Patients by Average Daily Dosage of MMF Received by Time Period in Study 2
| 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% |
| 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. |
||||
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.
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 17 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 17: Incidence of BPAR, Graft Loss, Death or Lost to Follow-up at 12 Months in Kidney Transplant Patients in Study 2
| 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%) |
| a 95% confidence interval calculated using normal approximation. | ||
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 18.
Table 18: Estimated Glomerular Filtration Rate (mL/min/1.73m²) by MDRD Formula at 12 Months Post-Kidney Transplant in Study 2
| ASTAGRAF XL + MMF and steroids (N=287) |
Prograf + MMF and steroids (N=300) |
|
| Month 1 Baseline Mean (SD) | 51 (19) | 52 (20) |
| Month 12 LOCFa | ||
| Mean (Standard deviation) Mean Difference ASTAGRAF XL minus | 52 (20) | 55 (19) |
| Prograf (tacrolimus immediate-release)b | -1.8 (-4.6, +0.8) | |
| 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®
[as' tah graf ex el']
(tacrolimus) extended-release capsules
Read this Medication Guide before you start taking ASTAGRAF XL and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about ASTAGRAF XL, ask your healthcare provider or pharmacist.
What is the most important information I should know about ASTAGRAF XL?
ASTAGRAF XL can cause serious side effects, including:
What is ASTAGRAF XL?
Who should not take ASTAGRAF XL?
What should I tell my healthcare provider before taking ASTAGRAF?
Before you take ASTAGRAF XL tell your healthcare provider if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, natural, herbal or nutritional supplements. ASTAGRAF XL may affect the way other medicines work, and other medicines may affect how ASTAGRAF XL works.
Especially tell your healthcare provider if you take:
Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above. ASTAGRAF XL may affect the way other medicines work, and other medicines may affect how ASTAGRAF XL works.
Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take ASTAGRAF XL?
What should I avoid while taking ASTAGRAF XL?
What are the possible side effects of ASTAGRAF XL?
ASTAGRAF XL may cause serious side effects, including:
The most common side effects of ASTAGRAF XL are diarrhea, constipation, nausea, swelling of the hands, ankles, or legs, and tremors (shaking of the body). These are not all the possible side effects of ASTAGRAF XL. For more information, ask your healthcare provider or pharmacist. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA1088.
How should I store ASTAGRAF XL?
General information about the safe and effective use of ASTAGRAF XL.
What are the ingredients in ASTAGRAF XL?
Active ingredient: tacrolimus. Inactive ingredients:
The capsule contains: ethylcellulose NF, hypromellose USP, magnesium stearate NF, and lactose monohydrate NF
The capsule shell contains: gelatin NF, titanium dioxide USP, ferric oxide NF, and sodium lauryl sulfate
This Medication Guide has been approved by the U.S. Food and Drug Administration0
