Astagraf Xl Drug Information

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.

Important Administration Instructions • ASTAGRAF XL should not be used without the supervision by a physician with experience in immunosuppressive therapy. • ASTAGRAF XL (tacrolimus extended-release capsules) is not interchangeable or substitutable for tacrolimus extended-release tablets, tacrolimus immediate-release capsules or tacrolimus for oral suspension. Under or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision. • Advise patients to swallow ASTAGRAF XL capsules whole with liquid; patients must not chew, divide, or crush the capsules. • ASTAGRAF XL should be taken consistently every morning at the same time to ensure consistent and maximum possible drug exposure, on an empty stomach at least 1 hour before a meal, or at least 2 hours after a meal. • If a dose is missed, the dose may be taken up to 14 hours after the scheduled time (i.e., for a missed 8:00 AM dose, a dose may be taken by 10:00 PM).

Beyond the 14-hour time frame, the patient should wait until the usual scheduled time the following morning to take the next regular daily dose. Instruct the patient not to double the next dose. • Advise patients to avoid eating grapefruit or drinking grapefruit juice or alcoholic beverages while taking ASTAGRAF XL. • Therapeutic drug monitoring is recommended for all patients receiving ASTAGRAF XL.

Dosage Recommendations for Kidney Transplant Patients Table 1 includes the recommended starting ASTAGRAF XL dosages and whole blood trough concentration ranges; the observed trough concentrations are shown in another section of the Full Prescribing Information. Titrate the ASTAGRAF XL dosage based on clinical assessments of rejection and tolerability, and to achieve target trough concentration ranges. Table 1: Recommended Starting Daily Dosage Regimen of ASTAGRAF XL

Dosage Modifications for African-American Patients, Patients with Hepatic Impairment, and Drug Interactions African-American patients, compared to Caucasian patients, may need to be titrated to higher ASTAGRAF XL dosages to attain comparable trough concentrations. 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. Dose adjustments of ASTAGRAF XL may be necessary when administered concomitantly with CYP3A inducers or CYP3A inhibitors or cannabidiol.

Therapeutic Drug Monitoring

Measure tacrolimus whole blood trough concentrations at least two times on separate days during the first week after initiation of dosing and after a change in dosage, after a change in co-administration of CYP3A4 inducers and/or inhibitors or cannabidiol, 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.

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.

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below. Kidney transplant patients were treated with ASTAGRAF XL (N=214) or tacrolimus immediate-release product (N=212) and concomitant immunosuppressants (median duration of exposure of 12 months) in a randomized, open-label, active-controlled trial of mostly U.S. patients (Study 1).

The types of adverse reactions seen in Study 1 were similar to the adverse reactions seen in Study 2. The most common adverse reactions leading to discontinuation in ASTAGRAF XL-treated patients were related to infections or renal/urinary disorders. Infections The overall incidence of infections, serious infections, and infections with identified etiology reported in patients treated with the ASTAGRAF XL or tacrolimus immediate-release product in Study 1 are shown in Table 2.

Table 2: Percentage of Patients with Infections in Study 1 a Through One Year Post-Kidney Transplant New Onset Diabetes After Transplant (NODAT) The incidence of new onset diabetes after transplantation (defined by the composite occurrence of ≥ 2 fasting plasma glucose values that were > 126 mg/dL at ≥ 30 days apart, insulin use for ≥ 30 consecutive days, oral hypoglycemic use for ≥ 30 consecutive days, and/or HbA 1C ≥ 6.5%) is summarized in Table 3 below for Study 1 through one year post-transplant. Common Adverse Reactions The most common (≥ 30%) adverse reactions observed with ASTAGRAF XL in Study 1 were: diarrhea, constipation, nausea, peripheral edema, tremor, and anemia. The incidence of adverse reactions that occurred in ≥ 15% of ASTAGRAF XL-treated patients compared to tacrolimus immediate-release product through one year of treatment in Study 1 is shown by treatment groups in Table 4.

Table 4: Adverse Reactions (≥ 15%) in Kidney Transplant Patients Through One Year Post-Transplant in Study 1 a Less Frequently Reported Adverse Reactions (< 15% in ASTAGRAF XL-treated patients) by System Organ Class The following adverse reactions were reported in clinical studies of kidney transplant patients who were treated with ASTAGRAF XL, MMF, and steroids (Studies 1 and 2): • Blood and Lymphatic System Disorders: Hemolytic anemia, leukocytosis, neutropenia, thrombocytopenia, thrombotic microangiopathy • Cardiac Disorders: Atrial fibrillation, atrial flutter, tachycardia • Ear Disorders: Tinnitus • Eye Disorders: Vision blurred, conjunctivitis • Gastrointestinal Disorders: Abdominal distension, abdominal pain, aphthous stomatitis, dyspepsia, esophagitis, flatulence, gastritis, gastroesophageal reflux disease • General Disorders and Administration Site Conditions: Anasarca, asthenia, edema, pyrexia • Hepatobiliary Disorders: Abnormal hepatic function, cholestasis, hepatitis (acute and chronic), hepatotoxicity • Infections and Infestations: Condyloma acuminatum, tinea versicolor • Injury: Fall • Investigations: Increased blood lactate dehydrogenase, increased blood urea, increased hepatic enzyme • Metabolism and Nutrition Disorders: Anorexia, hyperphosphatemia, hyperuricemia, hypokalemia, hyponatremia, metabolic acidosis • Musculoskeletal and Connective Tissue Disorders: Arthralgia, osteopenia, osteoporosis • Neoplasms: Kaposi’s sarcoma • Nervous System Disorders: Convulsion, dizziness, hypoesthesia, neurotoxicity, paresthesia, peripheral neuropathy • Psychiatric Disorders: Agitation, anxiety, confusional state, depression, hallucination, mood swings, nightmare • Renal and Urinary Disorders: Anuria, oliguria, proteinuria, renal failure, renal tubular necrosis, toxic nephropathy • Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, dyspnea, pulmonary edema, productive cough • Skin and Subcutaneous Tissue Disorders: Acne, alopecia, dermatitis, hyperhidrosis, hypotrichosis, pruritus, rash • Vascular Disorders: Deep vein thrombosis, flushing Pediatrics De Novo Pediatric Transplant Patients A study was conducted in 44 de novo pediatric transplant patients (including 25 kidney transplant patients; 13 randomized to ASTAGRAF XL and 12 randomized to Prograf), who were started on 0.3 mg/kg daily of tacrolimus product, given once daily for ASTAGRAF XL and divided into two doses for Prograf. Two kidney transplant patients on Prograf discontinued the study (withdrawn consent, sapovirus enteritis). Thirteen pediatric kidney transplant patients completed 52 weeks on ASTAGRAF XL.

The most common adverse reactions were diarrhea, increased blood creatinine, hypertension, cough, and upper respiratory tract infection. Seventy-six 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 common adverse reactions were diarrhea (13.9%), headache (13.9%) and cough (11.4%).

Postmarketing Experience

The following adverse reactions have been reported from marketing experience with tacrolimus in the U.S. and outside the U.S. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to ASTAGRAF XL: • Blood and Lymphatic System Disorders: Agranulocytosis, disseminated intravascular coagulation, hemolytic uremic syndrome, febrile neutropenia, pancytopenia, pure red cell aplasia, coagulopathy, thrombotic thrombocytopenic purpura, prolonged activated partial thromboplastin time, decreased blood fibrinogen • Cardiac Disorders: Cardiac arrest, myocardial infarction, ventricular fibrillation, congestive cardiac failure, hypertrophic cardiomyopathy, pericardial effusion, angina pectoris, supraventricular extrasystoles, supraventricular tachycardia, bradycardia, Torsades de pointes, QT prolongation • Ear Disorders: Hearing loss • Eye Disorders: Blindness, optic neuropathy, optic atrophy, photophobia • Gastrointestinal Disorders: Gastrointestinal hemorrhage, gastrointestinal perforation, pancreatitis, peritonitis, stomach ulcer, intestinal obstruction, ascites, colitis, ileus, impaired gastric emptying, dysphagia • Hepatobiliary Disorders: Hepatic failure, hepatic necrosis, cirrhosis, cholangitis, venoocclusive liver disease, bile duct stenosis, hepatic steatosis, jaundice • Hypersensitivity Reactions: Hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria • Immune System Disorders: Graft versus host disease (acute and chronic) • Investigations: Increased international normalized ratio • Metabolism and Nutrition Disorders: Hypoproteinemia • Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, myalgia, polyarthritis, pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) • Neoplasms: Lymphoma including EBV-associated lymphoproliferative disorder, hepatosplenic T-cell lymphoma, PTLD, leukemia, melanoma • Nervous System Disorders: Cerebral infarction, progressive multifocal leukoencephalopathy (PML) sometimes fatal, posterior reversible encephalopathy syndrome (PRES), coma, status epilepticus, quadriplegia, flaccid paralysis, hemiparesis, aphasia, syncope, carpal tunnel syndrome, nerve compression, mutism, dysarthria, somnolence • Psychiatric Disorders: Mental status changes • Renal and Urinary Disorders: Hemorrhagic cystitis, hematuria, urinary retention, urinary incontinence • Respiratory, Thoracic and Mediastinal Disorders: Interstitial lung disease, pulmonary hypertension, lung infiltration, rhinitis allergic, hiccups • Skin and Subcutaneous Tissue Disorders: Hyperpigmentation, photosensitivity • Vascular Disorders: Hemorrhage

Mycophenolic Acid When ASTAGRAF XL is prescribed with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher with ASTAGRAF XL 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.

Effects of Other Drugs on ASTAGRAF XL Table 5 displays the effects of other drugs on ASTAGRAF XL. Grapefruit or grapefruit juice b May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation). 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). Avoid alcoholic beverages. Strong CYP3A Inducers c: 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.

Increase ASTAGRAF XL dose and monitor tacrolimus whole blood trough concentrations. Strong CYP3A Inhibitors c: 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.

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. Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1-3 days and continue monitoring as necessary. 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).

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). Mild or Moderate CYP3A Inducers Methylprednisolone, prednisone May decrease tacrolimus whole blood trough concentrations. Caspofungin May decrease tacrolimus whole blood trough concentrations.

Direct Acting Antiviral (DAA) Therapy 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.

Cannabidiol

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.

Pregnancy Pregnancy Exposure Registry 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/.

Risk Summary 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. 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. 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/m 2 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/m 2 basis).

Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died. 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 respectively.

Clinical Considerations 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 long-term 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. ASTAGRAF XL may exacerbate hypertension in pregnant women and increase pre-eclampsia.

Monitor and control blood pressure. 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.

Data 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. 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, on a mg/m 2 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). Effects on parturition (incomplete delivery of nonviable pups) were observed at 1 mg/kg (0.8 times the maximum recommended clinical dose).

Pediatric Use 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 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. De Novo Pediatric Kidney Transplant Patients 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. 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. Stable Pediatric Kidney Transplant Patients 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.

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.

ASTAGRAF XL is contraindicated in patients with known hypersensitivity to tacrolimus. Known hypersensitivity to tacrolimus.

• Postmarketing cases of overdose with tacrolimus have been reported. Overdosage adverse reactions included:
• Nervous system disorders (tremor, headache, confusional state, balance disorders, encephalopathy, lethargy and somnolence)
• Gastrointestinal disturbances (nausea, vomiting, and diarrhea)
• Abnormal renal function (increased blood urea nitrogen and elevated serum creatinine)
• Urticaria
• Hypertension
• Peripheral edema, and
• Infections. 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.