Astagraf XL
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Astagraf XL Side Effects
Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.
Serious and sometimes fatal infections may occur during treatment with tacrolimus. Stop using this medicine and call your doctor right away if you have signs of infection such as: sudden weakness or ill feeling, fever, chills, sweating, sore throat, painful mouth sores, skin warmth or redness, flu symptoms, muscle aches, cough, pale skin, easy bruising, or unusual bleeding.
Also call your doctor at once if you have:
- general ill feeling, pain or swelling near your transplanted organ;
- change in your mental state, problems with speech or walking, decreased vision (may start gradually and get worse quickly);
- little or no urinating; painful or difficult urination; swelling in your feet or ankles;
- headache with chest pain and severe dizziness, fainting, fast or pounding heartbeats;
- high blood pressure--severe headache, blurred vision, pounding in your neck or ears, anxiety;
- high blood sugar--increased thirst, increased urination, hunger, fruity breath odor, nausea, loss of appetite, drowsiness, blurred vision, confusion;
- high potassium--slow heart rate, weak pulse, muscle weakness, tingly feeling;
- low magnesium or phosphate--bone pain, jerky muscle movements, muscle weakness or limp feeling, slow reflexes;
- nervous system problems--confusion, headache, vision problems, tremors, numbness and tingly feeling, seizure (convulsions); or
- signs of stomach bleeding--bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds.
Common side effects may include:
- infections, high blood pressure, low phosphate, high potassium;
- kidney problems, urination problems;
- tremors or shaking, numbness or tingling;
- nausea, diarrhea, constipation, stomach pain;
- weakness, headache, general pain;
- sleep problems (insomnia); or
- swelling in your hands or feet.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Before Using Astagraf XL
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:
Allergies
Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
Pediatric
Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of tacrolimus in children with liver transplants.
Appropriate studies have not been performed on the relationship of age to the effects of tacrolimus in children with kidney and heart transplants. Safety and efficacy have not been established.
Geriatric
Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of tacrolimus in the elderly. However, elderly patients are more likely to have kidney, liver, or heart problems, which may require caution and an adjustment in the dose for patients receiving tacrolimus.
Pregnancy
| Pregnancy Category | Explanation | |
|---|---|---|
| All Trimesters | C | Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. |
Breast Feeding
There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.
Interactions with Medicines
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.
- Amifampridine
- Amisulpride
- Bepridil
- Cisapride
- Dronedarone
- Fluconazole
- Mesoridazine
- Mifepristone
- Nelfinavir
- Pimozide
- Piperaquine
- Ritonavir
- Saquinavir
- Sparfloxacin
- Terfenadine
- Thioridazine
- Ziprasidone
Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
- Aceclofenac
- Acemetacin
- Afatinib
- Alefacept
- Alfuzosin
- Amiodarone
- Amitriptyline
- Amlodipine
- Amprenavir
- Amtolmetin Guacil
- Anagrelide
- Apomorphine
- Aprepitant
- Aripiprazole
- Aripiprazole Lauroxil
- Arsenic Trioxide
- Asenapine
- Aspirin
- Astemizole
- Atazanavir
- Azithromycin
- Bedaquiline
- Blinatumomab
- Boceprevir
- Bosentan
- Bromfenac
- Bufexamac
- Buserelin
- Carbamazepine
- Caspofungin
- Celecoxib
- Ceritinib
- Chloroquine
- Chlorpromazine
- Choline Salicylate
- Ciprofloxacin
- Citalopram
- Clarithromycin
- Clomipramine
- Clonixin
- Clozapine
- Cobicistat
- Colchicine
- Conivaptan
- Crizotinib
- Cyclobenzaprine
- Cyclosporine
- Dabrafenib
- Dalfopristin
- Darunavir
- Dasabuvir
- Dasatinib
- Degarelix
- Delamanid
- Delavirdine
- Desipramine
- Deslorelin
- Deutetrabenazine
- Dexamethasone
- Dexibuprofen
- Dexketoprofen
- Diclofenac
- Diflunisal
- Diltiazem
- Dipyrone
- Disopyramide
- Dofetilide
- Dolasetron
- Domperidone
- Donepezil
- Doxepin
- Droperidol
- Droxicam
- Ebastine
- Echinacea
- Efavirenz
- Elbasvir
- Eliglustat
- Eluxadoline
- Enzalutamide
- Eribulin
- Erythromycin
- Escitalopram
- Esomeprazole
- Etodolac
- Etofenamate
- Etoricoxib
- Etravirine
- Famotidine
- Felbamate
- Felbinac
- Fenoprofen
- Fepradinol
- Feprazone
- Fingolimod
- Flecainide
- Floctafenine
- Flufenamic Acid
- Fluoxetine
- Flurbiprofen
- Formoterol
- Fosamprenavir
- Fosaprepitant
- Foscarnet
- Fosphenytoin
- Galantamine
- Gatifloxacin
- Gemifloxacin
- Golimumab
- Gonadorelin
- Goserelin
- Granisetron
- Grazoprevir
- Guselkumab
- Halofantrine
- Haloperidol
- Histrelin
- Hydroquinidine
- Hydroxychloroquine
- Hydroxyzine
- Ibuprofen
- Ibuprofen Lysine
- Ibutilide
- Idelalisib
- Iloperidone
- Imatinib
- Imipramine
- Indinavir
- Indomethacin
- Infliximab
- Isavuconazonium Sulfate
- Itraconazole
- Ivabradine
- Ketoconazole
- Ketoprofen
- Ketorolac
- Lapatinib
- Leuprolide
- Levofloxacin
- Lornoxicam
- Loxoprofen
- Lumacaftor
- Lumefantrine
- Lumiracoxib
- Meclofenamate
- Mefenamic Acid
- Mefloquine
- Meloxicam
- Methadone
- Metronidazole
- Mibefradil
- Mitotane
- Mizolastine
- Modafinil
- Moricizine
- Morniflumate
- Moxifloxacin
- Nabumetone
- Nafarelin
- Naproxen
- Nefazodone
- Nepafenac
- Netupitant
- Nevirapine
- Nicardipine
- Niflumic Acid
- Nilotinib
- Nimesulide
- Nimesulide Beta Cyclodextrin
- Norfloxacin
- Octreotide
- Ofloxacin
- Olanzapine
- Ombitasvir
- Omeprazole
- Ondansetron
- Oxaprozin
- Oxcarbazepine
- Oxyphenbutazone
- Paliperidone
- Panobinostat
- Parecoxib
- Paritaprevir
- Paroxetine
- Pasireotide
- Pazopanib
- Pentamidine
- Perphenazine
- Phenobarbital
- Phenylbutazone
- Phenytoin
- Piketoprofen
- Pimavanserin
- Pipamperone
- Piroxicam
- Pitolisant
- Pixantrone
- Posaconazole
- Prednisone
- Primidone
- Probucol
- Procainamide
- Prochlorperazine
- Proglumetacin
- Promethazine
- Propafenone
- Propionic Acid
- Propyphenazone
- Proquazone
- Protriptyline
- Quetiapine
- Quinidine
- Quinine
- Quinupristin
- Ranolazine
- Ribociclib
- Rifabutin
- Rifampin
- Rilpivirine
- Risperidone
- Rofecoxib
- Salicylic Acid
- Salsalate
- Schisandra sphenanthera
- Secukinumab
- Sertindole
- Sevoflurane
- Sirolimus
- Sodium Phosphate
- Sodium Phosphate, Dibasic
- Sodium Phosphate, Monobasic
- Sodium Salicylate
- Solifenacin
- Sorafenib
- Sotalol
- St John's Wort
- Sulindac
- Sulpiride
- Sunitinib
- Tamoxifen
- Telaprevir
- Telavancin
- Telithromycin
- Tenoxicam
- Tetrabenazine
- Tiaprofenic Acid
- Tizanidine
- Tolfenamic Acid
- Tolmetin
- Tolterodine
- Toremifene
- Trazodone
- Trimipramine
- Triptorelin
- Valdecoxib
- Vandetanib
- Vardenafil
- Varicella Virus Vaccine
- Vemurafenib
- Venlafaxine
- Verapamil
- Vilanterol
- Vinflunine
- Voriconazole
- Vorinostat
- Zuclopenthixol
Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
- Aluminum Carbonate, Basic
- Aluminum Hydroxide
- Aluminum Phosphate
- Chloramphenicol
- Clotrimazole
- Danazol
- Dihydroxyaluminum Aminoacetate
- Dihydroxyaluminum Sodium Carbonate
- Ertapenem
- Lansoprazole
- Magnesium Carbonate
- Magnesium Hydroxide
- Magnesium Oxide
- Magnesium Trisilicate
- Metoclopramide
- Nifedipine
Interactions with Food/Tobacco/Alcohol
Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.
- Ethanol
- Grapefruit Juice
Other Medical Problems
The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:
- Congestive heart failure or
- Diabetes or
- Heart disease or
- Heart rhythm problems (eg, QT prolongation), or family history of or
- Hyperkalemia (high potassium in the blood) or
- Hypertension (high blood pressure) or
- Myocardial hypertrophy (heart is larger than normal), history of or
- Paresthesias (numbness or tingling in the hands, arms, legs, or feet), history of or
- Seizures (convulsions), history of or
- Tremors—Use with caution. May make these conditions worse.
- Infection, active (eg, bacteria, fungus, or virus)—May decrease your body's ability to fight an infection.
- Kidney disease or
- Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.
What are some things I need to know or do while I take Astagraf XL?
- Tell all of your health care providers that you take Astagraf XL. This includes your doctors, nurses, pharmacists, and dentists.
- You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
- Check your drug when you get a new prescription to make sure you have the right drug. Call your doctor right away if you think you were given the wrong drug or if you are not sure what your drug should look like.
- Do not switch between different forms of this medicine without first talking with the doctor.
- Have blood work checked as you have been told by the doctor. Talk with the doctor.
- Many other drugs affect how much of Astagraf XL is in your body. This may raise the chance of organ rejection or raise the chance of side effects. If you take other drugs, check with your doctor to see if you need to have your blood work checked more closely while taking them with this medicine.
- High blood pressure has happened with Astagraf XL. Have your blood pressure checked as you have been told by your doctor.
- This medicine may raise the chance of high blood sugar (diabetes). The chance may be raised in people who are black or Hispanic. Talk with the doctor.
- Check your blood sugar as you have been told by your doctor.
- Avoid grapefruit and grapefruit juice.
- Avoid drinking alcohol while taking this medicine.
- If you are taking a salt substitute that has potassium, potassium-sparing diuretics, or potassium, talk with your doctor.
- Talk with your doctor before getting any vaccines. Use with Astagraf XL may either raise the chance of an infection or make the vaccine not work as well.
- There is a chance of skin cancer. Avoid sun, sunlamps, and tanning beds. Use sunscreen and wear clothing and eyewear that protects you from the sun.
- Very bad and sometimes deadly holes in the GI (gastrointestinal) tract have happened with this medicine. Talk with the doctor.
- A very bad and sometimes deadly brain problem called posterior reversible encephalopathy syndrome (PRES) has happened with Astagraf XL. Call your doctor right away if you have signs like feeling confused, lowered alertness, change in eyesight, loss of eyesight, seizures, or very bad headache.
- This medicine may cause a type of abnormal heartbeat (prolonged QT interval). If this happens, the chance of other unsafe and sometimes deadly abnormal heartbeats may be raised. Talk with the doctor.
- Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
If OVERDOSE is suspected
If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.
Indications and Usage for Astagraf XL
Astagraf XL is indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants.
Limitation of Use
Astagraf XL extended-release capsules are not interchangeable or substitutable with other tacrolimus extended-release or immediate-release products [see Warnings and Precautions (5.4)].
Use in specific populations
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy in humans has been associated with neonatal hyperkalemia and renal dysfunction.
Tacrolimus given orally to pregnant rabbits at 0.5 times the maximum clinical dose and pregnant rats at 0.8 times the maximum clinical dose was associated with an increased incidence of fetal death in utero, fetal malformations (cardiovascular, skeletal, omphalocele, and gallbladder agenesis) and maternal toxicity. Astagraf XL should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
In pregnant rabbits, tacrolimus at oral doses of 0.32 and 1.0 mg/kg (0.5 and 1.6 times the maximum clinical dose based on body surface area, respectively) was associated with maternal toxicity as well as an increased incidence of abortions. At the 1 mg/kg dose, fetal rabbits showed an increased incidence of malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, interrupted ossification of vertebral arch, vertebral and rib malformations, omphalocele, and gallbladder agenesis) and developmental variations. In pregnant rats, tacrolimus at oral doses of 3.2 mg/kg (2.6 times the maximum clinical dose) was associated with maternal toxicity, an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally to pregnant rats after organogenesis and during lactation at 1.0 and 3.2 mg/kg (0.8 and 2.6 times the maximum recommended clinical dose, respectively) was associated with reduced pup weights and pup viability (3.2 mg/kg only); among the high dose pups that died early, an increased incidence of kidney hydronephrosis was observed.
Nursing Mothers
Tacrolimus is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from Astagraf XL, a decision should be made whether to discontinue nursing or to discontinue Astagraf XL, taking into account the importance of drug to the mother.
Pediatric Use
The safety and effectiveness of Astagraf XL in pediatric patients less than 16 years of age have not been established.
Geriatric Use
Clinical studies of Astagraf XL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In Studies 1 and 2, 29 patients were 65 years of age and older, and 3 patients were 75 years of age and over [see Clinical Studies (14)]. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Renal Impairment
The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy subjects with normal renal function. However, due to its potential for nephrotoxicity, monitoring of renal function in patients with renal impairment is recommended; tacrolimus dosage should be reduced if indicated [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].
Hepatic Impairment
The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: > 10) compared to healthy subjects with normal hepatic function [see Clinical Pharmacology (12.3)]. 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 (2.2)]. For patients with moderate hepatic impairment, monitor tacrolimus whole blood trough concentrations. For patients with mild hepatic impairment, no dosage adjustments are needed.
Race
African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients [see Dosage and Administration (2.2), Clinical Pharmacology (12.3), and Clinical Studies (14)].
Astagraf XL - Clinical Pharmacology
Mechanism of Action
Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (an ubiquitous mammalian intracellular enzyme) is then formed and the phosphatase activity of calcineurin 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).
Pharmacokinetics
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 pharmacokinetic studies were measured using validated HPLC/MS/MS assays.
| 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 c Arithmetic 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 | ||||||
| Population | Astagraf XL Dosea | Dayb | Pharmacokinetic Parameters of Astagraf XL | |||
| Cmaxc (ng/mL) | Tmaxd (hr) | AUC24c (ng•hr/mL) | C24f (ng/mL) | |||
| Healthy Subjects (n=24) | 4 mg 4 mg | Day 1 Day 10 | 6.2 ± 2.1 11.6 ± 3.4 | 2.0 [1.0-5.0] 2.0 [1.0-3.0] | 74 ± 22 155 ± 46 | 2.3 ± 0.8 4.7 ± 1.5 |
| Adult Kidney De novoe (n=17) | 0.20 mg/kg 0.19 mg/kg 0.18 mg/kg 0.18 mg/kg | Day 1 Day 3 Day 7 Day 14 | 26.0 ± 13.7 31.0 ± 13.9 32.2 ± 10.2 32.7 ± 9.0 | 3.0 [2-24] 2.0 [0.5-2.0] 2.0 [1-6] 2.0 [1-4] | 372 ± 202 437 ± 175 405 ± 117 412 ± 109 | 12.1 ± 7.2 13.5 ± 5.6 11.4 ± 4.0 11.2 ± 3.9 |
| Adult Kidney | 5.2 mg/dayg | Day 14g | 16.1 ± 5.3 | 2.0 [1.0 - 6.0] | 222 ± 64 | 6.7 ± 1.9h |
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 pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy [see Dosage and Administration (2.3)].
Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.
Absorption
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.
Distribution
The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 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 (CYP3A). 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.
Specific Populations
Renal Impairment
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 Dosage and Administration (2.2) and Use in Specific Populations (8.6)].
Hepatic Impairment
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 6 patients with severe hepatic impairment (mean Pugh score: > 10). The mean clearance was substantially lower in patients with severe hepatic impairment [see Dosage and Administration (2.3) and Use in Specific Populations (8.7)].
Race
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 (2.2), Use in Specific Populations (8.8), and Clinical Studies (14)]:
Gender
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.
Drug Interactions
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 (5.10) and Drug Interactions (7.2)].
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. For the clinical recommendations, see Drug Interactions (7.2).
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)
How Supplied/Storage and Handling
ASTAGRAF XL (tacrolimus) extended-release capsules are supplied in short, square bottles as well as in blister cartons (see Table 17).
| 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 capsule cap. Both bottle and blister packaging are branded with matching brown stripes. • 30-count in short, square bottles with brown caps (NDC 0469-0647-73) • Blister cartons containing 5 blister cards of 10 capsules on each card(NDC 0469-0647-11). |
| 1 mg | Oblong capsule with a white cap and orange body. Capsule is branded with red “ 677” on capsule body and “1 mg” on capsule cap. Both bottle and blister packaging are branded with matching blue stripes. • 30-count in short, square bottles with blue caps (NDC 0469-0677-73) • Blister cartons containing 5 blister cards of 10 capsules on each card(NDC 0469-0677-11). |
| 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 capsule cap. Both bottle and blister packaging are branded with matching orange stripes. • 30-count in short, square bottles with orange caps (NDC 0469-0687-73) • Blister cartons containing 5 blister cards of 10 capsules on each card(NDC 0469-0687-11). |
Store and Dispense
Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Administration
Advise patients to:
Development of Lymphoma and Other Malignancies
Inform patients that they are at an increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and use a sunscreen with a high protection factor [see Boxed Warning and Warnings and Precautions (5.1)].
Increased Risk of Infection
Inform patients that they are at an increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection [see Boxed Warning and Warnings and Precautions (5.2)].
New Onset Diabetes After Transplant
Inform patients that Astagraf XL can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst or hunger [see Warnings and Precautions (5.5)].
Nephrotoxicity
Inform patients that Astagraf XL can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team [see Warnings and Precautions (5.6)].
Neurotoxicity
Inform patients that they are at risk of developing adverse neurologic reactions including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, delirium, or tremors [see Warnings and Precautions (5.7)].
Hyperkalemia
Inform patients that Astagraf XL can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia [see Warnings and Precautions (5.8)].
Hypertension
Inform patients that Astagraf XL can cause high blood pressure which may require treatment with anti-hypertensive therapy [see Warnings and Precautions (5.9)].
Drug Interactions
Instruct patients to tell their healthcare providers when they start or stop taking any concomitant medications, including prescription and non-prescription medicines, herbal and dietary supplements. Some medications could alter tacrolimus concentrations in the blood and thus may require the adjustment of the dosage of Astagraf XL [see Warnings and Precautions (5.10) and Drug Interactions (7)].
Immunizations
Inform patients that Astagraf XL can interfere with the usual response to immunizations and that they should avoid live vaccines [see Warnings and Precautions (5.12)].
Product of Japan
Manufactured by:
Astellas Ireland Co., Limited
Killorglin, County Kerry, Ireland
Marketed by:
Astellas Pharma US, Inc.
Northbrook, IL 60062
Astagraf XL® is a registered trademark of Astellas Pharma Inc.
PROGRAF® is a registered trademark of Astellas Pharma Inc.
14E029-AST
PACKAGE/LABEL PRINCIPAL DISPLAY PANEL – 0.5 mg bottle label
NDC 0469-0647-73
Astagraf XL®
(tacrolimus extended-release capsules)
0.5 mg
ONCE-DAILY
Swallow capsule whole.
Do not cut, crush, or chew capsule.
30 Capsules