ASTAGRAF XL (tacrolimus extended-release capsules)

ASTAGRAF XL (tacrolimus extended-release capsules)

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ASTAGRAF XL (tacrolimus extended-release capsules)

Tacrolimus is the active ingredient in ASTAGRAF XL. Tacrolimus is a calcineurin-inhibitor 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.

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 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.

Indications and usage

ASTAGRAF XL is a calcineurin-inhibitor immunosuppressant 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.

Mechanism of Action

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 colonystimulating 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).

Dosage and administration

  • 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

Contraindications

ASTAGRAF XL is contraindicated in patients with known hypersensitivity to tacrolimus

Warnings and precautions

Lymphoma and Other Malignancies: Immunosuppressants, including ASTAGRAF XL, increase the risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Examine patients for skin changes and advise to avoid or limit exposure to sunlight and UV light by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor.

Serious Infections: Immunosuppressants, including ASTAGRAF XL, increase the risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Serious viral infections reported include:

  • Polyomavirus-associated nephropathy (especially due to BK virus infection)
  • JC virus-associated progressive multifocal leukoencephalopathy (PML)
  • Cytomegalovirus (CMV) infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at highest risk of CMV viremia and CMV disease.

Increased Mortality in Female Liver Transplant Patients: In a clinical trial of 471 liver transplant patients randomized to ASTAGRAF XL or tacrolimus immediate-release product, mortality at 12 months was 10% higher among the 76 female patients (18%) treated with ASTAGRAF XL compared to the 64 female patients (8%) treated with tacrolimus immediate-release product. ASTAGRAF XL is not approved for the prophylaxis of organ rejection in patients who received a liver transplant.

Not Interchangeable with Other Tacrolimus Products – Medication Errors: Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and ASTAGRAF XL (tacrolimus extended-release capsules) were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under- or over-exposure to tacrolimus. ASTAGRAF XL is not interchangeable or substitutable for tacrolimus extended-release tablets, tacrolimus immediaterelease 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 and to confirm with the healthcare provider if a different product is dispensed or if dosing instructions have changed.

New Onset Diabetes After Transplant: ASTAGRAF XL caused new onset diabetes after transplant (NODAT) in kidney transplant patients, which may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Monitor blood glucose concentrations and treat appropriately.

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

Neurotoxicity: ASTAGRAF XL may cause a spectrum of neurotoxicities. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions. 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.

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Hyperkalemia: Mild to severe hyperkalemia, which may require treatment, has been reported with tacrolimus including ASTAGRAF XL. Concomitant use of agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) may increase the risk for hyperkalemia. Monitor serum potassium levels periodically during treatment.

Hypertension: Hypertension is a common adverse reaction of ASTAGRAF XL therapy and may require antihypertensive therapy. Some antihypertensive drugs can increase the risk for hyperkalemia. Calcium-channel blocking agents may increase tacrolimus blood concentrations and require dosage reduction of ASTAGRAF XL.

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

Immunizations: Whenever possible, administer the complete complement of vaccines before transplantation and treatment with ASTAGRAF XL. Avoid the use of live attenuated vaccines during treatment with ASTAGRAF XL (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines).

Adverse reactions

The most common adverse reactions (≥ 30%) are: diarrhea, constipation, nausea, peripheral edema, tremor and anemia.

Drug interactions

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 coadministration than with cyclosporine coadministration 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.

Grapefruit or grapefruit juice: May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation)

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: 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: 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

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). Monitor tacrolimus whole blood trough concentrations and reduce ASTAGRAF XL dose if needed

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 concentrations.

Use in specific populations

Pregnancy: 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.

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 longterm effects on the offspring were reported.

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

Renal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in infants of mothers taking ASTAGRAF XL.

There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to ASTAGRAF XL.

Lactation: 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.

Contraception: 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

Overdosage

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 [one fatal postmarketing case of bilateral pneumopathy and CMV infection was attributed to tacrolimus (extended-release) overdose].

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.

Store and Dispense

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

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