June 29, 2016
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Astagraf XL

"Analysis of three biomarkers in the urine of kidney transplant recipients can diagnose — and even predict — transplant rejection, according to results from a clinical trial sponsored by the National Institute of Allergy and Infect"...

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Astagraf XL




Astagraf XL Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

Last reviewed on RxList 12/26/2015

Astagraf XL (tacrolimus) Extended-Release Capsules is a macrolide immunosuppressant used with other medicines to help prevent organ rejection in people who have had a kidney transplant. Common side effects of Astagraf XL include diarrhea, constipation, nausea, vomiting, swelling of the hands/ankles/legs, tremors (shaking of the body), low red blood cell count (anemia), fatigue, headache, high blood sugar (hyperglycemia), high blood pressure (hypertension), insomnia, sensitivity to sunlight, and urinary tract infection.

Dosing of Astagraf XL is adjusted for each patient based on the patient's weight, clinical assessments of rejection and tolerability, and to maintain blood concentration ranges. Astagraf XL may interact with cyclosporine, azole antifungals, calcium channel blockers, antibiotics, rifampin, anticonvulsants, St. John's Wort, proton pump inhibitors, amiodarone, bromocriptine, nefazodone, metoclopramide, danazol, ethinyl estradiol, methylprednisolone, "live" vaccines, alcoholic beverages, grapefruit and grapefruit juice. Tell your doctor all medications and supplements you use and all vaccines you recently received. Talk to your doctor about taking Astagraf XL if you are pregnant or plan to become pregnant. It may harm a fetus. Astagraf XL passes into breast milk. Consult your doctor before breastfeeding.

Our Astagraf XL (tacrolimus) Extended-Release Capsules Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

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.

What is Prescribing information?

The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.

Astagraf XL FDA Prescribing Information: Side Effects
(Adverse Reactions)

SIDE EFFECTS

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) [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.

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 3.

Table 3: Percentage of Patients with Infections in Study 1a Through One Year Post-Renal Transplant

  ASTAGRAF XL, MMF, steroids, basiliximab induction
N=214
Tacrolimus immediate-releaseproduct, 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.

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 HbA1C ≥ 6.5%) is summarized in Table 4 below for Study 1 through one year post-transplant [see WARNINGS AND PRECAUTIONS].

Table 4: Percentage of Patients with NODAT Through 1 Year Post-Renal Transplant in Study 1a

  ASTAGRAF XL, MMF, steroids, basiliximab induction
N=162
Tacrolimus immediate-releaseproduct, 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.

Hyperkalemia

In Study 1 [see Clinical Studies], 73 out 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.

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 5.

Table 5: 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-releaseproduct, 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.

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

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.

Blood and Lymphatic System Disorders: Agranulocytosis, disseminated intravascular coagulation, hemolytic uremic syndrome, pancytopenia, pure red cell aplasia [see WARNINGS AND PRECAUTIONS], 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, Torsade de Pointes, QT prolongation

Ear Disorders: Hearing loss

Eye Disorders: Blindness, 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: Hypoproteinaemia

Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, myalgia, polyarthritis

Neoplasms: Lymphoma including EBV-associated lymphoproliferative disorder, hepatosplenic T-cell lymphoma, PTLD [see WARNINGS AND PRECAUTIONS], leukemia, melanoma

Nervous System Disorders: Cerebral infarction, progressive multifocal leukoencephalopathy (PML) sometimes fatal [see WARNINGS AND PRECAUTIONS], posterior reversible encephalopathy syndrome (PRES) [see WARNINGS AND PRECAUTIONS], 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

Read the entire FDA prescribing information for Astagraf XL (Tacrolimus Extended-release Capsules)

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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