Astagraf XL

SIDE EFFECTS

The following clinically significant adverse drug reactions are discussed in greater detail in other sections of labeling:

• Lymphoma and Other Malignancies [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
• Serious Infections [see BOXED WARNINGs, WARNINGS AND PRECAUTIONS]
• Increased Mortality in Female Liver Transplant Patients [see WARNINGS AND PRECAUTIONS]
• New Onset Diabetes after Transplant [see WARNINGS AND PRECAUTIONS]
• Nephrotoxicity due to ASTAGRAF XL and DRUG INTERACTIONS [see WARNINGS AND PRECAUTIONS]
• Neurotoxicity [see WARNINGS AND PRECAUTIONS]
• Hyperkalemia [see WARNINGS AND PRECAUTIONS]
• Hypertension [see WARNINGS AND PRECAUTIONS]
• QT Prolongation [see WARNINGS AND PRECAUTIONS]
• Pure Red Cell Aplasia [see WARNINGS AND PRECAUTIONS]

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 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 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 1^a

Hyperkalemia

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].

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 (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%)].

Stable Pediatric Transplant Patients

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%).

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 [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 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 [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)