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Tanzeum（albiglutide）获FDA批准，作为每周一次的皮下注射药物，辅助饮食和运动，用于改善2型糖尿病成人患者的血糖控制
TANZEUM is a GLP-1 receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1) Limitations of Use: • Not recommended as first-line therapy for patients inadequately controlled on diet and exercise. ( 1, 5.1) • Has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis. ( 1, 5.2) • Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis. ( 1) • Not for patients with pre-existing severe gastrointestinal disease. ( 1) • Has not been studied in combination with prandial insulin. ( 1) DOSAGE AND ADMINISTRATION • Administer once weekly at any time of day, without regard to meals. ( 2.1) • Inject subcutaneously in the abdomen, thigh, or upper arm. ( 2.1) • Initiate at 30 mg subcutaneously once weekly. Dose can be increased to 50 mg once weekly in patients requiring additional glycemic control. ( 2.1) • If a dose is missed, administer within 3 days of missed dose. ( 2.1) • See Full Prescribing Information and Patient Instructions for Use for reconstitution of lyophilized powder and administration. ( 2.4, 2.5, 17) DOSAGE FORMS AND STRENGTHS For injection: 30 mg or 50 mg in a single-dose Pen. (3) CONTRAINDICATIONS • TANZEUM is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2. ( 4.1) • TANZEUM is contraindicated in patients with a prior serious hypersensitivity reaction to albiglutide or any of the product components. ( 4.2, 5.4) WARNINGS AND PRECAUTIONS • Thyroid C-cell Tumors: See Boxed Warning. ( 5.1) • Pancreatitis: Discontinue promptly if suspected. Do not restart if confirmed. Consider other antidiabetic therapies in patients with a history of pancreatitis. ( 5.2) • Hypoglycemia: Can occur when used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Consider lowering sulfonylurea or insulin dosage when starting TANZEUM. ( 5.3) • Hypersensitivity Reactions: Discontinue TANZEUM if suspected. Monitor and treat promptly per standard of care until signs and symptoms resolve. ( 5.4) • Renal Impairment: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions. ( 5.5) • Macrovascular Outcomes: There have been no clinical trials establishing conclusive evidence of macrovascular risk reduction with TANZEUM or any other antidiabetic drug. ( 5.6) ADVERSE REACTIONS Adverse reactions, reported in ≥5% of patients treated with TANZEUM and more frequently than in patients on placebo, were upper respiratory tract infection, diarrhea, nausea, injection site reaction, cough, back pain, arthralgia, sinusitis, and influenza. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS TANZEUM delays gastric emptying. May impact absorption of concomitantly administered oral medications. (7) USE IN SPECIFIC POPULATIONS • Pregnancy: TANZEUM may cause fetal harm; only use if potential benefit justifies potential risk to fetus. ( 8.1) • Nursing Mothers: Discontinue nursing or discontinue TANZEUM. ( 8.3) • Renal Impairment: No dosage adjustment recommended. Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions. ( 5.5, 8.6) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 5/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE TANZEUM is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14)]. Limitations of Use: • TANZEUM is not recommended as first-line therapy for patients inadequately controlled on diet and exercise because of the uncertain relevance of the rodent C-cell tumor findings to humans. Prescribe TANZEUM only to patients for whom the potential benefits are considered to outweigh the potential risk [see Warnings and Precautions (5.1)]. • TANZEUM has not been studied in patients with a history of pancreatitis [see Warnings and Precautions (5.2)]. Consider other antidiabetic therapies in patients with a history of pancreatitis. • TANZEUM is not indicated in the treatment of patients with type 1 diabetes mellitus or for the treatment of patients with diabetic ketoacidosis. TANZEUM is not a substitute for insulin in these patients. • TANZEUM has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis. The use of TANZEUM is not recommended in patients with pre-existing severe gastrointestinal disease [see Adverse Reactions (6.1)]. • TANZEUM has not been studied in combination with prandial insulin. 2 DOSAGE AND ADMINISTRATION 2.1 Dosage The recommended dosage of TANZEUM is 30 mg once weekly given as a subcutaneous injection in the abdomen, thigh, or upper arm region. The dosage may be increased to 50 mg once weekly if the glycemic response is inadequate. TANZEUM may be administered at any time of day without regard to meals. Instruct patients to administer TANZEUM once a week on the same day each week. The day of weekly administration may be changed if necessary as long as the last dose was administered 4 or more days before. If a dose is missed, instruct patients to administer as soon as possible within 3 days after the missed dose. Thereafter, patients can resume dosing on their usual day of administration. If it is more than 3 days after the missed dose, instruct patients to wait until their next regularly scheduled weekly dose. 2.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin When initiating TANZEUM, consider reducing the dosage of concomitantly administered insulin secretagogues (e.g., sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.3)]. 2.3 Dosage in Patients with Renal Impairment No dose adjustment is needed in patients with mild, moderate, or severe renal impairment (eGFR 15 to 89 mL/min/1.73 m2). Use caution when initiating or escalating doses of TANZEUM in patients with renal impairment. Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions [see Warnings and Precautions (5.5), Use in Specific Populations (8.6)]. 2.4 Reconstitution of the Lyophilized Powder The lyophilized powder contained within the Pen must be reconstituted prior to administration. See Patient Instructions for Use for complete administration instructions with illustrations. The instructions may also be found at www.TANZEUM.com. Instruct patients as follows: Pen Reconstitution • Hold the Pen body with the clear cartridge pointing up to see the [1] in the number window. • To reconstitute the lyophilized powder with the diluent in the Pen, twist the clear cartridge on the Pen in the direction of the arrow until the Pen is felt/heard to “click” into place and the [2] is seen in the number window. This mixes the diluent with the lyophilized powder. • Slowly and gently rock the Pen side-to-side 5 times to mix the reconstituted solution of TANZEUM. Advise the patient to not shake the Pen hard to avoid foaming. • Wait 15 minutes for the 30-mg Pen and 30 minutes for the 50-mg Pen to ensure that the reconstituted solution is mixed. Preparing Pen for Injection • Slowly and gently rock the Pen side-to-side 5 additional times to mix the reconstituted solution. • Visually inspect the reconstituted solution in the viewing window for particulate matter. The reconstituted solution will be yellow in color. After reconstitution, use TANZEUM within 8 hours. • Holding the Pen upright, attach the needle to the Pen. Gently tap the clear cartridge to bring large bubbles to the top. See Dosage and Administration (2.5) for important administration instructions, including the injection procedure. Alternate Method of Reconstitution (Healthcare Professional Use Only) The Patient Instructions for Use provide directions for the patient to wait 15 minutes for the 30-mg Pen and 30 minutes for the 50-mg Pen after the lyophilized powder and diluent are mixed to ensure reconstitution. Healthcare professionals may utilize the following alternate method of reconstitution. Because this method relies on appropriate swirling and visual inspection of the solution, it should only be performed by healthcare professionals. • Follow Step A (Inspect Your Pen and Mix Your Medication) in the Instructions for Use. Make sure you have: • Inspected the Pen for [1] in the number window and expiration date. • Twisted the clear cartridge until [2] appears in the number window and a “click” is heard. This combines the medicine powder and liquid in the clear cartridge. • Hold the Pen with the clear cartridge pointing up and maintain this orientation throughout the reconstitution. • Gently swirl the Pen in small circular motions for at least one minute. Avoid shaking as this can result in foaming, which may affect the dose. • Inspect the solution, and if needed, continue to gently swirl the Pen until all the powder is dissolved and you see a clear yellow solution that is free of particles. A small amount of foam, on top of the solution at the end of reconstitution, is normal. • For 30-mg Pen: Complete dissolution usually occurs within 2 minutes but may take up to 5 minutes, as confirmed by visual inspection for a clear yellow solution free of particles. • For 50-mg Pen: Complete dissolution usually occurs within 7 minutes but may take up to 10 minutes. • After reconstitution, continue to follow the steps in the Instructions for Use, starting at Step B: Attach the Needle. 2.5 Important Administration Instructions Instruct patients as follows: • The pen should be used within 8 hours of reconstitution prior to attaching the needle. • After attaching the supplied needle, remove air bubbles by slowly twisting the Pen until you see the [3] in the number window. At the same time, the injection button will be automatically released from the bottom of the Pen. • Use immediately after the needle is attached and primed. The product can clog the needle if allowed to dry in the primed needle. • After subcutaneously inserting the needle into the skin in the abdomen, thigh, or upper arm region, press the injection button. Hold the injection button until you hear a “click” and then hold the button for 5 additional seconds to deliver the full dose. When using TANZEUM with insulin, instruct patients to administer as separate injections and to never mix the products. It is acceptable to inject TANZEUM and insulin in the same body region but the injections should not be adjacent to each other. When injecting in the same body region, advise patients to use a different injection site each week. TANZEUM must not be administered intravenously or intramuscularly. 3 DOSAGE FORMS AND STRENGTHS TANZEUM is supplied as follows: • For injection: 30-mg lyophilized powder in a single-dose Pen (pen injector) for reconstitution. • For injection: 50-mg lyophilized powder in a single-dose Pen (pen injector) for reconstitution. 4 CONTRAINDICATIONS 4.1 Medullary Thyroid Carcinoma TANZEUM is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)]. 4.2 Hypersensitivity TANZEUM is contraindicated in patients with a prior serious hypersensitivity reaction to albiglutide or to any of the product components [see Warnings and Precautions (5.4)]. 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-cell Tumors Carcinogenicity of albiglutide could not be assessed in rodents due to the rapid development of drug-clearing, anti-drug antibodies [see Nonclinical Toxicology (13.1)]. Other GLP-1 receptor agonists have caused dose-related and treatment-duration-dependent thyroid C-cell tumors (adenomas or carcinomas) in rodents. Human relevance of GLP-1 receptor agonist induced C-cell tumors in rodents has not been determined. It is unknown whether TANZEUM causes thyroid C-cell tumors, including MTC, in humans [see Boxed Warning, Contraindications (4.1)]. Across 8 Phase III clinical trials [see Clinical Studies (14)], MTC was diagnosed in 1 patient receiving TANZEUM and 1 patient receiving placebo. Both patients had markedly elevated serum calcitonin levels at baseline. Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. TANZEUM is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of TANZEUM and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, or persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TANZEUM. Such monitoring may increase the risk of unnecessary procedures, due to the low specificity of serum calcitonin testing for MTC and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis In clinical trials, acute pancreatitis has been reported in association with TANZEUM. Across 8 Phase III clinical trials [see Clinical Studies (14)], pancreatitis adjudicated as likely related to therapy occurred more frequently in patients receiving TANZEUM (6 of 2,365 [0.3%]) than in patients receiving placebo (0 of 468 [0%]) or active comparators (2 of 2,065 [0.1%]). After initiation of TANZEUM, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, promptly discontinue TANZEUM. If pancreatitis is confirmed, TANZEUM should not be restarted. TANZEUM has not been studied in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis. 5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin The risk of hypoglycemia is increased when TANZEUM is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Therefore, patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting [see Dosage and Administration (2.2), Adverse Reactions (6.1)]. 5.4 Hypersensitivity Reactions Across 8 Phase III clinical trials [see Clinical Studies (14)], a serious hypersensitivity reaction with pruritus, rash, and dyspnea occurred in a patient treated with TANZEUM. If hypersensitivity reactions occur, discontinue use of TANZEUM; treat promptly per standard of care and monitor until signs and symptoms resolve [see Contraindications (4.2)]. 5.5 Renal Impairment In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. In a trial of TANZEUM in patients with renal impairment [see Clinical Studies (14.3)], the frequency of such gastrointestinal reactions increased as renal function declined [see Use in Specific Populations (8.6)]. Because these reactions may worsen renal function, use caution when initiating or escalating doses of TANZEUM in patients with renal impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.6)]. 5.6 Macrovascular Outcomes There have been no clinical trials establishing conclusive evidence of macrovascular risk reduction with TANZEUM or any other antidiabetic drug. 6 ADVERSE REACTIONS The following serious reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)] • Acute Pancreatitis [see Warnings and Precautions (5.2)] • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.3)] • Hypersensitivity Reactions [see Warnings and Precautions (5.4)] • Renal Impairment [see Warnings and Precautions (5.5)] 6.1 Clinical Trials 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pool of Placebo-Controlled Trials The data in Table 1 are derived from 4 placebo-controlled trials. TANZEUM was used as monotherapy in 1 trial and as add-on therapy in 3 trials [see Clinical Studies (14)]. These data reflect exposure of 923 patients to TANZEUM and a mean duration of exposure to TANZEUM of 93 weeks. The mean age of participants was 55 years, 1% of participants were 75 years or older and 53% of participants were male. The population in these studies was 48% white, 13% African/African American, 7% Asian, and 29% Hispanic/Latino. At baseline, the population had type 2 diabetes for an average of 7 years and had a mean HbA1c of 8.1%. At baseline, 17% of the population in these studies reported peripheral neuropathy and 4% reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR >60 mL/min/1.73 m2) in 91% of the study population and moderately impaired (eGFR 30 to 60 mL/min/1.73 m2) in 9%. Table 1 shows common adverse reactions excluding hypoglycemia associated with the use of TANZEUM in the pool of placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on TANZEUM than on placebo, and occurred in at least 5% of patients treated with TANZEUM. Table 1. Adverse Reactions in Placebo-controlled Trials Reported in ≥5% of Patients Treated with TANZEUMa
b See below for other events of injection site reactions reported Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal complaints occurred more frequently among patients receiving TANZEUM (39%) than patients receiving placebo (33%). In addition to diarrhea and nausea (see Table 1), the following gastrointestinal adverse reactions also occurred more frequently in patients receiving TANZEUM: vomiting (2.6% versus 4.2% for placebo versus TANZEUM), gastroesophageal reflux disease (1.9% versus 3.5% for placebo versus TANZEUM), and dyspepsia (2.8% versus 3.4% for placebo versus TANZEUM). Constipation also contributed to the frequently reported reactions. In the group treated with TANZEUM, investigators graded the severity of GI reactions as “mild” in 56% of cases, “moderate” in 37% of cases, and “severe” in 7% of cases. Discontinuation due to GI adverse reactions occurred in 2% of individuals on TANZEUM or placebo. Injection Site Reactions In the pool of placebo-controlled trials, injection site reactions occurred more frequently on TANZEUM (18%) than on placebo (8%). In addition to the term injection site reaction (see Table 1), the following other types of injection site reactions also occurred more frequently on TANZEUM: injection site hematoma (1.9% versus 2.1% for placebo versus TANZEUM ), injection site erythema (0.4% versus 1.7% for placebo versus TANZEUM), injection site rash (0% versus 1.4% for placebo versus TANZEUM), injection site hypersensitivity (0% versus 0.8% for placebo versus TANZEUM), and injection site hemorrhage (0.6% versus 0.7% for placebo versus TANZEUM). Injection site pruritus also contributed to the frequently reported reactions. The majority of injection site reactions were judged as “mild” by investigators in both groups (73% for TANZEUM versus 94% for placebo). More patients on TANZEUM than on placebo: discontinued due to an injection site reaction (2% versus 0.2%), experienced more than 2 reactions (38% versus 20%), had a reaction judged by investigators to be “moderate” or “severe” (27% versus 6%) and required local or systemic treatment for the reactions (36% versus 11%). Pool of Placebo- and Active-controlled Trials The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 7 placebo- and active-controlled trials. These trials evaluated the use of TANZEUM as monotherapy, and as add-on therapy to oral antidiabetic agents, and as add-on therapy to basal insulin [see Clinical Studies (14)]. In this pool, a total of 2,116 patients with type 2 diabetes were treated with TANZEUM for a mean duration of 75 weeks. The mean age of patients treated with TANZEUM was 55 years, 1.5% of the population in these studies was 75 years or older and 51% of participants were male. Forty-eight percent of patients were white, 15% African/African American, 9% Asian, and 26% were Hispanic/Latino. At baseline, the population had diabetes for an average of 8 years and had a mean HbA1c of 8.2%. At baseline, 21% of the population reported peripheral neuropathy and 5% reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR >60 mL/min/1.73 m2) in 92% of the population and moderately impaired (eGFR 30 to 60 mL/min/1.73 m2) in 8% of the population. In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions excluding hypoglycemia were similar to those listed in Table 1. Other Adverse Reactions Hypoglycemia The proportion of patients experiencing at least one documented symptomatic hypoglycemic episode on TANZEUM and the proportion of patients experiencing at least one severe hypoglycemic episode on TANZEUM in clinical trials [see Clinical Studies (14)] is shown in Table 2. Hypoglycemia was more frequent when TANZEUM was added to sulfonylurea or insulin [see Warnings and Precautions (5.3)]. Table 2. Incidence (%) of Hypoglycemia in Clinical Trials of TANZEUMa
a Data presented are to the primary endpoint and include only events occurring on-therapy with randomized medications and excludes events occurring after use of glycemic rescue medications (i.e., primarily metformin or insulin). b In this trial, no documented symptomatic or severe hypoglycemia were reported for TANZEUM 50 mg and these data are omitted from the table. c Plasma glucose concentration ≤70 mg/dL and presence of hypoglycemic symptoms. d Event requiring another person to administer a resuscitative action. e Rate of documented symptomatic hypoglycemia for active controls 18% (glimepiride) and 2% (sitagliptin). Pneumonia In the pool of 7 placebo- and active-controlled trials, the adverse reaction of pneumonia was reported more frequently in patients receiving TANZEUM (1.8%) than in patients in the all-comparators group (0.8%). More cases of pneumonia in the group receiving TANZEUM were serious (0.4% for TANZEUM versus 0.1% for all comparators). Atrial Fibrillation/Flutter In the pool of 7 placebo- and active-controlled trials, adverse reactions of atrial fibrillation (1.0%) and atrial flutter (0.2%) were reported more frequently for TANZEUM than for all comparators (0.5% and 0%, respectively). In both groups, patients with events were generally male, older, and had underlying renal impairment or cardiac disease (e.g., history of arrhythmia, palpitations, congestive heart failure, cardiomyopathy, etc.). Appendicitis In the pool of placebo- and active-controlled trials, serious events of appendicitis occurred in 0.3% of patients treated with TANZEUM compared with 0% among all comparators. Immunogenicity In the pool of 7 placebo- and active-controlled trials, 116 (5.5%) of 2,098 patients exposed to TANZEUM tested positive for anti-albiglutide antibodies at any time during the trials. None of these antibodies were shown to neutralize the activity of albiglutide in an in vitro bioassay. Presence of antibody did not correlate with reduced efficacy as measured by HbA1c and fasting plasma glucose or specific adverse reactions. Consistent with the high homology of albiglutide with human GLP-1, the majority of patients (approximately 79%) with anti-albiglutide antibodies also tested positive for anti-GLP-1 antibodies; none were neutralizing. A minority of patients (approximately 17%) who tested positive for anti-albiglutide antibodies also transiently tested positive for antibodies to human albumin. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to albiglutide cannot be directly compared with the incidence of antibodies of other products. Liver Enzyme Abnormalities In the pool of placebo- and active-controlled trials, a similar proportion of patients experienced at least one event of alanine aminotransferase (ALT) increase of 3-fold or greater above the upper limit of normal (0.9% and 0.9% for all comparators versus TANZEUM). Three subjects on TANZEUM and one subject in the all-comparator group experienced at least one event of ALT increase of 10-fold or greater above the upper limit of normal. In one of the 3 cases an alternate etiology was identified to explain the rise in liver enzyme (acute viral hepatitis). In one case, insufficient information was obtained to establish or refute a drug-related causality. In the third case, elevation in ALT (10 times the upper limit of normal) was accompanied by an increase in total bilirubin (4 times the upper limit of normal) and occurred 8 days after the first dose of TANZEUM. The etiology of hepatocellular injury was possibly related to TANZEUM but direct attribution to TANZEUM was confounded by the presence of gallstone disease diagnosed on ultrasound 3 weeks after the event. Gamma Glutamyltransferase (GGT) Increase In the pool of placebo-controlled trials, the adverse event of increased GGT occurred more frequently in the group treated with TANZEUM (0.9% and 1.5% for placebo versus TANZEUM). Heart Rate Increase In the pool of placebo-controlled trials, mean heart rate in patients treated with TANZEUM was higher by an average of 1 to 2 bpm compared with mean heart rate in patients treated with placebo across study visits. The long-term clinical effects of the increase in heart rate have not been established [see Warnings and Precautions (5.6)]. 7 DRUG INTERACTIONS TANZEUM did not affect the absorption of orally administered medications tested in clinical pharmacology studies to any clinically relevant degree [see Clinical Pharmacology (12.3)]. However, TANZEUM causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with TANZEUM. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of TANZEUM in pregnant women. Nonclinical studies have shown reproductive toxicity, but not teratogenicity, in mice treated with albiglutide at up to 39 times human exposure resulting from the maximum recommended dose of 50 mg/week, based on AUC [see Nonclinical Toxicology (13.1, 13.3)]. TANZEUM should not be used during pregnancy unless the expected benefit outweighs the potential risks. Due to the long washout period for TANZEUM, consider stopping TANZEUM at least 1 month before a planned pregnancy. There are no data on the effects of TANZEUM on human fertility. Studies in mice showed no effects on fertility [see Nonclinical Toxicology (13.1)]. The potential risk to human fertility is unknown. 8.3 Nursing Mothers There are no adequate data to support the use of TANZEUM during lactation in humans. It is not known if TANZEUM is excreted into human milk during lactation. Given that TANZEUM is an albumin-based protein therapeutic, it is likely to be present in human milk. Decreased body weight in offspring was observed in mice treated with TANZEUM during gestation and lactation [see Nonclinical Toxicology (13.3)]. A decision should be made whether to discontinue nursing or to discontinue TANZEUM, taking into account the importance of the drug to the mother and the potential risks to the infant. 8.4 Pediatric Use Safety and effectiveness of TANZEUM have not been established in pediatric patients (younger than 18 years). 8.5 Geriatric Use Of the total number of patients (N = 2,365) in 8 Phase III clinical trials who received TANZEUM, 19% (N = 444) were 65 years and older, and <3% (N = 52) were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment Of the total number of patients (N = 2,365) in 8 Phase III clinical trials who received TANZEUM, 54% (N = 1,267) had mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2), 12% (N = 275) had moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2) and 1% (N = 19) had severe renal impairment (eGFR 15 to <30 mL/min/1.73 m2). No dosage adjustment is required in patients with mild (eGFR 60 to 89 mL/min/1.73 m2), moderate (eGFR 30 to 59 mL/min/1.73 m2), or severe (eGFR 15 to <30 mL/min/1.73 m2) renal impairment. Efficacy of TANZEUM in patients with type 2 diabetes and renal impairment is described elsewhere [see Clinical Studies (14.3)]. There is limited clinical experience in patients with severe renal impairment (19 subjects). The frequency of GI events increased as renal function declined. For patients with mild, moderate, or severe impairment, the respective event rates were: diarrhea (6%, 13%, 21%), nausea (3%, 5%, 16%), and vomiting (1%, 2%, 5%). Therefore, caution is recommended when initiating or escalating doses of TANZEUM in patients with renal impairment [see Dosage and Administration (2.3), Warnings and Precautions (5.5), Clinical Pharmacology (12.3)]. 10 OVERDOSAGE No data are available with regard to overdosage in humans. Anticipated symptoms of an overdose may be severe nausea, vomiting, and headache. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical signs and symptoms. A prolonged period of observation and treatment for these symptoms may be necessary, taking into account the half-life of TANZEUM (5 days). 11 DESCRIPTION TANZEUM is a GLP-1 receptor agonist, a recombinant fusion protein comprised of 2 tandem copies of modified human GLP-1 genetically fused in tandem to human albumin. The human GLP-1 fragment sequence 7 – 36 has been modified with a glycine substituted for the naturally-occurring alanine at position 8 in order to confer resistance to dipeptidylpeptidase IV (DPP-IV) mediated proteolysis. The human albumin moiety of the recombinant fusion protein, together with the DPP-IV resistance, extends the half-life allowing once-weekly dosing. TANZEUM has a molecular weight of 72,970 Daltons. TANZEUM is produced by a strain of Saccharomyces cerevisiae modified to express the therapeutic protein. TANZEUM 30-mg Pen for injection (for subcutaneous use) contains 40.3 mg lyophilized albiglutide and 0.65 mL Water for Injection diluent designed to deliver a dose of 30 mg in a volume of 0.5 mL after reconstitution. TANZEUM 50-mg Pen for injection (for subcutaneous use) contains 67 mg lyophilized albiglutide and 0.65 mL Water for Injection diluent designed to deliver a dose of 50 mg in a volume of 0.5 mL after reconstitution. The lyophilized powder of both dose strengths is white to yellow in color and the solvent is a clear and colorless solution. The reconstituted solution is yellow in color. Inactive ingredients include 153 mM mannitol, 0.01% (w/w) polysorbate 80, 10 mM sodium phosphate, and 117 mM trehalose dihydrate. TANZEUM does not contain a preservative. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action TANZEUM is an agonist of the GLP-1 receptor and augments glucose-dependent insulin secretion. TANZEUM also slows gastric emptying. 12.2 Pharmacodynamics TANZEUM lowers fasting glucose and reduces postprandial glucose excursions in patients with type 2 diabetes mellitus. The majority of the observed reduction in fasting plasma glucose occurs after a single dose, consistent with the pharmacokinetic profile of albiglutide. In a Phase II trial in Japanese patients with type 2 diabetes mellitus who received TANZEUM 30 mg, a reduction (22%) in postprandial glucose AUC(0-3 h) was observed at steady state (Week 16) compared with placebo following a mixed meal. A single dose of TANZEUM 50 mg subcutaneous (SC) did not impair glucagon response to low glucose concentrations. Gastric Motility TANZEUM slowed gastric emptying compared with placebo for both solids and liquids when albiglutide 100 mg (2 times the maximum approved dosage) was administered as a single dose in healthy subjects. Cardiac Electrophysiology At doses up to the maximum recommended dose (50 mg), TANZEUM does not prolong QTc to any clinically relevant extent. 12.3 Pharmacokinetics Absorption Following SC administration of a single 30-mg dose to subjects with type 2 diabetes mellitus, maximum concentrations of albiglutide were reached at 3 to 5 days post-dosing. The mean peak concentration (Cmax) and mean area under the time-concentration curve (AUC) of albiglutide were 1.74 mcg/mL and 465 mcg.h/mL, respectively, following a single dose of 30 mg albiglutide in type 2 diabetes mellitus subjects. Steady-state exposures are achieved following 4 to 5 weeks of once-weekly administration. Exposures at the 30-mg and 50-mg dose levels were consistent with a dose-proportional increase. Similar exposure is achieved with SC administration of albiglutide in the abdomen, thigh, or upper arm. The absolute bioavailability of albiglutide following SC administration has not been evaluated. Distribution The mean estimate of apparent volume of distribution of albiglutide following SC administration is 11 L. As albiglutide is an albumin fusion molecule, plasma protein binding has not been assessed. Metabolism Albiglutide is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by ubiquitous proteolytic enzymes. Classical biotransformation studies have not been performed. Because albiglutide is an albumin fusion protein, it likely follows a metabolic pathway similar to native human serum albumin which is catabolized primarily in the vascular endothelium. Elimination The mean apparent clearance of albiglutide is 67 mL/h with an elimination half-life of approximately 5 days, making albiglutide suitable for once-weekly administration. Specific Patient Populations Age, Gender, Race, and Body Weight: Based on the population pharmacokinetic analysis with data collected from 1,113 subjects, age, gender, race, and body weight had no clinically relevant effect on the pharmacokinetics of albiglutide. Pediatric: No pharmacokinetic data are available in pediatric patients. Renal: In a population pharmacokinetic analysis including a Phase III trial in patients with mild, moderate, and severe renal impairment, exposures were increased by approximately 30% to 40% in severe renal impairment compared with those observed in type 2 diabetic patients with normal renal function. Hepatic: No clinical trials were conducted to examine the effects of mild, moderate, or severe hepatic impairment on the pharmacokinetics of albiglutide. Therapeutic proteins such as albiglutide are catabolized by widely distributed proteolytic enzymes, which are not restricted to hepatic tissue; therefore, changes in hepatic function are unlikely to have any effect on the elimination of albiglutide. Drug Interactions In multiple-dose, drug-drug interaction trials no significant change in systemic exposures of the co-administered drugs were observed, except simvastatin (see Table 3). When albiglutide was co-administered with simvastatin, Cmax of simvastatin and its active metabolite simvastatin acid was increased by approximately 18% and 98%, respectively. In the same trial, AUC of simvastatin decreased by 40% and AUC of simvastatin acid increased by 36%. Clinical relevance of these changes has not been established (see Table 3). Additionally, no clinically relevant pharmacodynamic effects on luteinizing hormone, follicle-stimulating hormone, or progesterone were observed when albiglutide and a combination oral contraceptive were co-administered. Albiglutide did not significantly alter the pharmacodynamic effects of warfarin as measured by the international normalized ratio (INR). Table 3. Effect of Albiglutide on Systemic Exposure of Co-administered Drugs
a Single dose unless otherwise noted. b AUC inf for drugs given as a single dose and AUC 24h for drugs given as multiple doses. c Subjects received low-dose oral contraceptive for two 28-day treatment cycles (21 days active/7 days placebo). 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility As albiglutide is a recombinant protein, no genotoxicity studies have been conducted. Carcinogenicity of albiglutide could not be assessed in rodents due to the rapid development of drug-clearing, anti-drug antibodies. Other GLP-1 receptor agonists have caused thyroid C-cell tumors in rodent carcinogenicity studies. Human relevance of GLP-1 receptor agonist induced rodent thyroid C-cell tumors has not been determined. In a mouse fertility study, males were treated with SC doses of 5, 15, or 50 mg/kg/day for 7 days prior to cohabitation with females, and continuing through mating. In a separate fertility study, females were treated with SC doses of 1, 5, or 50 mg/kg/day for 7 days prior to cohabitation with males, and continuing through mating. Reductions in estrous cycles were observed at 50 mg/kg/day, a dose associated with maternal toxicity (body weight loss and reduced food consumption). There were no effects on mating or fertility in either sex at doses up to 50 mg/kg/day (up to 39 times clinical exposure based on AUC). 13.3 Reproductive and Developmental Toxicity In order to minimize the impact of the drug-clearing, anti-drug antibody response, reproductive and developmental toxicity assessments in the mouse were partitioned to limit the dosing period to no more than approximately 15 days in each study. In pregnant mice given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 1 to 6, there were no adverse effects on early embryonic development through implantation at 50 mg/kg/day (39 times clinical exposure based on AUC). In pregnant mice given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 6 through 15 (organogenesis), embryo-fetal lethality (post-implantation loss) and bent (wavy) ribs were observed at 50 mg/kg/day (39 times clinical exposure based on AUC), a dose associated with maternal toxicity (body weight loss and reduced food consumption). Pregnant mice were given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 6 to 17. Offspring of pregnant mice given 50 mg/kg/day (39 times clinical exposure based on AUC), a dose associated with maternal toxicity, had reduced body weight pre-weaning, dehydration and coldness, and a delay in balanopreputial separation. Pregnant mice were given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 15 to lactation Day 10. Increased mortality and morbidity were seen at all doses (≥1 mg/kg/day) in lactating females in mouse pre- and postnatal development studies. Mortalities have not been observed in previous toxicology studies in non-lactating or non-pregnant mice, nor in pregnant mice. These findings are consistent with lactational ileus syndrome which has been previously reported in mice. Since the relative stress of lactation energy demands is lower in humans than mice and humans have large energy reserves, the mortalities observed in lactating mice are of questionable relevance to humans. The offspring had decreased pre-weaning body weight which reversed post-weaning in males but not females at ≥5 mg/kg/day (2.2 times clinical exposure based on AUC) with no other effects on development. Low levels of albiglutide were detected in plasma of offspring. Lactating mice were given SC doses of 1, 5, or 50 mg/kg/day from lactation Day 7 to 21 (weaning) under conditions that limit the impact of lactational ileus (increased caloric intake and culling of litters). Doses ≥1 mg/kg/day (exposures below clinical AUC) caused reduced weight gain in the pups during the treatment period. 14 CLINICAL STUDIES TANZEUM has been studied as monotherapy and in combination with metformin, metformin and a sulfonylurea, a thiazolidinedione (with and without metformin), and insulin glargine (with or without oral anti-diabetic drugs). The efficacy of TANZEUM was compared with placebo, glimepiride, pioglitazone, liraglutide, sitagliptin, insulin lispro, and insulin glargine. Trials evaluated the use of TANZEUM 30 mg and 50 mg. Five of the 8 trials allowed optional uptitration of TANZEUM from 30 mg to 50 mg if glycemic response with 30 mg was inadequate. In patients with type 2 diabetes mellitus, TANZEUM produced clinically relevant reduction from baseline in HbA1c compared with placebo. No overall differences in glycemic effectiveness or body weight were observed across demographic subgroups (age, gender, race/ethnicity, duration of diabetes). 14.1 Monotherapy The efficacy of TANZEUM as monotherapy was evaluated in a 52-week, randomized, double-blind, placebo-controlled, multicenter trial. In this trial, 296 patients with type 2 diabetes inadequately controlled on diet and exercise were randomized (1:1:1) to TANZEUM 30 mg SC once weekly, TANZEUM 30 mg SC once weekly uptitrated to 50 mg once weekly at Week 12, or placebo. The mean age of participants was 53 years, 55% of patients were men, the mean duration of diabetes was 4 years, and the mean baseline eGFR was 84 mL/min/1.73 m2. Primary and secondary efficacy results are presented in Table 4. Figure 1 shows the mean adjusted changes in HbA1c from baseline across study visits. Compared with placebo, treatment with TANZEUM 30 mg or 50 mg resulted in statistically significant reductions in HbA1c from baseline at Week 52 (see Table 4). The adjusted mean change in weight from baseline did not differ significantly between TANZEUM (-0.4 to -0.9 kg) and placebo (-0.7 kg) at Week 52. Table 4. Results at Week 52 (LOCFa) in a Trial of TANZEUM as Monotherapy
Figure 1. Mean HbA1c Change from Baseline (ITT Population-LOCF) in a Trial of TANZEUM as Monotherapy
b Least squares mean adjusted for baseline value and stratification factors. c P <0.0137 for treatment difference. Figure 2. Mean HbA1c Over Time (ITT Population-LOCF) in a Trial Comparing TANZEUM with Placebo as Add-on Therapy in Patients Inadequately Controlled on Metformin
b Least squares mean adjusted for baseline value and stratification factors. c P <0.0001 for treatment difference. Add-on to Metformin Plus Sulfonylurea The efficacy of TANZEUM was evaluated in a 52-week randomized, double-blind, multicenter trial in 657 patients with type 2 diabetes mellitus inadequately controlled on metformin (≥1,500 mg daily) and glimepiride (4 mg daily). Patients were randomized to receive TANZEUM 30 mg SC weekly (with optional uptitration to 50 mg weekly after a minimum of 4 weeks), placebo, or pioglitazone 30 mg daily (with optional titration to 45 mg/day). The mean age of participants was 55 years, 53% of patients were men, the mean duration of type 2 diabetes was 9 years, and the mean baseline eGFR was 84 mL/min/1.73 m2. Results of the primary and main secondary analyses are presented in Table 7. Treatment with TANZEUM resulted in statistically significant reductions in HbA1c from baseline compared with placebo (see Table 7). Treatment with TANZEUM did not meet the pre-specified, non-inferiority margin (0.3%) against pioglitazone. In this trial, TANZEUM provided less HbA1c reduction than pioglitazone and the treatment difference was statistically significant (see Table 7). The change from baseline in body weight for TANZEUM did not differ significantly from placebo but was significantly different compared with pioglitazone (see Table 7). Table 7. Results at Week 52 (LOCFa) in a Trial Comparing TANZEUM with Placebo as Add-on Therapy in Patients Inadequately Controlled on Metformin Plus Sulfonylurea
b Least squares mean adjusted for baseline value and stratification factors. c P <0.0001 for treatment difference. d Did not meet non-inferiority margin of 0.3%. Combination Therapy: Active-controlled Trial versus Liraglutide The efficacy of TANZEUM was evaluated in a 32-week, randomized, open-label, liraglutide-controlled, non-inferiority trial in 805 patients with type 2 diabetes mellitus inadequately controlled on monotherapy or combination oral antidiabetic therapy (metformin, thiazolidinedione, sulfonylurea, or a combination of these). Patients were randomized to TANZEUM 30 mg SC weekly (with uptitration to 50 mg weekly at Week 6) or liraglutide 1.8 mg daily (titrated up from 0.6 mg at Week 1, and 1.2 mg at Week 1 to Week 2). The mean age of participants was 56 years, 50% of patients were men, the mean duration of type 2 diabetes was 8 years, and the mean baseline eGFR was 95 mL/min/1.73 m2. Results of the primary and main secondary analyses are presented in Table 8. The between-treatment difference of 0.2% with 95% confidence interval (0.08, 0.34) between TANZEUM and liraglutide did not meet the pre-specified, non-inferiority margin (0.3%). In this trial, TANZEUM provided less HbA1c reduction than liraglutide and the treatment difference was statistically significant (see Table 8). Table 8. Results of Controlled Trial of TANZEUM versus Liraglutide at Week 32 (LOCFa)
b Least squares mean adjusted for baseline value and stratification factors. c Did not meet non-inferiority margin of 0.3%. d P <0.005 for treatment difference in favor of liraglutide. Combination Therapy: Active-controlled Trial versus Basal Insulin The efficacy of TANZEUM was evaluated in a 52-week, randomized (2:1), open-label, insulin glargine-controlled, non-inferiority trial in 735 patients with type 2 diabetes mellitus inadequately controlled on metformin ≥1,500 mg daily (with or without sulfonylurea). Patients were randomized to receive TANZEUM 30 mg SC weekly (with optional uptitration to 50 mg weekly) or insulin glargine (median starting dose of 10 units and titrated weekly per prescribing information). The primary endpoint was change in HbA1c from baseline compared with insulin glargine. The starting total daily dose of insulin glargine ranged between 2 and 40 units (median daily dose of 10 units) and ranged between 3 and 230 units (median daily dose of 30 units) at Week 52. Sixty-nine percent of patients treated with TANZEUM were uptitrated to 50 mg SC weekly. The mean age of participants was 56 years, 56% of patients were men, the mean duration of type 2 diabetes was 9 years, and the mean baseline eGFR was 85 mL/min/1.73 m2. Results of the primary and main secondary analyses are presented in Table 9. The between-treatment difference of 0.1% with 95% confidence interval (-0.04%, 0.27%) for TANZEUM and insulin glargine met the pre-specified, non-inferiority margin (0.3%). A mean decrease in body weight was observed for TANZEUM compared with a mean increase in body weight for insulin glargine, and the difference in weight change was statistically significant (see Table 9). Table 9. Results at Week 52 (LOCFa) in a Trial Comparing TANZEUM with Insulin Glargine as Add-on Therapy in Patients Inadequately Controlled on Metformin ± Sulfonylurea
b Least squares mean adjusted for baseline value and stratification factors. c Met non-inferiority margin of 0.3%. d P <0.0001 in favor of insulin glargine. e P <0.0001. Figure 3. Mean HbA1c Change from Baseline (Completers) in a Trial Comparing TANZEUM with Insulin Glargine as Add-on Therapy in Patients Inadequately Controlled on Metformin (with or without a Sulfonylurea)
b Least squares mean adjusted for baseline value and stratification factors. c Rules out a non-inferiority margin of 0.4%. d P <0.0001 for treatment difference. Figure 4. Mean HbA1c Change from Baseline (ITT-LOCF population) in a Trial Comparing TANZEUM with Insulin Lispro as Add-On Therapy in Patients Inadequately Controlled on Insulin Glargine
14.3 Type 2 Diabetes Mellitus Patients with Renal Impairment
b Least squares mean adjusted for baseline value and stratification factors. c P <0.0003 for treatment difference. d P = 0.0281 for treatment difference. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied TANZEUM is available in the following strengths and package size: 30 mg single-dose Pen (NDC 0173-0866-01): • carton of 4 (containing four 29-gauge, 5-mm, thinwall needles): NDC 0173-0866-35 50 mg single-dose Pen (NDC 0173-0867-01): • carton of 4 (containing four 29-gauge, 5-mm, thinwall needles): NDC 0173-0867-35 16.2 Storage and Handling Prior to dispensing: Store Pens in the refrigerator at 36°F to 46°F (2°C to 8°C). Pens may be stored refrigerated until the expiration date. • Following dispensing: Store Pens in the refrigerator at 36°F to 46°F (2°C to 8°C). Patients may store Pens at room temperature not to exceed 86°F (30°C) for up to 4 weeks prior to use. Store Pens in the original carton until use. • Do not freeze. • Do not use past the expiration date. • Use within 8 hours after reconstitution. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). The Medication Guide is contained in a separate leaflet that accompanies the product. • Inform patients about self-management practices, including the importance of proper storage of TANZEUM, injection technique, timing of dosage of TANZEUM and concomitant oral drugs, and recognition and management of hypoglycemia. • Inform patients that thyroid C-cell tumors have been observed in rodents treated with some GLP-1 receptor agonists, and the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, dysphagia, dyspnea, or persistent hoarseness) to their physician [see Boxed Warning, Warnings and Precautions (5.1)]. • Advise patients that persistent, severe abdominal pain that may radiate to the back and which may (or may not) be accompanied by vomiting is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue TANZEUM promptly and to contact their physician if persistent, severe abdominal pain occurs [see Warnings and Precautions (5.2)]. • The risk of hypoglycemia is increased when TANZEUM is used in combination with an agent that induces hypoglycemia, such as sulfonylurea or insulin. Instructions for hypoglycemia should be reviewed with patients and reinforced when initiating therapy with TANZEUM, particularly when concomitantly administered with a sulfonylurea or insulin [see Warnings and Precautions (5.3)]. • Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking TANZEUM and seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.4)]. • Instruct patients to read the Instructions for Use before starting therapy. Instruct patients on proper use, storage, and disposal of the pen [see How Supplied/Storage and Handling (16.2), Patient Instructions for Use]. • Instruct patients to read the Medication Guide before starting TANZEUM and to read again each time the prescription is renewed. Instruct patients to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens. • Inform patients not to take an extra dose of TANZEUM to make up for a missed dose. If a dose is missed, instruct patients to take a dose as soon as possible within 3 days after the missed dose. Instruct patients to then take their next dose at their usual weekly time. If it has been longer than 3 days after the missed dose, instruct patients to wait and take TANZEUM at the next usual weekly time. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5fcad939-76e7-49cf-af94-4e6aef17901f | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
