Albiglutide

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# Black Box Warning

# Overview
Albiglutide is an antidiabetic drug that is FDA approved for the treatment of type 2 diabetes mellitus in adults. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include upper respiratory tract infection, diarrhea, nausea, and injection site reaction..

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

# Indications
- TANZEUM is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

# Limitations of Use
- Albiglutide 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 albiglutide only to patients for whom the potential benefits are considered to outweigh the potential risk.
- Albiglutide has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.
- Albiglutide is not indicated in the treatment of patients with type 1 diabetes mellitus or for the treatment of patients with diabetic ketoacidosis. Albiglutide is not a substitute for insulin in these patients.
- Albiglutide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis. The use of albiglutide is not recommended in patients with pre-existing severe gastrointestinal disease.
- Albiglutide has not been studied in combination with prandial insulin.

# Dosage
- The recommended dosage of albiglutide 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.
- Albiglutide may be administered at any time of day without regard to meals. Instruct patients to administer albiglutide 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.
Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
- When initiating albiglutide, consider reducing the dosage of concomitantly administered insulin secretagogues (e.g., sulfonylureas) or insulin to reduce the risk of hypoglycemia.
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 albiglutide in patients with renal impairment. Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions.
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.Albiglutide.com. Instruct patients as follows:
Pen Reconstitution
- Hold the Pen body with the clear cartridge pointing up to see the  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  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 albiglutide. 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 Albiglutide 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.
Alternate Method of Reconstitution
- 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  in the number window and expiration date.
- Twisted the clear cartridge until  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.

# DOSAGE FORMS AND STRENGTHS
- Albiglutide 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.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Albiglutide in adult patients.

### NonGuideline-Supported Use
- There is limited information regarding Off-Label NonGuideline-Supported Use of Albiglutide in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Albiglutide in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Albiglutide in pediatric patients.

### NonGuideline-Supported Use
- There is limited information regarding Off-Label NonGuideline-Supported Use of Albiglutide in pediatric patients.

# Contraindications
Medullary Thyroid Carcinoma
- Albiglutide 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).
Hypersensitivity
- Albiglutide is contraindicated in patients with a prior serious hypersensitivity reaction to albiglutide or to any of the product components.

# Warnings
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. 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 albiglutide causes thyroid C-cell tumors, including MTC, in humans.
- Across 8 Phase III clinical trials, MTC was diagnosed in 1 patient receiving albiglutide 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.
- Albiglutide 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 albiglutide 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 albiglutide. 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.
Acute Pancreatitis
- In clinical trials, acute pancreatitis has been reported in association with albiglutide.
- Across 8 Phase III clinical trials, pancreatitis adjudicated as likely related to therapy occurred more frequently in patients receiving albiglutide (6 of 2,365 ) than in patients receiving placebo (0 of 468 ) or active comparators (2 of 2,065 ).
- After initiation of albiglutide, 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 albiglutide. If pancreatitis is confirmed, albiglutide should not be restarted.
- Albiglutide 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.
Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
- The risk of hypoglycemia is increased when albiglutide 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.
Hypersensitivity Reactions
Across 8 Phase III clinical trials, a serious hypersensitivity reaction with pruritus, rash, and dyspnea occurred in a patient treated with albiglutide. If hypersensitivity reactions occur, discontinue use of albiglutide; treat promptly per standard of care and monitor until signs and symptoms resolve.
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 albiglutide in patients with renal impairment, the frequency of such gastrointestinal reactions increased as renal function declined. Because these reactions may worsen renal function, use caution when initiating or escalating doses of albiglutide in patients with renal impairment.
Macrovascular Outcomes
- There have been no clinical trials establishing conclusive evidence of macrovascular risk reduction with albiglutide or any other antidiabetic drug.

# Adverse Reactions

## Clinical Trials Experience
- The following serious reactions are described below or elsewhere in the prescribing information:
- Risk of Thyroid C-cell Tumors
- Acute Pancreatitis
- Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
- Hypersensitivity Reactions
- Renal Impairment

# 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. Albiglutide was used as monotherapy in 1 trial and as add-on therapy in 3 trials. These data reflect exposure of 923 patients to albiglutide and a mean duration of exposure to albiglutide 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 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 albiglutide in the pool of placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on albiglutide than on placebo, and occurred in at least 5% of patients treated with albiglutide.
Gastrointestinal Adverse Reactions
- In the pool of placebo-controlled trials, gastrointestinal complaints occurred more frequently among patients receiving albiglutide (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 albiglutide: vomiting (2.6% versus 4.2% for placebo versus albiglutide), gastroesophageal reflux disease (1.9% versus 3.5% for placebo versus albiglutide), and dyspepsia (2.8% versus 3.4% for placebo versus albiglutide). Constipation also contributed to the frequently reported reactions. In the group treated with albiglutide, 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 albiglutide or placebo.
Injection Site Reactions
- In the pool of placebo-controlled trials, injection site reactions occurred more frequently on albiglutide (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 albiglutide: injection site hematoma (1.9% versus 2.1% for placebo versus albiglutide ), injection site erythema (0.4% versus 1.7% for placebo versus albiglutide), injection site rash (0% versus 1.4% for placebo versus albiglutide), injection site hypersensitivity (0% versus 0.8% for placebo versus albiglutide), and injection site hemorrhage (0.6% versus 0.7% for placebo versus albiglutide). 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 albiglutide versus 94% for placebo). More patients on albiglutide 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 albiglutide as monotherapy, and as add-on therapy to oral antidiabetic agents, and as add-on therapy to basal insulin. In this pool, a total of 2,116 patients with type 2 diabetes were treated with albiglutide for a mean duration of 75 weeks. The mean age of patients treated with albiglutide 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 albiglutide and the proportion of patients experiencing at least one severe hypoglycemic episode on TANZEUM in clinical trials is shown in Table 2. Hypoglycemia was more frequent when TANZEUM was added to sulfonylurea or insulin.
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 albiglutide were serious (0.4% for albiglutide 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 albiglutide 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 albiglutide 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 albiglutide 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 albiglutide). Three subjects on albiglutide 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 albiglutide. The etiology of hepatocellular injury was possibly related to albiglutide but direct attribution to albiglutide 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.

## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Albiglutide in the drug label.

# Drug Interactions
- TANZEUM did not affect the absorption of orally administered medications tested in clinical pharmacology studies to any clinically relevant degree. 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.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
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 . 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. The potential risk to human fertility is unknown.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Albiglutide in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Albiglutide during labor and delivery.

### 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. 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.

### Pediatric Use
- Safety and effectiveness of TANZEUM have not been established in pediatric patients (younger than 18 years).

### Geriatic 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.

### Gender
There is no FDA guidance on the use of Albiglutide with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Albiglutide with respect to specific racial populations.

### 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. 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.

### Hepatic Impairment
There is no FDA guidance on the use of Albiglutide in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Albiglutide in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Albiglutide in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Subcutaneous
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  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.

### Monitoring
There is limited information regarding Monitoring of Albiglutide in the drug label.

# IV Compatibility
- There is limited information regarding IV Compatibility of Albiglutide in the drug label.

# Overdosage
- No data are available with regard to overdosage in humans. Anticipated symptoms of an overdose may be severe nausea and vomiting.
- In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patients 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).

# Pharmacology

## Mechanism of Action
- TANZEUM is an agonist of the GLP-1 receptor and augments glucose-dependent insulin secretion. TANZEUM also slows gastric emptying.

## Structure
There is limited information regarding Albiglutide Structure in the drug label.

## 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.

## 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).

## Nonclinical Toxicology
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).
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.

# 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).
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.
Combination Therapy
Add-on to Metformin
- The efficacy of TANZEUM was evaluated in a 104-week randomized, double-blind, multicenter trial in 999 patients with type 2 diabetes mellitus inadequately controlled on background metformin therapy (1,500 mg daily). In this trial, TANZEUM 30 mg SC weekly (with optional uptitration to 50 mg weekly after a minimum of 4 weeks) was compared with placebo, sitagliptin 100 mg daily, or glimepiride 2 mg daily (with optional titration to 4 mg daily). The mean age of participants was 55 years, 48% of patients were men, the mean duration of type 2 diabetes was 6 years, and the mean baseline eGFR was 86 mL/min/1.73 m2. Results of the primary and secondary analyses are presented in Table 5. Figure 2 shows the mean adjusted changes in HbA1c across study visits.
- Reduction in HbA1c from baseline achieved with TANZEUM was significantly greater than HbA1c reduction achieved with placebo, sitagliptin, and glimepiride at Week 104 (see Table 5). The difference in body weight change from baseline between TANZEUM and glimepiride was significant at Week 104.
Add-on to Pioglitazone
- The efficacy of TANZEUM was evaluated in a 52-week randomized, double-blind, multicenter trial in 299 patients with type 2 diabetes mellitus inadequately controlled on pioglitazone 30 mg daily (with or without metformin 1,500 mg daily). Patients were randomized to receive TANZEUM 30 mg SC weekly or placebo. The mean age of participants was 55 years, 60% of patients were men, the mean duration of type 2 diabetes was 8 years, and the mean baseline eGFR was 83 mL/min/1.73 m2. Results of the primary and secondary analyses are presented in Table 6.
- Compared with placebo, treatment with TANZEUM resulted in a statistically significant reduction in HbA1c from baseline at Week 52 (see Table 6). The adjusted mean change from baseline in weight did not differ significantly between TANZEUM (+0.3 kg) and placebo (+0.5 kg) at Week 52.
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).
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).
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 (started at 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. Seventy-seven 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).
Combination Therapy: Active-controlled Trial versus Prandial Insulin
- The efficacy of TANZEUM was evaluated in a 26-week, randomized, open-label, multicenter, non-inferiority trial in 563 patients with type 2 diabetes mellitus inadequately controlled on insulin glargine (started at 10 units and titrated to 20 units per day). Patients were randomized to receive TANZEUM 30 mg SC once weekly (with uptitration to 50 mg if inadequately controlled after Week 8) or insulin lispro (administered daily at meal times, started according to standard of care and titrated to effect). At Week 26, the mean daily dose of insulin glargine was 53 IU for TANZEUM and 51 IU for insulin lispro. The mean daily dose of insulin lispro at Week 26 was 31 IU, and 69% of patients treated with TANZEUM were on 50 mg weekly. The mean age of participants was 56 years, 47% of patients were men, the mean duration of type 2 diabetes was 11 years, and the mean baseline eGFR was 91 mL/min/1.73 m2. Results of the primary and main secondary analyses are presented in Table 10. Figure 4 shows the mean adjusted changes in HbA1c from baseline across study visits.
- The between-treatment difference of -0.2% with 95% confidence interval (-0.32%, 0.00%) between albiglutide and insulin lispro met the pre-specified non-inferiority margin (0.4%). Treatment with TANZEUM resulted in a mean weight loss for TANZEUM compared with a mean weight gain for insulin lispro, and the difference between treatment groups was statistically significant (see Table 10).
Type 2 Diabetes Mellitus Patients with Renal Impairment
- The efficacy of TANZEUM was evaluated in a 26-week, randomized, double-blind, active-controlled trial in 486 patients with mild (n = 250), moderate (n = 200), and severe renal impairment (n = 36) inadequately controlled on a current regimen of diet and exercise or other antidiabetic therapy. Patients were randomized to receive TANZEUM 30 mg SC weekly (with uptitration to 50 mg weekly if needed as early as Week 4) or sitagliptin. Sitagliptin was dosed according to renal function (100 mg, 50 mg, and 25 mg daily in mild, moderate, and severe renal impairment, respectively). The mean age of participants was 63 years, 54% of patients were men, the mean duration of type 2 diabetes was 11 years, and the mean baseline eGFR was 60 mL/min/1.73 m2.
- Results of the primary and main secondary analyses are presented in Table 11. Treatment with TANZEUM resulted in statistically significant reductions in HbA1c from baseline at Week 26 compared with sitagliptin (see Table 11).

# 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

## Storage
- Prior to dispensing: Store Pens in the refrigerator at 36F to 46F (2C to 8C). Pens may be stored refrigerated until the expiration date.
- Following dispensing: Store Pens in the refrigerator at 36F to 46F (2C to 8C). Patients may store Pens at room temperature not to exceed 86F (30C) 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.

# Images

## Drug Images

## Package and Label Display Panel
[File:Albiglutide medication guide.png[

# Patient Counseling Information
- See 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.
- 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.
- 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.
- Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking TANZEUM and seek medical advice promptly if such symptoms occur.
- Instruct patients to read the Instructions for Use before starting therapy.
- Instruct patients on proper use, storage, and disposal of the pen.
- 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.

# Precautions with Alcohol
- Alcohol-Albiglutide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- TANZEUM 

# Look-Alike Drug Names
- A  B

# Drug Shortage Status

# Price