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 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

a)

Hold the Pen body with the clear cartridge pointing up to see the [1] in the number window.

b)

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.

c)

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.

d)

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

e)

Slowly and gently rock the Pen side-to-side 5 additional times to mix the reconstituted solution.

f)

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.

g)

Holding the Pen upright, attach the needle to the Pen by pushing it straight down until there is a click and the needle snaps into place. 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.

a)

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.

b)

Hold the Pen with the clear cartridge pointing up and maintain this orientation throughout the reconstitution.

c)

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.

d)

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.

e)

After reconstitution, continue to follow the steps in the Instructions for Use, starting at Step B: Attach the Needle.

2.4 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.

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 2,062 [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

Serious hypersensitivity reactions (including angioedema and generalized pruritus and rash with dyspnea) have been reported with TANZEUM. If hypersensitivity reactions occur, discontinue use of TANZEUM; treat promptly per standard of care, and monitor until signs and symptoms resolve. Do not use in patients with a previous hypersensitivity reaction to TANZEUM [see Contraindications (4)].

Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to these reactions with TANZEUM.

5.5 Acute Kidney Injury

There have been postmarketing cases of worsening renal function and acute kidney injury in patients treated with TANZEUM, some of which required hemodialysis. Some of the postmarketing events were reported in the absence of gastrointestinal adverse reactions and in patients without known underlying renal disease.

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 and/or in those reporting severe gastrointestinal symptoms. Advise patients treated with TANZEUM of the potential risk of dehydration in relation to gastrointestinal side effects and to take precautions to avoid fluid depletion [see 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.

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

a Adverse reactions reported include those occurring with the use of glycemic rescue medications which included metformin (17% for placebo and 10% for TANZEUM) and insulin (24% for placebo and 14% for TANZEUM).

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, 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 frequencies 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

OAD = Oral antidiabetic agents.

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 was 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.

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)].

6.2 Immunogenicity

Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with TANZEUM may develop anti-albiglutide antibodies. 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 in the studies described below cannot be directly compared with the incidence of antibodies in other studies or to other products.

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.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of TANZEUM. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Angioedema.

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 and/or in those reporting severe gastrointestinal symptoms [see Warnings and Precautions (5.5), Clinical Pharmacology (12.3)].

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 subjects with type 2 diabetes mellitus. 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 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 Patients: No pharmacokinetic data are available in pediatric patients.

Patients with Renal Impairment: 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.

Patients with Hepatic Impairment: 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 Interaction Studies

In multiple-dose, drug-drug interaction trials no significant change in systemic exposures of the coadministered drugs were observed, except simvastatin (see Table 3). When albiglutide was coadministered 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 coadministered. 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 Coadministered Drugs

qw = Once weekly.

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).

13.1 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 Days 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 Days 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 Days 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 Days 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.

14.1 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

a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 52, primary efficacy data was imputed for 63%, 34%, and 41% of individuals randomized to placebo, TANZEUM 30 mg, and TANZEUM 50 mg, respectively.

b Least squares mean adjusted for baseline value and stratification factors.

c P <0.0001 for treatment difference.

Figure 1. Mean HbA1c Change from Baseline (ITT Population-LOCF) in a Trial of TANZEUM as Monotherapy

14.2 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.

Table 5. Results at Week 104 (LOCFa) in a Trial Comparing TANZEUM with Placebo as Add-On Therapy in Patients Inadequately Controlled on Metformin

a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 104, primary efficacy data was imputed for 76%, 46%, 55%, and 51% of individuals randomized to placebo, TANZEUM, sitagliptin, and glimepiride, respectively.

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

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.

Table 6. Results at Week 52 (LOCFa) in a Trial Comparing TANZEUM with Placebo as Add-On Therapy in Patients Inadequately Controlled on Pioglitazone (with or without Metformin)

a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 52, primary efficacy data was imputed for 58% and 32% of individuals randomized to placebo and TANZEUM, respectively.

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

a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 52, primary efficacy data was imputed for 70%, 35%, and 34% of individuals randomized to placebo, TANZEUM, and pioglitazone, respectively.

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 from 1.2 mg at 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)

a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 32, primary efficacy data was imputed for 31% and 24% of individuals randomized to TANZEUM and liraglutide, respectively.

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

a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 52, primary efficacy data was imputed for 41% and 36% of individuals randomized to TANZEUM and insulin glargine, respectively.

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)

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 (≥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 51% 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).

Table 10. Results at Week 26 (LOCFa) in a Trial Comparing TANZEUM with Insulin Lispro as Add-On Therapy in Patients Inadequately Controlled on Insulin Glargine

a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 26, primary efficacy data was imputed for 29% and 29% of individuals randomized to TANZEUM and insulin lispro, respectively.

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

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).

Table 11. Results at Week 26 (LOCFa) in a Trial Comparing TANZEUM with Sitagliptin in Patients with Renal Impairment

a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 26 primary efficacy data was imputed for 17% and 25% of individuals randomized to TANZEUM and sitagliptin, respectively.

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.

16.1 How Supplied

TANZEUM is available in the following strengths and package size:

30-mg single-dose Pen (NDC 0173-0866-01):

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carton of 4 (containing four 29-gauge, 5-mm, thinwall needles): NDC 0173-0866-35

50-mg single-dose Pen (NDC 0173-0867-01):

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carton of 4 (containing four 29-gauge, 5-mm, thinwall needles): NDC 0173-0867-35

16.2 Storage and Handling

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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.

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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.

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Do not freeze.

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Do not use past the expiration date.

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Use within 8 hours after reconstitution.