Limitations of Use

Alogliptin and metformin HCl tablets should not recommended for use in patients with type 1 diabetes mellitus.

2.1 Recommended Dosage

• Individualize the starting dosage of alogliptin and metformin HCl tablets based on the patient’s current regimen.
• Alogliptin and metformin HCl tablets should be taken orally twice daily with food with gradual dose escalation to reduce the gastrointestinal (GI) side effects due to metformin. Do not split tablets.
• Adjust the dosage based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg alogliptin and 2000 mg metformin hydrochloride (HCl).

2.2 Recommendations for Use in Renal Impairment

• Assess renal function prior to initiation of alogliptin and metformin HCl tablets and periodically thereafter.
• Alogliptin and metformin HCl tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2 [see Contraindications (4), Warnings and Precautions (5.1)].
• Alogliptin and metformin HCl tablets are not recommended in patients with an eGFR between 30 and 59 mL/min/1.73 m2 because these patients require a lower daily dosage of alogliptin than what is available in the fixed combination alogliptin and metformin HCl tablets product.
• Alogliptin and metformin HCl tablets require no dose adjustment in patients with an eGFR of 60 mL/min/1.73 m2 or greater.

2.3 Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue alogliptin and metformin HCl tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart alogliptin and metformin HCl tablets if renal function is stable [see Warnings and Precautions (5.1)].

5.1 Lactic Acidosis

5.2 Pancreatitis

Acute pancreatitis has been reported in the postmarketing setting and in randomized clinical trials. In glycemic control trials in patients with type 2 diabetes mellitus, acute pancreatitis was reported in 6 (0.2%) patients treated with alogliptin 25 mg and 2 (<0.1%) patients treated with active comparators or placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes mellitus and high cardiovascular (CV) risk), acute pancreatitis was reported in 10 (0.4%) patients treated with alogliptin and in 7 (0.3%) patients treated with placebo.

It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using alogliptin and metformin HCl tablets.

After initiation of alogliptin and metformin HCl tablets, patients should be observed for signs and symptoms of pancreatitis. If pancreatitis is suspected, alogliptin should promptly be discontinued and appropriate management should be initiated.

5.3 Heart Failure

In the EXAMINE trial which enrolled patients with type 2 diabetes mellitus and recent acute coronary syndrome, 106 (3.9%) of patients treated with alogliptin and 89 (3.3%) of patients treated with placebo were hospitalized for congestive heart failure.

Consider the risks and benefits of alogliptin and metformin HCl tablets prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Patients should be advised of the characteristic symptoms of heart failure and should be instructed to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of alogliptin and metformin HCl tablets.

5.4 Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin [see Adverse Reactions (6.2)]. These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue alogliptin and metformin HCl tablets, assess for other potential causes for the event and institute alternative treatment for diabetes mellitus. Use caution in patients with a history of angioedema with another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with alogliptin and metformin HCl tablets.

5.5 Hepatic Effects

There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking alogliptin, although some of the reports contain insufficient information necessary to establish the probable cause [see Adverse Reactions (6.2)].

In glycemic control trials in patients with type 2 diabetes mellitus, serum alanine aminotransferase (ALT) elevations greater than three times the upper limit of normal (ULN) were reported in 1.3% of patients treated with alogliptin 25 mg and 1.7% of patients treated with active comparators or placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes mellitus and high cardiovascular (CV) risk), increases in serum alanine aminotransferase three times the upper limit of the reference range occurred in 2.4% of patients treated with alogliptin and in 1.8% of patients treated with placebo.

Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have clinically significant liver enzyme elevations and if abnormal liver tests persist or worsen, alogliptin and metformin HCl tablets should be interrupted and investigation done to establish the probable cause. Alogliptin and metformin HCl tablets should not be restarted in these patients without another explanation for the liver test abnormalities.

5.6 Vitamin B12 Levels

In metformin clinical trials of 29 week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2 to 3 year intervals in patients on alogliptin with metformin and manage any abnormalities [see Adverse Reactions (6.1)].

5.7 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues

Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dosage of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with alogliptin and metformin HCl tablets.

5.8 Severe and Disabling Arthralgia

There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.

5.9 Bullous Pemphigoid

Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving alogliptin and metformin HCl tablets. If bullous pemphigoid is suspected, alogliptin and metformin HCl tablets should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postmarketing use. 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.

Metformin HCl

Alogliptin

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

There is the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some premenopausal anovulatory women.

8.4 Pediatric Use

The safety and effectiveness of alogliptin and metformin HCl tablets have not been established in pediatric patients.

Effectiveness of alogliptin was not demonstrated in a 52 week, randomized, double-blind, placebo-controlled trial (NCT02856113) in 151 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus.

8.5 Geriatric Use

8.6 Renal Impairment

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Alogliptin and metformin HCl tablets are contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m2 [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Alogliptin and metformin HCl tablets are not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].

Alogliptin

Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)].

In the event of an overdose, it is reasonable to institute the necessary clinical monitoring and supportive therapy as dictated by the patient's clinical status. Per clinical judgment, it may be reasonable to initiate removal of unabsorbed material from the gastrointestinal tract.

Alogliptin is minimally dialyzable; over a three-hour hemodialysis session, approximately 7% of the drug was removed. Therefore, hemodialysis is unlikely to be beneficial in an overdose situation. It is not known if alogliptin is dialyzable by peritoneal dialysis.

Metformin HCl

Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

In the event of an overdose, contact the Poison Help Line, call (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

Alogliptin

Alogliptin is a selective, orally bioavailable inhibitor of the enzymatic activity of DPP-4. Chemically, alogliptin is prepared as a benzoate salt, which is identified as 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile monobenzoate. It has a molecular formula of C18H21N5O2∙C7H6O2 and a molecular weight of 461.51 daltons; the structural formula is:

Alogliptin benzoate is a white to off-white crystalline powder containing one asymmetric carbon in the aminopiperidine moiety. It is soluble in dimethylsulfoxide, sparingly soluble in water and methanol, slightly soluble in ethanol and very slightly soluble in octanol and isopropyl acetate.

Metformin HCl

Metformin HCl (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin HCl is a white to off-white crystalline compound with a molecular formula of C4H11N5∙HCl and a molecular weight of 165.63. Metformin HCl is freely soluble in water and is practically insoluble in acetone, ether and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin HCl is 6.68. The structural formula is as shown:

Alogliptin and metformin HCl tablets are available as a tablet for oral administration containing 17 mg alogliptin benzoate equivalent to 12.5 mg alogliptin and:

• 500 mg metformin HCl which is equivalent to 389.93 mg metformin base (12.5 mg/500 mg) or
• 1000 mg metformin HCl which is equivalent to 779.86 mg metformin base (12.5 mg/1000 mg).

Alogliptin and metformin HCl tablets contain the following inactive ingredients: crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, and povidone; the tablets are film-coated with ferric oxide yellow, hypromellose 2910, talc, and titanium dioxide.

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Overview of Clinical Trials in Adults with Type 2 Diabetes Mellitus

The coadministration of alogliptin and metformin has been studied in patients with type 2 diabetes mellitus inadequately controlled on either diet and exercise alone, on metformin alone or metformin in combination with a thiazolidinedione.

A total of 2,114 patients with type 2 diabetes mellitus were randomized in three double-blind, placebo- or active-controlled clinical safety and efficacy trials conducted to evaluate the effects of alogliptin and metformin HCl tablets on glycemic control. Among those, 2,095 patients were exposed to the trial medication. The racial distribution of patients exposed to trial medication was 69% White, 16% Asian, 7% Black or African American, 2% American Indian or Alaska Native, 0% Native Hawaiian/Other Pacific Islander and 6% Multiracial or other racial groups. The ethnic distribution was 24% Hispanic or Latino. Patients had an overall mean age of approximately 54.4 years (range 22 to 80 years). In patients with type 2 diabetes mellitus, treatment with alogliptin and metformin HCl tablets produced clinically meaningful and statistically significant improvements in A1C versus comparator. As is typical for trials of agents to treat type 2 diabetes mellitus, the mean reduction in hemoglobin A1c (A1C) with alogliptin and metformin HCl tablets appears to be related to the degree of A1C elevation at baseline.

14.2 Alogliptin and Metformin Coadministration in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Diet and Exercise

In a 26 week, double-blind, placebo-controlled trial, a total of 784 patients inadequately controlled on diet and exercise alone (mean baseline A1C = 8.4%) were randomized to one of seven treatment groups: placebo; metformin HCl 500 mg or metformin HCl 1000 mg twice daily, alogliptin 12.5 mg twice daily, or alogliptin 25 mg daily; alogliptin 12.5 mg in combination with metformin HCl 500 mg or metformin HCl 1000 mg twice daily. Both coadministration treatment arms (alogliptin 12.5 mg + metformin HCl 500 mg and alogliptin 12.5 mg + metformin HCl 1000 mg) resulted in significant improvements in A1C (Figure 3) and FPG when compared with their respective individual alogliptin and metformin component regimens (Table 6). Coadministration treatment arms demonstrated improvements in two-hour postprandial glucose (PPG) compared to alogliptin alone or metformin alone (Table 6). A total of 12% of patients receiving alogliptin 12.5 mg + metformin HCl 500 mg, 3% of patients receiving alogliptin 12.5 mg + metformin HCl 1000 mg, 17% of patients receiving alogliptin 12.5 mg, 23% of patients receiving metformin HCl 500 mg, 11% of patients receiving metformin HCl 1000 mg and 39% of patients receiving placebo required glycemic rescue.

Improvements in A1C were not affected by gender, age, race or baseline BMI. The mean decrease in body weight was similar between metformin alone and alogliptin when coadministered with metformin HCl. Lipid effects were neutral.

Figure 3. Change from Baseline A1C at Week 26 with Alogliptin and Metformin Alone and Alogliptin in Combination with Metformin

14.3 Alogliptin and Metformin Coadministration in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin Alone

In a 26 week, double-blind, placebo-controlled trial, a total of 527 patients already on metformin (mean baseline A1C = 8%) were randomized to receive alogliptin 12.5 mg, alogliptin 25 mg, or placebo once daily. Patients were maintained on a stable dose of metformin HCl (median daily dose = 1700 mg) during the treatment period. Alogliptin 25 mg in combination with metformin resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, when compared to placebo (Table 7). A total of 8% of patients receiving alogliptin 25 mg and 24% of patients receiving placebo required glycemic rescue. Improvements in A1C were not affected by gender, age, race, baseline BMI or baseline metformin dose.

The mean decrease in body weight was similar between alogliptin 25 mg and placebo when given in combination with metformin. Lipid effects were also neutral.

14.4 Alogliptin Add-On Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on the Combination of Metformin and Pioglitazone

In a 52 week, active-comparator trial, a total of 803 patients inadequately controlled (mean baseline A1C = 8.2%) on a current regimen of pioglitazone 30 mg and metformin were randomized to either receive the addition of once-daily alogliptin 25 mg or the titration of pioglitazone 30 mg to 45 mg following a four week single-blind, placebo run-in period. Patients were maintained on a stable dose of metformin HCl (median daily dose = 1700 mg). Patients who failed to meet prespecified hyperglycemic goals during the 52 week treatment period received glycemic rescue therapy.

In combination with pioglitazone and metformin, alogliptin 25 mg was shown to be statistically superior in lowering A1C and FPG compared with the titration of pioglitazone from 30 to 45 mg at Week 26 and at Week 52 (Table 8). A total of 11% of patients in the alogliptin 25 mg in combination with pioglitazone 30 mg and metformin treatment group and 22% of patients in the up titration of pioglitazone in combination with metformin treatment group required glycemic rescue. Improvements in A1C were not affected by gender, age, race or baseline BMI.

The mean increase in body weight was similar in both treatment arms. Lipid effects were neutral.

14.5 Cardiovascular Safety Trial

A randomized, double-blind, placebo-controlled cardiovascular outcomes trial (EXAMINE) was conducted to evaluate the cardiovascular risk of alogliptin. The trial compared the risk of major adverse cardiovascular events (MACE) between alogliptin (N=2701) and placebo (N=2679) when added to standard of care therapies for diabetes mellitus and atherosclerotic vascular disease (ASCVD). The trial was event driven and patients were followed until a sufficient number of primary outcome events accrued.

Eligible patients were adults with type 2 diabetes mellitus who had inadequate glycemic control at baseline (e.g., HbA1c >6.5%) and had been hospitalized for an acute coronary syndrome event (e.g., acute myocardial infarction or unstable angina requiring hospitalization) 15 to 90 days prior to randomization. The dose of alogliptin was based on estimated renal function at baseline per dosage and administration recommendations. The average time between an acute coronary syndrome event and randomization was approximately 48 days.

The mean age of the population was 61 years. Most patients were male (68%), White (73%), and were recruited from outside of the United States (86%). Asian and Black or African American patients contributed 20% and 4% of the total population, respectively. At the time of randomization patients had a diagnosis of type 2 diabetes mellitus for approximately 9 years, 87% had a prior myocardial infarction and 14% were current smokers. Hypertension (83%) and renal impairment (27% with an eGFR ≤60 mL/min/1.73 m2) were prevalent co-morbid conditions. Use of medications to treat diabetes mellitus (e.g., metformin 73%, sulfonylurea 54%, insulin 41%), and ASCVD (e.g., statin 94%, aspirin 93%, renin-angiotensin system blocker 88%, beta-blocker 87%) was similar between patients randomized to alogliptin and placebo at baseline. During the trial, medications to treat diabetes mellitus and ASCVD could be adjusted to ensure care for these conditions adhered to standard of care recommendations set by local practice guidelines.

The primary endpoint in EXAMINE was the time to first occurrence of a MACE defined as the composite of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke. The trial was designed to exclude a pre-specified risk margin of 1.3 for the hazard ratio of MACE. The median exposure to trial drug was 526 days and 95% of the patients were followed to trial completion or death.

Table 9 shows the trial results for the primary MACE composite endpoint and the contribution of each component to the primary MACE endpoint. The upper bound of the confidence interval was 1.16 and excluded a risk margin larger than 1.3.

The Kaplan-Meier based cumulative event probability is presented in Figure 4 for the time to first occurrence of the primary MACE composite endpoint by treatment arm. The curves for placebo and alogliptin overlap throughout the duration of the trial. The observed incidence of MACE was highest within the first 60 days after randomization in both treatment arms (14.8 MACE per 100 PY), decreased from day 60 to the end of the first year (8.4 per 100 PY) and was lowest after 1 year of follow-up (5.2 per 100 PY).

Figure 4. Observed Cumulative Rate of MACE in EXAMINE

The rate of all cause death was similar between treatment arms with 153 (3.6 per 100 PY) recorded among patients randomized to alogliptin and 173 (4.1 per 100 PY) among patients randomized to placebo. A total of 112 deaths (2.9 per 100 PY) among patients on alogliptin and 130 among patients on placebo (3.5 per 100 PY) were adjudicated as cardiovascular deaths.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed.

Lactic Acidosis

• Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue alogliptin and metformin HCl tablets immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving alogliptin with metformin HCl tablets. Instruct patients to inform their doctor that they are taking alogliptin with metformin HCl tablets prior to any surgical or radiological procedure, as temporary discontinuation may be required [see Warnings and Precautions (5.1)].

Pancreatitis

• Inform patients that acute pancreatitis has been reported during use of alogliptin. Educate patients that persistent, severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to promptly discontinue alogliptin and metformin HCl tablets and contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions (5.2)].

Heart Failure

Inform patients of the signs and symptoms of heart failure. Before initiating alogliptin and metformin HCl tablets, patients should be asked about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Instruct patients to contact their healthcare providers as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight, or swelling of the feet [see Warnings and Precautions (5.3)].

Hypersensitivity Reactions

Inform patients that allergic reactions have been reported during use of alogliptin and metformin. Instruct patients if symptoms of allergic reactions (including skin rash, hives and swelling of the face, lips, tongue and throat that may cause difficulty in breathing or swallowing) occur, patients should instructed discontinue alogliptin and metformin HCl tablets and seek medical advice promptly [see Warnings and Precautions (5.4)].

Hepatic Effects

Inform patients that postmarketing reports of liver injury, sometimes fatal, have been reported during use of alogliptin. Instruct patients that if signs or symptoms of liver injury occur, patients should be instructed to discontinue alogliptin and metformin HCl tablets and seek medical advice promptly [see Warnings and Precautions (5.5)].

Vitamin B12 Levels

Inform patients about the importance of regular hematological parameters while receiving treatment with metformin [see Warnings and Precautions (5.6)].

Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues

Inform patients that hypoglycemia can occur, particularly when an insulin secretagogue or insulin is used in combination with alogliptin with metformin HCl tablets. Educate patients about the risks, symptoms and appropriate management of hypoglycemia [see Warnings and Precautions (5.7)].

Severe and Disabling Arthralgia

Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs [see Warnings and Precautions (5.8)].

Bullous Pemphigoid

Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur [see Warnings and Precautions (5.9)].

Dosage

Instruct patients to take alogliptin with metformin HCl tablets only as prescribed twice daily and that it should be taken with food. Instruct patients if a dose is missed, not to double their next dose. Instruct patients that the tablets must never be split.

Females of Reproductive Age

Inform female patients that treatment with metformin may result in an unintended pregnancy in some premenopausal anovulatory females due to its effects on ovulation [see Use in Specific Populations (8.3)].