Alogliptin And Metformin Hydrochloride - Alogliptin And Metformin Hydrochloride tablet, Film Coated prescribing information
WARNING: LACTIC ACIDOSIS
Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL [see Warnings and Precautions (5.1) ] .
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information [see Dosage and Administration (2.2) , Contraindications (4) , Warnings and Precautions (5.1) , Drug Interactions (7) , Use in Specific Populations (8.6 , 8.7) ] .
If metformin-associated lactic acidosis is suspected, immediately discontinue alogliptin and metformin HCl tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1) ].
INDICATIONS AND USAGE
Alogliptin and metformin HCl tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Limitations of Use
Alogliptin and metformin HCl tablets should not recommended for use in patients with type 1 diabetes mellitus.
DOSAGE AND ADMINISTRATION
- Individualize the starting dosage based on the patient's current regimen. (2.1 )
- Given orally twice daily with food. (2.1 )
- Adjust the dosage based on effectiveness and tolerability while not exceeding the maximum recommended daily dosage of 25 mg alogliptin and 2000 mg metformin HCl. (2.1 )
- Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). (2.2 )
- Do not use in patients with eGFR below 60 mL/min/1.73 m 2 .
- Alogliptin and metformin HCl tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (2.3 )
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).
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 m 2 [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 m 2 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 m 2 or greater.
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 m 2 ; 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) ] .
DOSAGE FORMS AND STRENGTHS
- 12.5 mg/500 mg tablets are pale yellow, oblong, film-coated tablets with "12.5/500" debossed on one side and "322M" debossed on the other side
- 12.5 mg/1000 mg tablets are pale yellow, oblong, film-coated tablets with "12.5/1000" debossed on one side and "322M" debossed on the other side
USE IN SPECIFIC POPULATIONS
- Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3 )
- Pediatrics: Safety and effectiveness of alogliptin and metformin HCl tablets in pediatric patients have not been established. (8.4 )
- Geriatric Use: Assess renal function more frequently. (8.5 )
- Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7 )
Pregnancy
Risk Summary
Limited available data with alogliptin and metformin HCl tablets or alogliptin in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data ] . There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations ].
Concomitant administration of alogliptin and metformin in pregnant rats during the period of organogenesis did not cause adverse developmental effects in offspring at maternal exposures up to 28 times and two times the 25 mg and 2000 mg clinical doses, respectively [see Data ].
The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes mellitus with a HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Disease-associated Maternal and/or Embryo/Fetal Risk
Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major malformations, still birth, and macrosomia related morbidity.
Data
Human Data
Published data from postmarketing studies do not report a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin is used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.
Animal Data
Alogliptin and Metformin
Concomitant administration of alogliptin and metformin in pregnant rats during the period of organogenesis did not cause adverse developmental effects in offspring at a dose of 100 mg/kg alogliptin and 150 mg/kg metformin, or approximately 28 and two times the clinical dose of alogliptin (25 mg) and metformin (2000 mg), respectively based on plasma drug exposure (AUC).
Alogliptin
Alogliptin administered to pregnant rabbits and rats during the period of organogenesis did not cause adverse developmental effects at doses of up to 200 mg/kg and 500 mg/kg, or 149 times and 180 times the 25 mg clinical dose, respectively, based on plasma drug exposure (AUC).
Placental transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats.
No adverse developmental outcomes were observed in offspring when alogliptin was administered to pregnant rats during gestation and lactation at doses up to 250 mg/kg (approximately 95 times the 25 mg clinical dose, based on AUC).
Metformin HCl
Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about two to six times a clinical dose of 2000 mg based on body surface area (mg/m 2 ) for rats and rabbits, respectively.
Lactation
Risk Summary
There is no information regarding the presence of alogliptin and metformin or alogliptin in human milk, the effects on the breastfed infant, or the effects on milk production . Alogliptin is present in rat milk. Limited published studies report that metformin is present in human milk [see Data ]. However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for alogliptin and metformin HCl tablets and any potential adverse effects on the breastfed infant from alogliptin and metformin HCl tablets or from the underlying maternal condition.
Data
Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio (based on AUC) ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.
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.
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.
Geriatric Use
Alogliptin and Metformin HCl
Elderly patients are more likely to have decreased renal function. Monitor renal function in the elderly more frequently [see Warnings and Precautions (5.1) , Clinical Pharmacology (12.3) ] .
Of the total number of patients (N = 2095) in clinical safety and efficacy studies, 343 (16.4%) patients were 65 years and older and 37 (1.8%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients.
Alogliptin
Of the total number of patients (N=9052) in clinical safety and efficacy studies treated with alogliptin, 2,257 (24.9%) patients were 65 years and older and 386 (4.3%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients.
Metformin HCl
Controlled trials of metformin did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal and cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Contraindications (4) , Warnings and Precautions (5.1) , Clinical Pharmacology (12.3) ].
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 m 2 [see Dosage and Administration (2.2) , Contraindications (4) , Warnings and Precautions (5.1) , Clinical Pharmacology (12.3) ] .
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) ] .
CONTRAINDICATIONS
Alogliptin and metformin HCl tablets are contraindicated in patients with:
- Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [see Warnings and Precautions (5.1) ].
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma.
- History of serious hypersensitivity reaction to alogliptin or metformin or any of the excipients, such as anaphylaxis, angioedema and severe cutaneous adverse reactions [see Warnings and Precautions (5.4) , Adverse Reactions (6.2) ] .
WARNINGS AND PRECAUTIONS
- Lactic acidosis: See boxed warning. (5.1 )
- Pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue alogliptin and metformin HCl tablets. (5.2 )
- Heart failure: Consider the risks and benefits of alogliptin and metformin HCl tablets prior to initiating treatment in patients at risk for heart failure. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of alogliptin and metformin HCl tablets. (5.3 )
- Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin such as anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If hypersensitivity reactions occur, discontinue alogliptin and metformin HCl tablets, treat promptly and monitor until signs and symptoms resolve. (5.4 )
- Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt alogliptin and metformin HCl tablets and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart alogliptin and metformin HCl tablets if liver injury is confirmed and no alternative etiology can be found. (5.5 )
- Vitamin B 12 deficiency: Metformin may lower vitamin B 12 levels. Measure hematologic parameters annually and B 12 at 2 to 3 year intervals and manage any abnormalties. (5.6 )
- Hypoglycemia: Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating Alogliptin and metformin HCl tablets. (5.7 )
- Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. (5.8 )
- Bullous pemphigoid: There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue alogliptin and metformin HCl tablets. (5.9 )
Lactic Acidosis
Lactic Acidosis
There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally greater than 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of alogliptin and metformin HCl tablets. In alogliptin and metformin HCl tablets-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue alogliptin and metformin HCl tablets and report these symptoms to their healthcare provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:
Renal Impairment
The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Dosage and Administration (2.2) , Clinical Pharmacology (12.3) ]:
- Before initiating alogliptin and metformin HCl tablets, obtain an eGFR.
- Alogliptin and metformin HCl tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Contraindications (4) ] .
- Alogliptin and metformin HCl tablets are not recommended in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 because these patients require a lower dosage of alogliptin than what is available in the fixed combination alogliptin and metformin HCl tablets product.
- Obtain an eGFR at least annually in all patients taking alogliptin and metformin HCl tablets. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
Drug Interactions
The concomitant use of alogliptin and metformin HCl tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7) ]. Therefore, consider more frequent monitoring of patients.
Age 65 or Greater
The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5) ].
Radiological Studies with Contrast
Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop 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 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart alogliptin and metformin HCl tablets if renal function is stable.
Surgery and Other Procedures
Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Alogliptin and metformin HCl tablets should be temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic States
Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue alogliptin and metformin HCl tablets.
Excessive Alcohol Intake
Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving alogliptin and metformin HCl tablets.
Hepatic Impairment
Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of alogliptin and metformin HCl tablets in patients with clinical or laboratory evidence of hepatic disease.
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.
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.
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.
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.
Vitamin B 12 Levels
In metformin clinical trials of 29 week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on alogliptin with metformin and manage any abnormalities [ see Adverse Reactions (6.1) ] .
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.
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.
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.
ADVERSE REACTIONS
The following serious adverse reactions are described below or elsewhere in the prescribing information:
- Pancreatitis [see Warnings and Precautions (5.2) ]
- Heart Failure [see Warnings and Precautions (5.3) ]
- Hypersensitivity Reactions [see Warnings and Precautions (5.4) ]
- Hepatic Effects [see Warnings and Precautions (5.5) ]
- Severe and Disabling Arthralgia [see Warnings and Precautions (5.8) ]
- Bullous Pemphigoid [see Warnings and Precautions (5.9) ]
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.
Alogliptin and Metformin HCl
Over 2,700 patients with type 2 diabetes mellitus have received alogliptin coadministered with metformin in four large, randomized, double-blind controlled clinical trials. The racial distribution of patients exposed to trial medication was 65% White, 20% Asian, 7% Black or African American, 4% American Indian or Alaska Native, 0% Native Hawaiian/Other Pacific Islander and 4% Multiracial or other racial groups. The ethnic distribution was 23% Hispanic or Latino and 77% was not Hispanic or Latino. The mean exposure to alogliptin and metformin HCl tablets was 58 weeks, with more than 1,400 subjects treated for more than one year. These included two 26 week placebo-controlled trials, one 52 week active control study and an interim analysis of a 104 week active-controlled trial. In the alogliptin and metformin HCl tablets arm, the mean duration of diabetes mellitus was approximately six years, the mean body mass index (BMI) was 31 kg/m 2 (56% of patients had a BMI ≥30 kg/m 2 ) and the mean age was 55 years (18% of patients ≥65 years of age).
In a pooled analysis of these four controlled clinical studies, the overall incidence of adverse reactions was 74% in patients treated with alogliptin and metformin HCl tablets compared to 75% treated with placebo. Overall discontinuation of therapy due to adverse reactions was 6.2% with alogliptin and metformin HCl tablets compared to 1.9% in placebo, 6.4% in metformin and 5.0% in alogliptin.
Adverse reactions reported in ≥4% of patients treated with alogliptin and metformin HCl tablets and more frequently than in patients who received alogliptin, metformin or placebo are summarized in Table 1.
| Number of Patients (%) | ||||
|---|---|---|---|---|
| Alogliptin and Metformin HCl Tablets Alogliptin and metformin HCl tablets – includes data pooled for patients receiving alogliptin 25 and 12.5 mg combined with various doses of metformin | Alogliptin Alogliptin – includes data pooled for patients receiving alogliptin 25 and 12.5 mg | Metformin Metformin – includes data pooled for patients receiving various doses of metformin | Placebo | |
| N=2794 | N=222 | N=1592 | N=106 | |
| Upper respiratory tract infection | 224 (8) | 6 (3) | 105 (7) | 3 (3) |
| Nasopharyngitis | 191 (7) | 7 (3) | 93 (6) | 2 (2) |
| Diarrhea | 155 (6) | 4 (2) | 105 (7) | 3 (3) |
| Hypertension | 154 (6) | 5 (2) | 96 (6) | 6 (6) |
| Headache | 149 (5) | 11 (5) | 74 (5) | 3 (3) |
| Back pain | 119 (4) | 1 (1) | 72 (5) | 1 (1) |
| Urinary tract infection | 116 (4) | 4 (2) | 59 (4) | 2 (2) |
Alogliptin
A total of 14,778 patients with type 2 diabetes mellitus participated in 14 randomized, double-blind, controlled clinical trials of whom 9,052 subjects were treated with alogliptin, 3,469 subjects were treated with placebo and 2,257 were treated with an active comparator. The racial distribution of patients exposed to trial medication was 71% White, 17% Asian, 6% Black or African American, 2% American Indian or Alaska Native, 0% Native Hawaiian/Other Pacific Islander and 5% Multiracial or other racial groups. The ethnic distribution was 30% Hispanic or Latino and 70% was not Hispanic or Latino. The mean duration of diabetes mellitus was seven years, the mean body mass index (BMI) was 31 kg/m 2 (49% of patients had a BMI ≥30 kg/m 2 ), and the mean age was 58 years (26% of patients ≥65 years of age). The mean exposure to alogliptin was 49 weeks with 3,348 subjects treated for more than one year.
In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse reactions was 73% in patients treated with alogliptin 25 mg compared to 75% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse reactions was 6.8% with alogliptin 25 mg compared to 8.4% with placebo or 6.2% with active comparator.
Adverse reactions reported in ≥4% of patients treated with alogliptin 25 mg and more frequently than in patients who received placebo are summarized in Table 2.
| Number of Patients (%) | |||
|---|---|---|---|
| Alogliptin 25 mg | Placebo | Active Comparator | |
| N=6447 | N=3469 | N=2257 | |
| Nasopharyngitis | 309 (5) | 152 (4) | 113 (5) |
| Upper Respiratory Tract Infection | 287 (5) | 121 (4) | 113 (5) |
| Headache | 278 (4) | 101 (3) | 121 (5) |
Hypoglycemia
Alogliptin and Metformin HCl
In a 26 week, double-blind, placebo-controlled trial of alogliptin in combination with metformin, the number of patients reporting hypoglycemia was 1.9% in the alogliptin 12.5 mg with metformin HCl 500 mg, 5.3% in the alogliptin 12.5 mg with metformin HCl 1000 mg, 1.8% in the metformin HCl 500 mg and 6.3% in the metformin HCl 1000 mg treatment groups.
In a 26 week placebo-controlled trial of alogliptin 25 mg administered once daily as add-on to metformin regimen, the number of patients reporting hypoglycemic events was 0% in the alogliptin coadministered with metformin HCl and 2.9% in the placebo treatment groups.
In a 52 week, active-controlled, double-blind trial of alogliptin once daily as add-on therapy to the combination of pioglitazone 30 mg and metformin compared to the titration of pioglitazone 30 mg to 45 mg and metformin, the number of patients reporting hypoglycemia was 4.5% in the alogliptin 25 mg with pioglitazone 30 mg and metformin group versus 1.5% in the pioglitazone 45 mg with metformin group.
In an interim analysis conducted in a 104 week, double-blind, active-controlled trial of alogliptin 25 mg in combination with metformin, the number of patients reporting hypoglycemia was 1.4% in the alogliptin 25 mg with metformin group versus 23.8% in the glipizide with metformin group.
Alogliptin
Hypoglycemic events were documented based upon a blood glucose value and/or clinical signs and symptoms of hypoglycemia.
In the monotherapy trial, the incidence of hypoglycemia was 1.5% in patients treated with alogliptin compared to 1.6% with placebo. The use of alogliptin as add-on therapy to glyburide or insulin did not increase the incidence of hypoglycemia compared to placebo. In a monotherapy trial comparing alogliptin to a sulfonylurea in elderly patients, the incidence of hypoglycemia was 5.4% with alogliptin compared to 26% with glipizide.
In the EXAMINE trial, the incidence of investigator reported hypoglycemia was 6.7% in patients receiving alogliptin and 6.5% in patients receiving placebo. Serious adverse reactions of hypoglycemia were reported in 0.8% of patients treated with alogliptin and in 0.6% of patients treated with placebo.
Metformin HCl
| Adverse Reaction | Metformin Monotherapy (n=141) | Placebo (n=145) |
|---|---|---|
| % of Patients | ||
| Diarrhea | 53.2 | 11.7 |
| Nausea/vomiting | 25.5 | 8.3 |
| Flatulence | 12.1 | 5.5 |
| Asthenia | 9.2 | 5.5 |
| Indigestion | 7.1 | 4.1 |
| Abdominal discomfort | 6.4 | 4.8 |
| Headache | 5.7 | 4.8 |
Laboratory Abnormalities
Alogliptin and Metformin HCl
No clinically meaningful differences were observed among treatment groups regarding hematology, serum chemistry or urinalysis results.
Metformin HCl
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.
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.
Alogliptin
Gastrointestinal Disorders: acute pancreatitis, diarrhea, constipation, nausea, ileus
Hepatobiliary Disorders: fulminant hepatic failure
Immune System Disorders: hypersensitivity reactions including anaphylaxis
Investigations: hepatic enzyme elevations
Musculoskeletal and Connective Tissue Disorders: severe and disabling arthralgia, rhabdomyolysis
Renal and Urinary Disorders: tubulointerstitial nephritis
Skin and Subcutaneous Tissue Disorders: angioedema, rash, urticaria and severe cutaneous adverse reactions including Stevens-Johnson syndrome, bullous pemphigoid
Metformin
Hepatobiliary Disorders: Cholestatic, hepatocellular, mixed hepatocellular liver injury
DRUG INTERACTIONS
- Carbionic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. (7 )
- Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine), may increase the accumulation of metformin. Consider the benefits and risks of concomitant use. (7 )
- Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. (7 )
Metformin HCl
| Carbonic Anhydrase Inhibitors | |
| Clinical Impact: | Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with ALOGLIPTIN WITH METFORMIN HCl TABLETS may increase the risk of lactic acidosis. |
| Intervention: | Consider more frequent monitoring of these patients. |
| Examples: | Topiramate, zonisamide, acetazolamide or dichlorphenamide |
| Drugs that Reduce Metformin Clearance | |
| Clinical Impact: | Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3) ] . |
| Intervention: | Consider the benefits and risks of concomitant use. |
| Examples: | Ranolazine, vandetanib, dolutegravir, and cimetidine |
| Alcohol | |
| Clinical Impact: | Alcohol is known to potentiate the effect of metformin on lactate metabolism. |
| Intervention: | Warn patients against excessive alcohol intake while receiving ALOGLIPTIN WITH METFORMIN HCl TABLETS. |
| Insulin Secretagogues and Insulin | |
| Clinical Impact: | Coadministration of ALOGLIPTIN WITH METFORMIN HCl TABLETS with an insulin secretagogue (e.g., sulfonylurea) or with insulin may increase the risk of hypoglycemia. |
| Intervention: | Patients may require a lower dose of the insulin secretagogue or insulin. |
| Drugs Affecting Glycemic Control | |
| Clinical Impact: | Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. |
| Intervention: | When such drugs are administered to a patient receiving ALOGLIPTIN WITH METFORMIN HCl TABLETS, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving ALOGLIPTIN WITH METFORMIN HCl TABLETS, the patient should be observed closely for hypoglycemia. |
| Examples: | Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs and isoniazid |
Alogliptin
| Cytochrome (CYP) P450, CYP-Substrates or Inhibitors | |
| Clinical Impact: | Insulin Secretagogues and Insulin Insulin and insulin secretagogues are known to cause hypoglycemia. Coadministration of alogliptin and metformin HCl tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.7) ]. |
DESCRIPTION
Alogliptin and metformin HCl tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes mellitus: alogliptin and metformin HCl.
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-[(3 R )-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2 H )-yl}methyl)benzonitrile monobenzoate. It has a molecular formula of C 18 H 21 N 5 O 2 ∙C 7 H 6 O 2 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 C 4 H 11 N 5 ∙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.
CLINICAL PHARMACOLOGY
Mechanism of Action
Alogliptin and Metformin HCl
Alogliptin and metformin HCl tablets combine two antihyperglycemic agents with complementary and distinct mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus: alogliptin, a selective inhibitor of DPP-4, and metformin HCl, a member of the biguanide class.
Alogliptin
Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes mellitus, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Alogliptin is a DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus. Alogliptin selectively binds to and inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.
Metformin HCl
Metformin is a biguanide that improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease.
Pharmacodynamics
Dose-Response Relationships
Alogliptin
Single-dose administration of alogliptin to healthy subjects resulted in a peak inhibition of DPP-4 within two to three hours after dosing. The peak inhibition of DPP-4 exceeded 93% across doses of 12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at 24 hours for doses greater than or equal to 25 mg. Peak and total exposure over 24 hours to active GLP-1 were three- to four-fold greater with alogliptin (at doses of 25 to 200 mg) than placebo. In a 16 week, double-blind, placebo-controlled study, alogliptin 25 mg demonstrated decreases in postprandial glucagon while increasing postprandial active GLP-1 levels compared to placebo over an eight hour period following a standardized meal. It is unclear how these findings relate to changes in overall glycemic control in patients with type 2 diabetes mellitus. In this study, alogliptin 25 mg demonstrated decreases in two hour postprandial glucose compared to placebo (-30 mg/dL versus 17 mg/dL, respectively).
Multiple-dose administration of alogliptin to patients with type 2 diabetes mellitus also resulted in a peak inhibition of DPP-4 within one to two hours and exceeded 93% across all doses (25 mg, 100 mg and 400 mg) after a single dose and after 14 days of once daily dosing. At these doses of alogliptin, inhibition of DPP-4 remained above 81% at 24 hours after 14 days of dosing.
Cardiac Electrophysiology
Alogliptin
In a randomized, placebo-controlled, four-arm, parallel-group study, 257 subjects were administered either alogliptin 50 mg, alogliptin 400 mg, moxifloxacin 400 mg or placebo once daily for a total of seven days. No increase in corrected QT (QTc) was observed with either dose of alogliptin. At the 400 mg dose, peak alogliptin plasma concentrations were 19-fold higher than the peak concentrations following the maximum recommended clinical dose of 25 mg.
Pharmacokinetics
Absorption
Alogliptin and Metformin HCl
There is no clinically meaningful difference in PK exposures (AUC and C max ) of alogliptin and metformin when taken a single dose of the combination tablet alogliptin and metformin taken concomitantly.
Alogliptin
After administration of single, oral doses up to 800 mg in healthy subjects, the peak plasma alogliptin concentration (median T max ) occurred one to two hours after dosing. The absolute bioavailability of alogliptin is approximately 100%.
Metformin HCl
Studies using single oral doses of metformin HCl tablets 500 mg to 1500 mg and 850 mg to 2550 mg indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. The absolute bioavailability of metformin following administration of a 500 mg metformin HCl tablet given under fasting conditions is approximately 50% to 60%.
Effect of Food
Alogliptin and Metformin HCl
Administration of alogliptin and metformin HCl tablets with food resulted in no change in total exposure (AUC) of alogliptin and metformin. Mean peak plasma concentrations of alogliptin and metformin were decreased by 13% and 28%, respectively, when administered with food. There was no change in time to peak plasma concentrations (T max ) for alogliptin under fed conditions, however, there was a delayed T max for metformin of 1.5 hours. These changes are not likely to be clinically significant.
Alogliptin
Administration of alogliptin with a high-fat meal results in no significant change in total and peak exposure to alogliptin.
Metformin HCl
Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (C max ), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (T max ) following administration of a single 850 mg tablet of metformin HCl with food compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
Distribution
Alogliptin
Following a single, 12.5 mg intravenous infusion of alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L, indicating that the drug is well distributed into tissues.
Alogliptin is 20% bound to plasma proteins.
Metformin HCl
The apparent volume of distribution (V/F) of metformin following single oral doses of immediate release metformin HCl tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.
Elimination
Alogliptin
Alogliptin was eliminated with a mean terminal half-life (t 1/2 ) of approximately 21 hours. The renal clearance of alogliptin (9.6 L/hr) indicates some active renal tubular secretion and systemic clearance was 14.0 L/hr.
Metformin HCl
In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. The plasma elimination half-life is approximately 6.2 hours. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin excretion.
Metabolism
Alogliptin
Alogliptin does not undergo extensive metabolism and 60% to 71% of the dose is excreted as unchanged drug in the urine.
Two minor metabolites were detected following administration of an oral dose of [ 14 C] alogliptin, N -demethylated, M-I (less than 1% of the parent compound), and N -acetylated alogliptin, M-II (less than 6% of the parent compound). M-I is an active metabolite and is an inhibitor of DPP-4 similar to the parent molecule; M-II does not display any inhibitory activity toward DPP-4 or other DPP-related enzymes. In vitro data indicate that CYP2D6 and CYP3A4 contribute to the limited metabolism of alogliptin.
Alogliptin exists predominantly as the ( R )-enantiomer (more than 99%) and undergoes little or no chiral conversion in vivo to the ( S )-enantiomer. The ( S )-enantiomer is not detectable at the 25 mg dose.
Metformin HCl
Intravenous single-dose trials in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.
Excretion
Alogliptin
The primary route of elimination of [ 14 C] alogliptin-derived radioactivity occurs via renal excretion (76%) with 13% recovered in the feces, achieving a total recovery of 89% of the administered radioactive dose.
Metformin HCl
Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours.
Specific Populations
Geriatric Patients
Due to declining renal function in the elderly, measurement of creatinine clearance should be obtained prior to initiation of therapy.
Alogliptin
Age (18 to 80 years old) did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.
Metformin HCl
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C max is increased, compared to healthy young subjects. From these data it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.
Male and Female Patients
Alogliptin
Gender did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.
Metformin HCl
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to gender. Similarly, in controlled clinical studies in patients with type 2 diabetes mellitus, the antihyperglycemic effect of metformin HCl tablets was comparable in males and females.
Racial or Ethnic Groups
Alogliptin
Race (White, Black or African American and Asian) did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.
Metformin HCl
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes mellitus, the antihyperglycemic effect was comparable in Whites (n=249), Blacks or African Americans (n=51) and Hispanics or Latino (n=24).
Patients with Renal Impairment
Metformin HCl
In patients with decreased renal function (based on measured creatine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see Contraindications (4) , Warnings and Precautions (5.1) ] .
Patients with Hepatic Impairment
Alogliptin
Total exposure to alogliptin was approximately 10% lower and peak exposure was approximately 8% lower in patients with moderate hepatic impairment (Child-Pugh Grade B) compared to healthy subjects. The magnitude of these reductions is not considered to be clinically meaningful. Patients with severe hepatic impairment (Child-Pugh Grade C) have not been studied.
Metformin HCl
No pharmacokinetic studies of metformin have been conducted in subjects with hepatic impairment.
Drug Interaction Studies
Alogliptin and Metformin HCl
Administration of alogliptin 100 mg once daily with metformin HCl 1000 mg twice daily for six days had no meaningful effect on the pharmacokinetics of alogliptin or metformin.
Specific pharmacokinetic drug interaction studies with alogliptin and metformin HCl tablets have not been performed, although such studies have been conducted with the individual components of alogliptin and metformin HCl tablets (alogliptin and metformin).
Alogliptin
Clinical Studies
In Vivo Assessment of Drug Interactions
Effects of Alogliptin on the Pharmacokinetics of Other Drugs
In clinical studies, alogliptin did not meaningfully increase the systemic exposure to the following drugs that are metabolized by CYP isozymes or excreted unchanged in urine (Figure 1) . No dose adjustment of alogliptin is recommended based on results of the described pharmacokinetic studies.
Figure 1. Effect of Alogliptin on the Pharmacokinetic Exposure to Other Drugs
• Warfarin was given once daily at a stable dose in the range of 1 mg to 10 mg. Alogliptin had no significant effect on the prothrombin time (PT) or International Normalized Ratio (INR).
•• Caffeine (1A2 substrate), tolbutamide (2C9 substrate), dextromethorphan (2D6 substrate), midazolam (3A4 substrate) and fexofenadine (P-gp substrate) were administered as a cocktail.
Effects of Other Drugs on the Pharmacokinetics of Alogliptin
There are no clinically meaningful changes in the pharmacokinetics of alogliptin when alogliptin is administered concomitantly with the drugs described below (Figure 2).
Figure 2. Effect of Other Drugs on the Pharmacokinetic Exposure of Alogliptin
Metformin HCl
Pharmacokinetic drug interaction studies have been performed on metformin (Tables 4 and 5) .
| Coadministered Drug | Dose of Coadministered Drug All metformin and coadministered drugs were given as single doses | Dose of Metformin HCl | Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1.00 | |
|---|---|---|---|---|
| AUC AUC = AUC 0˗∞ | C max | |||
| No dosing adjustments required for the following: | ||||
| Glyburide | 5 mg | 500 mg Metformin HCl extended-release tablets 500 mg | 0.98 Ratio of arithmetic means | 0.99 |
| Furosemide | 40 mg | 850 mg | 1.09 | 1.22 |
| Nifedipine | 10 mg | 850 mg | 1.16 | 1.21 |
| Propranolol | 40 mg | 850 mg | 0.90 | 0.94 |
| Ibuprofen | 400 mg | 850 mg | 1.05 | 1.07 |
| Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin [see Warnings and Precautions (5) , Drug Interactions (7) ] | ||||
| Cimetidine | 400 mg | 850 mg | 1.40 | 1.61 |
| Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5) , Drug Interactions (7) ] | ||||
| Topiramate | 100 mg At steady-state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC 0-12h | 500 mg | 1.25 | 1.17 |
| Coadministered Drug | Dose of Coadministered Drug All metformin and coadministered drugs were given as single doses | Dose of Metformin HCl | Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1.00 | |
|---|---|---|---|---|
| AUC AUC = AUC 0˗∞ | C max | |||
| No dosing adjustments required for the following: | ||||
| Glyburide | 5 mg | 500 mg AUC 0-24 hr reported | 0.78 Ratio of arithmetic means, p-value of difference <0.05 | 0.63 |
| Furosemide | 40 mg | 850 mg | 0.87 | 0.69 |
| Nifedipine | 10 mg | 850 mg | 1.10 | 1.08 |
| Propranolol | 40 mg | 850 mg | 1.01 | 0.94 |
| Ibuprofen | 400 mg | 850 mg | 0.97 Ratio of arithmetic means | 1.01 |
| Cimetidine | 400 mg | 850 mg | 0.95 | 1.01 |
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Alogliptin and Metformin HCl
No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with alogliptin and metformin HCl tablets. The following data are based on findings in studies performed with alogliptin or metformin individually.
Alogliptin
Rats were administered oral doses of 75, 400 and 800 mg/kg alogliptin for two years. No drug-related tumors were observed up to 75 mg/kg or approximately 32 times the maximum recommended clinical dose of 25 mg, based on area under the plasma concentration curve (AUC) exposure. At higher doses (approximately 308 times the maximum recommended clinical dose of 25 mg), a combination of thyroid C-cell adenomas and carcinomas increased in male but not female rats. No drug-related tumors were observed in mice after administration of 50, 150 or 300 mg/kg alogliptin for two years, or up to approximately 51 times the maximum recommended clinical dose of 25 mg, based on AUC exposure.
Alogliptin was not mutagenic or clastogenic, with and without metabolic activation, in the Ames test with S. typhimurium and E. coli or the cytogenetic assay in mouse lymphoma cells. Alogliptin was negative in the in vivo mouse micronucleus study.
In a fertility study in rats, alogliptin had no adverse effects on early embryonic development, mating or fertility, at doses up to 500 mg/kg, or approximately 172 times the clinical dose based on plasma drug exposure (AUC).
Metformin HCl
Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg and 1500 mg/kg, respectively. These doses are both approximately four times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg.
There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test ( S. typhimurium ), gene mutation test (mouse lymphoma cells) or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.
CLINICAL STUDIES
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.
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.
| Placebo | Alogliptin 12.5 mg twice daily | Metformin HCl 500 mg twice daily | Metformin HCl 1000 mg twice daily | Alogliptin 12.5 mg + Metformin HCl 500 mg twice daily | Alogliptin 12.5 mg + Metformin HCl 1000 mg twice daily | |
|---|---|---|---|---|---|---|
| A1C (%) Intent-to-treat population using last observation on trial prior to discontinuation of double-blind trial medication or sulfonylurea rescue therapy for patients needing rescue | N=102 | N=104 | N=103 | N=108 | N=102 | N=111 |
| Baseline (mean) | 8.5 | 8.4 | 8.5 | 8.4 | 8.5 | 8.4 |
| Change from baseline (adjusted mean Least squares means adjusted for treatment, geographic region and baseline value ) | 0.1 | -0.6 | -0.7 | -1.1 | -1.2 | -1.6 |
| Difference from metformin (adjusted meanwith 95% confidence interval) | - | - | - | - | -0.6 p<0.05 when compared to metformin and alogliptin alone (-0.9, -0.3) | -0.4 (-0.7, -0.2) |
| Difference from alogliptin (adjusted meanwith 95% confidence interval) | - | - | - | - | -0.7 (-1.0, -0.4) | -1.0 (-1.3, -0.7) |
| % of Patients (n/N) achieving A1C <7% Compared using logistic regression | 4% (4/102) | 20% (21/104) | 27% (28/103) | 34% (37/108) | 47% (48/102) | 59% (66/111) |
| FPG (mg/dL) | N=105 | N=106 | N=106 | N=110 | N=106 | N=112 |
| Baseline (mean) | 187 | 177 | 180 | 181 | 176 | 185 |
| Change from baseline (adjusted mean) | 12 | -10 | -12 | -32 | -32 | -46 |
| Difference from metformin (adjusted meanwith 95% confidence interval) | - | - | - | - | -20 (-33, -8) | -14 (-26, -2) |
| Difference from alogliptin (adjusted meanwith 95% confidence interval) | - | - | - | - | -22 (-35, -10) | -36 (-49, -24) |
| 2-Hour PPG (mg/dL) Intent-to-treat population using data available at Week 26 | N=26 | N=34 | N=28 | N=37 | N=31 | N=37 |
| Baseline (mean) | 263 | 272 | 247 | 266 | 261 | 268 |
| Change from baseline (adjusted mean) | -21 | -43 | -49 | -54 | -68 | -86 |
| Difference from metformin (adjusted meanwith 95% confidence interval) | - | - | - | - | -19 (-49, 11) | -32 (-58, -5) |
| Difference from alogliptin (adjusted meanwith 95% confidence interval) | - | - | - | - | -25 (-53, 3) | -43 (-70, -16) |
Figure 3. Change from Baseline A1C at Week 26 with Alogliptin and Metformin Alone and Alogliptin in Combination with Metformin
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.
| Alogliptin 25 mg + Metformin | Placebo + Metformin | |
|---|---|---|
| A1C (%) | N=203 | N=103 |
| Baseline (mean) | 7.9 | 8.0 |
| Change from baseline (adjusted mean Least squares means adjusted for treatment, baseline value, geographic region and baseline metformin dose. ) | -0.6 | -0.1 |
| Difference from placebo (adjusted meanwith 95% confidence interval) | -0.5 p<0.001 compared to placebo. (-0.7, -0.3) | ˗ |
| % of patients (n/N) achieving A1C ≤7% | 44% (92/207) | 18% (19/104) |
| FPG (mg/dL) | N=204 | N=104 |
| Baseline (mean) | 172 | 180 |
| Change from baseline (adjusted mean) | -17 | 0 |
| Difference from placebo (adjusted meanwith 95% confidence interval) | -17(-26, -9) | ˗ |
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.
| Alogliptin 25 mg + Pioglitazone 30 mg + Metformin | Pioglitazone 45 mg + Metformin | |
|---|---|---|
| A1C (%) | N=397 | N=394 |
| Baseline (mean) | 8.2 | 8.1 |
| Change from baseline (adjusted mean Least squares means adjusted for treatment, baseline value, geographic region and baseline metformin dose ) | -0.7 | -0.3 |
| Difference from pioglitazone 45 mg + metformin(adjusted meanwith 95% confidence interval) | -0.4 Noninferior and statistically superior to metformin + pioglitazone at the 0.025 one-sided significance level (-0.5, -0.3) | ˗ |
| % of Patients (n/N) achieving A1C ≤7% | 33% (134/404) p<0.001 compared to pioglitazone 45 mg + metformin | 21% (85/399) |
| Fasting Plasma Glucose (mg/dL) | N=399 | N=396 |
| Baseline (mean) | 162 | 162 |
| Change from baseline (adjusted mean) | -15 | -4 |
| Difference from pioglitazone 45 mg + metformin (adjusted meanwith 95% confidence interval) | -11(-16, -6) | ˗ |
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 m 2 ) 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.
| Composite of first event of CV death, nonfatal MI or nonfatal stroke (MACE) | Alogliptin | Placebo | Hazard Ratio | ||
| Number of Patients (%) | Rate per 100 PY Patient Years (PY) | Number of Patients (%) | Rate per 100 PY | (98% CI) | |
| N=2701 | N=2679 | ||||
| 305 (11.3) | 7.6 | 316 (11.8) | 7.9 | 0.96 (0.80, 1.16) | |
| CV Death | 89 (3.3) | 2.2 | 111 (4.1) | 2.8 | |
| Non-fatal MI | 187 (6.9) | 4.6 | 173 (6.5) | 4.3 | |
| Non-fatal stroke | 29 (1.1) | 0.7 | 32 (1.2) | 0.8 | |
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).
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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.
HOW SUPPLIED/STORAGE AND HANDLING
Alogliptin and metformin HCl tablets are available in the following strengths and packages: 12.5 mg/500 mg tablet: pale yellow, oblong, film-coated tablets with "12.5/500" debossed on one side and "322M" debossed on the other side, available in:
| NDC 45802-169-72 | Bottles of 60 tablets |
12.5 mg/1000 mg tablet: pale yellow, oblong, film-coated tablets with "12.5/1000" debossed on one side and "322M" debossed on the other side, available in:
| NDC 45802-211-72 | Bottles of 60 tablets |
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.
Mechanism of Action
Alogliptin and Metformin HCl
Alogliptin and metformin HCl tablets combine two antihyperglycemic agents with complementary and distinct mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus: alogliptin, a selective inhibitor of DPP-4, and metformin HCl, a member of the biguanide class.
Alogliptin
Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes mellitus, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Alogliptin is a DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus. Alogliptin selectively binds to and inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.
Metformin HCl
Metformin is a biguanide that improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease.
