Alogliptin and Metformin Tablets

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 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 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 in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major malformations, still birth, and macrosomia related morbidity.

Data

Human Data

Published data from post-marketing 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 Hydrochloride

Metformin hydrochloride 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/m2) 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

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

Geriatric Use

Alogliptin and Metformin Hydrochloride

Elderly patients are more likely to have decreased renal function. Monitor renal function in the elderly more frequently [see Warnings and Precautions (5.1) and 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. While this and other reported clinical experiences have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be excluded.

Alogliptin

Of the total number of patients (N=9052) in clinical safety and efficacy studies treated with alogliptin, 2257 (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 Hydrochloride

Controlled studies 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) and 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 is 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) and 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)].

Alogliptin and metformin HCl tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: alogliptin and metformin hydrochloride.

Alogliptin

Alogliptin is a selective, orally bioavailable inhibitor of the enzymatic activity of dipeptidyl peptidase-4 (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 Hydrochloride

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5∙HCl and a molecular weight of 165.63. Metformin hydrochloride 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 hydrochloride 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 hydrochloride (12.5 mg/500 mg) or
• 1000 mg metformin hydrochloride (12.5 mg/1000 mg).

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

Mechanism of Action

Alogliptin and Metformin Hydrochloride

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: 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, 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 Hydrochloride

Metformin is a biguanide that improves glucose tolerance in patients with type 2 diabetes, 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. Metformin does not produce hypoglycemia in patients with type 2 diabetes or in healthy subjects except in special circumstances [see Warnings and Precautions (5.7)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease.

Pharmacodynamics

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 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.

Pharmacokinetics

Absorption and Bioavailability

Alogliptin and Metformin Hydrochloride

In bioequivalence studies of alogliptin and metformin HCl tablets, the area under the plasma concentration curve (AUC) and maximum concentration (Cmax) of both the alogliptin and the metformin component following a single dose of the combination tablet were bioequivalent to the alogliptin 12.5 mg concomitantly administered with metformin HCl 500 or 1000 mg tablets under fasted conditions in healthy subjects. 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 (Tmax) for alogliptin under fed conditions, however, there was a delayed Tmax for metformin of 1.5 hours. These changes are not likely to be clinically significant.

Alogliptin

The absolute bioavailability of alogliptin is approximately 100%. Administration of alogliptin with a high-fat meal results in no significant change in total and peak exposure to alogliptin. Alogliptin may therefore be administered with or without food.

Metformin Hydrochloride

The absolute bioavailability of metformin following administration of a 500 mg metformin HCl tablet given under fasting conditions is approximately 50% to 60%. 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. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (Tmax) 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 Hydrochloride

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. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally less than 1 mcg/mL. During controlled clinical trials, which served as the basis for approval for metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

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 [14C] 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 Hydrochloride

Intravenous single-dose studies 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 and Elimination

Alogliptin

The primary route of elimination of [14C] 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. The renal clearance of alogliptin (9.6 L/hr) indicates some active renal tubular secretion and systemic clearance was 14.0 L/hr.

Metformin Hydrochloride

Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Special Populations

Renal Impairment

Metformin Hydrochloride

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)].

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 Hydrochloride

No pharmacokinetic studies of metformin have been conducted in subjects with hepatic impairment.

Gender

Alogliptin

No dose adjustment is necessary based on gender. Gender did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.

Metformin Hydrochloride

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender. Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets was comparable in males and females.

Geriatric

Due to declining renal function in the elderly, measurement of creatinine clearance should be obtained prior to initiation of therapy.

Alogliptin

No dose adjustment is necessary based on age. Age did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.

Metformin Hydrochloride

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 Cmax 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.

Pediatrics

Studies characterizing the pharmacokinetics of alogliptin in pediatric patients have not been performed.

Race

Alogliptin

No dose adjustment of alogliptin is necessary based on race. Race (white, black and Asian) did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.

Metformin Hydrochloride

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51) and Hispanics (n=24).

Drug Interactions

Alogliptin and Metformin Hydrochloride

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

In Vitro Assessment of Drug Interactions

In vitro studies indicate that alogliptin is neither an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4, nor an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP2D6 at clinically relevant concentrations.

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 Hydrochloride

Pharmacokinetic drug interaction studies have been performed on metformin (Tables 4 and 5).

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

• Inform patients of the potential risks and benefits of alogliptin and metformin HCl tablets.
• The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in Warnings and Precautions (5.1), should be explained to patients. Patients should be advised to discontinue alogliptin and metformin HCl tablets immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of alogliptin and metformin HCl tablets, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to recur. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
• Patients should be informed that acute pancreatitis has been reported during use of alogliptin. Patients should be informed 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. Patients should be instructed to promptly discontinue alogliptin and metformin HCl tablets and contact their physician if persistent severe abdominal pain occurs.
• Patients should be informed 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. Patients should be instructed 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.
• Patients should be informed that allergic reactions have been reported during use of alogliptin and metformin. 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 be instructed to discontinue alogliptin and metformin HCl tablets and seek medical advice promptly.
• Patients should be informed that postmarketing reports of liver injury, sometimes fatal, have been reported during use of alogliptin. If signs or symptoms of liver injury occur, patients should be instructed to discontinue alogliptin and metformin HCl tablets and seek medical advice promptly.
• Patients should be informed about the importance of regular testing of renal function and hematological parameters when receiving treatment with alogliptin and metformin HCl tablets.
• Instruct patients to inform their doctor that they are taking alogliptin and metformin HCl tablets prior to any surgical or radiological procedure, as temporary discontinuation of alogliptin and metformin HCl tablets may be required until renal function has been confirmed to be normal [see Warnings and Precautions (5.1)].
• Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving alogliptin and metformin HCl tablets.
• Inform patients that hypoglycemia can occur, particularly when an insulin secretagogue or insulin is used in combination with alogliptin and metformin HCl tablets. Explain the risks, symptoms and appropriate management of hypoglycemia.
• 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.
• 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 (5.10)].
• Instruct patients to take alogliptin and metformin HCl tablets only as prescribed twice daily. Alogliptin and metformin HCl tablets should be taken with food. If a dose is missed, advise patients not to double their next dose.
• Patients should be informed that the tablets must never be split.
• 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)].

Instruct patients to read the Medication Guide before starting alogliptin and metformin HCl tablets therapy and to reread each time the prescription is refilled. Instruct patients to inform their healthcare provider if an unusual symptom develops or if a symptom persists or worsens.

ALK334 R5

Alogliptin and Metformin HCl Tablets

Read this Medication Guide carefully before you start taking alogliptin and metformin HCl tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about alogliptin and metformin HCl tablets, ask your doctor or pharmacist.

What is the most important information I should know about alogliptin and metformin HCl tablets?

Alogliptin and metformin HCl tablets can cause serious side effects, including:

Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis:

• you feel cold in your hands or feet
• you feel dizzy or lightheaded
• you have a slow or irregular heartbeat
• you feel very weak or tired
• you have unusual (not normal) muscle pain
• you have trouble breathing
• you feel sleepy or drowsy
• you have stomach pains, nausea or vomiting

Most people who have had lactic acidosis with metformin have other things that, combined with metformin, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with alogliptin and metformin HCl tablets if you:

• have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye
• have liver problems
• drink alcohol very often, or drink a lot of alcohol in short-term "binge" drinking
• get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids
• have surgery
• have a heart attack, severe infection, or stroke

The best way to keep from having a problem with lactic acidosis from metformin is to tell your doctor if you have any of the problems listed above. You doctor may decide to stop alogliptin and metformin HCl tablets for a while if you have any of these things.

Alogliptin and metformin HCl tablets can have other serious side effects. See "What are the possible side effects of alogliptin and metformin HCl tablets?"

Before you start taking alogliptin and metformin HCl tablets:

Tell your doctor if you have ever had:

Stop taking alogliptin and metformin HCl tablets and call your doctor right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen through to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis.

Before you start taking alogliptin and metformin HCl tablets:

Tell your healthcare provider if you have ever had heart failure or have problems with your kidneys.

Contact your healthcare provider right away if you have any of the following symptoms:

These may be symptoms of heart failure.

What are alogliptin and metformin HCl tablets?

• Alogliptin and metformin HCl tablets contain 2 prescription diabetes medicines, alogliptin (NESINA) and metformin hydrochloride.
• Alogliptin and metformin HCl tablets are a prescription medicine used along with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes.
• Alogliptin and metformin HCl tablets are not for people with type 1 diabetes.
• Alogliptin and metformin HCl tablets are not for people with diabetic ketoacidosis (increased ketones in blood or urine).

It is not known if alogliptin and metformin HCl tablets are safe and effective in children under the age of 18.

Who should not take alogliptin and metformin HCl tablets?

Do not take alogliptin and metformin HCl tablets if you:

• have severe kidney problems
• have a condition called metabolic acidosis or have had diabetic ketoacidosis (increased ketones in your blood or urine)
• are going to get an injection of dye or contrast agents for an x-ray procedure, alogliptin and metformin HCl tablets may need to be stopped for a short time. Talk to your doctor about when you should stop alogliptin and metformin HCl tablets and when you should start alogliptin and metformin HCl tablets again
• are allergic to alogliptin or metformin or any of the ingredients in alogliptin and metformin HCl tablets or have had a serious allergic (hypersensitivity) reaction to alogliptin or metformin. See the end of this Medication Guide for a complete list of the ingredients in alogliptin and metformin HCl tablets

Symptoms of a serious allergic reaction to alogliptin and metformin HCl tablets may include:

If you have any of these symptoms, stop taking alogliptin and metformin HCl tablets and contact your doctor or go to the nearest hospital emergency room right away.

What should I tell my doctor before and during treatment with alogliptin and metformin HCl tablets?

Before you take alogliptin and metformin HCl tablets, tell your doctor if you:

• have or have had inflammation of your pancreas (pancreatitis)
• have severe kidney or liver problems
• have heart problems, including congestive heart failure
• are going to get an injection of dye or contrast agents for an x-ray procedure, alogliptin and metformin HCl tablets may need to be stopped for a short time. Talk to your doctor about when you should stop alogliptin and metformin HCl tablets and when you should start alogliptin and metformin HCl tablets again
• drink alcohol very often or drink a lot of alcohol in short-term "binge" drinking
• have other medical conditions
• are pregnant or plan to become pregnant. It is not known if alogliptin and metformin HCl tablets will harm your unborn baby. Talk with your doctor about the best way to control your blood sugar while you are pregnant or if you plan to become pregnant
• are breastfeeding or plan to breastfeed. It is not known whether alogliptin and metformin pass into your breast milk. Talk with your doctor about the best way to feed your baby if you are taking alogliptin and metformin HCl tablets

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist before you start any new medicine.

Alogliptin and metformin HCl tablets may affect the way other medicines work, and other medicines may affect how alogliptin and metformin HCl tablets work. Contact your doctor before you start or stop other types of medicines.

How should I take alogliptin and metformin HCl tablets?

• Take alogliptin and metformin HCl tablets exactly as your doctor tells you to take it.
• Take alogliptin and metformin HCl tablets 2 times each day.
• Take alogliptin and metformin HCl tablets with food to lower your chances of having an upset stomach.
• Do not break or cut alogliptin and metformin HCl tablets before swallowing.
• Your doctor may need to change your dose of alogliptin and metformin HCl tablets to control your blood glucose. Do not change your dose unless told to do so by your doctor.
• If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose, and take the next dose at your regular time. Do not take 2 doses of alogliptin and metformin HCl tablets at the same time.
• If you take too many alogliptin and metformin HCl tablets, call your doctor or go to the nearest hospital emergency room right away.
• If your body is under stress, such as from fever, infection, accident or surgery, the dose of your diabetes medicines may need to be changed. Call your doctor right away.
• Stay on your diet and exercise programs and check your blood sugar as your doctor tells you to.
• Your doctor may do certain blood tests before you start alogliptin and metformin HCl tablets and during treatment as needed. Your doctor may ask you to stop taking alogliptin and metformin HCl tablets based on the results of your blood tests due to how well your kidneys are working.
• Your doctor will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C.

What are the possible side effects of alogliptin and metformin HCl tablets?

Alogliptin and metformin HCl tablets can cause serious side effects, including:

• See "What is the most important information I should know about alogliptin and metformin HCl tablets?"
• Allergic (hypersensitivity) reactions, such as:

  swelling of your face, lips, throat and other areas on your skin raised, red areas on your skin (hives)

  difficulty swallowing or breathing skin rash, itching, flaking or peeling

  If you have these symptoms, stop taking alogliptin and metformin HCl tablets and contact your doctor right away.

• Liver problems. Call your doctor right away if you have unexplained symptoms, such as:

  nausea or vomiting loss of appetite

  stomach pain dark urine

  unusual or unexplained tiredness yellowing of your skin or the whites of your eyes

• Low blood sugar (hypoglycemia). If you take alogliptin and metformin HCl tablets with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take alogliptin and metformin HCl tablets. If you have symptoms of low blood sugar, you should check your blood sugar and treat if low, and then call your doctor. Signs and symptoms of low blood sugar may include:

  shaking or feeling jittery sweating

  fast heartbeat change in vision

  hunger headache

  change in mood confusion

  dizziness

• Joint pain. Some people who take medicines called DPP-4 inhibitors, one of the medicines in alogliptin and metformin HCl tablets, may develop joint pain that can be severe. Call your doctor if you have severe joint pain.
• Skin reaction. Some people who take medicines called DPP-4 inhibitors, one of the medicines in alogliptin and metformin HCl tablets, may develop a skin reaction called bullous pemphigoid that can require treatment in a hospital. Tell your doctor right away if you develop blisters or the breakdown of the outer layer of your skin (erosion). Your doctor may tell you to stop taking alogliptin and metformin HCl tablets.

The most common side effects of alogliptin and metformin HCl tablets include:

Taking alogliptin and metformin HCl tablets with food can help lessen the common stomach side effects of metformin that usually happen at the beginning of treatment. If you have unexplained stomach problems, tell your doctor. Stomach problems that start later, during treatment, may be a sign of something more serious.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of alogliptin and metformin HCl tablets. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store alogliptin and metformin HCl tablets?

• Store alogliptin and metformin HCl tablets at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep the container of alogliptin and metformin HCl tablets tightly closed.

Keep alogliptin and metformin HCl tablets and all medicines out of the reach of children.

General information about the safe and effective use of alogliptin and metformin HCl tablets

Medicines are sometimes prescribed for purposes other than those listed in the Medication Guide. Do not take alogliptin and metformin HCl tablets for a condition for which it was not prescribed. Do not give alogliptin and metformin HCl tablets to other people, even if they have the same symptoms you have. They may harm them.

This Medication Guide summarizes the most important information about alogliptin and metformin HCl tablets. If you would like to know more information, talk with your doctor. You can ask your doctor or pharmacist for information about alogliptin and metformin HCl tablets that is written for health professionals.

For more information go to www.perrigo.com or call 1-877-TAKEDA-7 (1-877-825-3327).

What are the ingredients in alogliptin and metformin HCl tablets?

Active ingredients: alogliptin and metformin hydrochloride

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

Distributed By
Perrigo®
Allegan, MI 49010 • www.perrigo.com

All trademarks are the property of their respective owners

ALK334 R5

This Medication Guide has been approved by the U.S. Food and Drug Administration.
2/2017

Rx Only

NDC 45802-169-72