Alogliptin Drug Information

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: Should not be used in patients with type 1 diabetes mellitus. Limitations of Use Alogliptin and metformin HCl tablets should not recommended for use in patients with type 1 diabetes mellitus.

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. 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.

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 ethnic distribution was 23% Hispanic or Latino and 77% was not Hispanic or Latino.

The mean exposure to alogliptin coadministered with metformin 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 trial and an interim analysis of a 104 week active-controlled trial. In a pooled analysis of these four controlled clinical studies, the overall incidence of adverse reactions was 74% in patients treated with alogliptin co-administered with metformin HCl compared to 75% treated with placebo.

Adverse reactions reported in ≥4% of patients treated with alogliptin co-administered with metformin HCl and more frequently than in patients who received alogliptin, metformin or placebo are summarized in Table 1. Table 1. Adverse Reactions Reported in ≥4% of Adults with Type 2 Diabetes Mellitus Treated with Alogliptin Co-administered with Metformin HCl and More Frequently Than in Patients Receiving Either Alogliptin, Metformin or 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 ethnic distribution was 30% Hispanic or Latino and 70% was not Hispanic or Latino. The mean exposure to alogliptin was 49 weeks with 3,348 subjects treated for more than one year. 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.

Table 2. 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 co-administered with metformin HCl and 2.9% in the placebo treatment groups. 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 Table 3. Most Common Adverse Reactions (≥5%) in a Placebo-Controlled Clinical Trial of Metformin Monotherapy Reactions that were more common in metformin than placebo-treated patients 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 B 12 levels was observed in approximately 7% of patients.

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of alogliptin and metformin HCl. 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

Carbionic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine), may increase the accumulation of metformin.

Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. Metformin HCl 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 /multidrug and toxin extrusion inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis.

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.

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. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy.

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. 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.

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

Alogliptin and metformin HCl tablets are contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ). 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 in alogliptin and metformin HCl tablets, such as anaphylaxis, angioedema and severe cutaneous adverse reactions.

Metabolic acidosis including diabetic ketoacidosis.

Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases.

In the event of an overdose, it is reasonable to institute the necessary clinical monitoring and supportive therapy as dictated by the patient's clinical status. Per clinical judgment, it may be reasonable to initiate removal of unabsorbed material from the gastrointestinal tract. Alogliptin is minimally dialyzable; over a three-hour hemodialysis session, approximately 7% of the drug was removed.

Therefore, hemodialysis is unlikely to be beneficial in an overdose situation. It is not known if alogliptin is dialyzable by peritoneal dialysis. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions.

Hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected. In the event of an overdose, contact the Poison Help Line, (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.