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Alogliptin and Pioglitazone

Pronunciation

(al oh GLIP tin & pye oh GLI ta zone)

Index Terms

  • Alogliptin Benz/Pioglitazone
  • Alogliptin Benz/Pioglitzone
  • Pioglitazone and Alogliptin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Oseni: Alogliptin 25 mg and pioglitazone 15 mg, Alogliptin 25 mg and pioglitazone 30 mg, Alogliptin 25 mg and pioglitazone 45 mg, Alogliptin 12.5 mg and pioglitazone 15 mg, Alogliptin 12.5 mg and pioglitazone 30 mg, Alogliptin 12.5 mg and pioglitazone 45 mg

Brand Names: U.S.

  • Oseni

Pharmacologic Category

  • Antidiabetic Agent, Dipeptidyl Peptidase 4 (DPP-4) Inhibitor
  • Antidiabetic Agent, Thiazolidinedione

Pharmacology

Alogliptin inhibits dipeptidyl peptidase 4 (DPP-4) enzyme resulting in prolonged active incretin levels. Incretin hormones (eg, glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic beta cells and decreasing glucagon secretion from pancreatic alpha cells. Decreased glucagon secretion results in decreased hepatic glucose production. Under normal physiologic circumstances, incretin hormones are released by the intestine throughout the day and levels are increased in response to a meal; incretin hormones are rapidly inactivated by the DPP-4 enzyme.

Pioglitazone is a thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin, without increasing pancreatic insulin secretion. It has a mechanism of action that is dependent on the presence of insulin for activity. Pioglitazone is a potent and selective agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma). Activation of nuclear PPARgamma receptors influences the production of a number of gene products involved in glucose and lipid metabolism. PPARgamma is abundant in the cells within the renal collecting tubules; fluid retention results from stimulation by thiazolidinediones which increases sodium reabsorption.

Use: Labeled Indications

Diabetes mellitus, type 2: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both alogliptin and pioglitazone is appropriate as monotherapy or combination therapy.

Contraindications

Serious hypersensitivity (eg, anaphylaxis, angioedema, severe dermatologic reactions) to products that contain alogliptin, pioglitazone, or any component of the formulation; initiation in patients with NYHA Class III or IV heart failure

Dosing: Adult

Type 2 diabetes mellitus: Oral: Initial doses should be based on current dose of alogliptin and pioglitazone. Maximum: alogliptin 25 mg/pioglitazone 45 mg daily

Patients inadequately controlled on diet and exercise, metformin alone, or alogliptin alone: Initial dose: Alogliptin 25 mg/pioglitazone 15 mg or alogliptin 25 mg/pioglitazone 30 mg once daily

Patients inadequately controlled on pioglitazone alone: Initial dose: Alogliptin 25 mg per day plus current daily dose of pioglitazone given once daily

Patients with NYHA Class I or II heart failure: Initial dose: Alogliptin 25 mg/pioglitazone 15 mg once daily

Patients switching from individual alogliptin and pioglitazone administration: Initial doses should be based on current dose of alogliptin and pioglitazone given once daily

Note: Patients currently receiving an adjusted dose of alogliptin for severe renal impairment or ESRD should not be switched to a combination product.

Concomitant use with insulin or insulin secretagogues: Reduced dose of insulin or insulin secretagogues (eg, sulfonylureas) may be needed.

Dosage adjustment with strong CYP2C8 inhibitors (eg, gemfibrozil): Maximum recommended dose: alogliptin 25 mg/pioglitazone 15 mg once daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥60 mL/minute: No dosage adjustment necessary.

CrCl ≥30 to <60 mL/minute:

Patients inadequately controlled on diet and exercise, metformin alone, or alogliptin alone: Initial dose: Alogliptin 12.5 mg/pioglitazone 15 mg or alogliptin 12.5 mg/pioglitazone 30 mg once daily. Maximum: Alogliptin 12.5 mg/pioglitazone 45 mg once daily

Patients inadequately controlled on pioglitazone alone: Initial dose: Alogliptin 12.5 mg daily plus current daily dose of pioglitazone given once daily. Maximum: Alogliptin 12.5 mg/pioglitazone 45 mg once daily

Patients with NYHA Class I or II heart failure: Initial dose: Alogliptin 12.5 mg/pioglitazone 15 mg once daily. Maximum: Alogliptin 12.5 mg/pioglitazone 45 mg daily

Patients switching from individual alogliptin and pioglitazone administration: Initial doses should be based on current dose of alogliptin and pioglitazone given once daily. Maximum: Alogliptin 12.5 mg/pioglitazone 45 mg daily

CrCl <30 mL/minute, or ESRD: Use is not recommended. Appropriately adjusted dosage of individual components may be considered.

Dosing: Hepatic Impairment

Note: Based upon individual components; information regarding combination product is unavailable.

Alogliptin:

Mild-to-moderate impairment (Child-Pugh score 7-9): No dosage adjustment necessary. Use with caution.

Severe impairment (Child-Pugh score >9): No dosage adjustment provided in manufacturer’s labeling (has not been studied).

Pioglitazone: Moderate-to-severe impairment: No dosage adjustment necessary. Clinical trials have generally excluded patients with serum ALT >2.5 x ULN; use caution in patients with liver disease.

Administration

May be taken with or without food. Swallow tablets whole; do not split or divide.

Dietary Considerations

May be taken with or without food. Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture and humidity.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy

ACE Inhibitors: DPP-IV Inhibitors may enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Clopidogrel: May increase the serum concentration of Pioglitazone. Monitor therapy

CYP2C8 Inducers (Strong): May increase the metabolism of CYP2C8 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C8 Inhibitors (Moderate): May decrease the metabolism of CYP2C8 Substrates. Monitor therapy

CYP2C8 Inhibitors (Strong): May increase the serum concentration of Pioglitazone. Management: Limit pioglitazone adult maximum dose to 15 mg/day when used in combination with any strong CYP2C8 inhibitor. Consider therapy modification

CYP2C8 Substrates: CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP2C8 Substrates. Management: Seek alternatives to the CYP2C8 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy

Gemfibrozil: May decrease the metabolism of Antidiabetic Agents (Thiazolidinedione). Management: Limit pioglitazone maximum adult dose to 15 mg/day, and consider dose reduction of rosiglitazone, when used in combination with gemfibrozil. Consider therapy modification

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Insulin: Pioglitazone may enhance the adverse/toxic effect of Insulin. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone, dose reductions should be considered to reduce the risk of hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure. Consider therapy modification

Lumacaftor: May increase the serum concentration of CYP2C8 Substrates. Lumacaftor may decrease the serum concentration of CYP2C8 Substrates. Monitor therapy

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2C8 Substrates. Management: Use CYP2C8 substrates at the lowest recommended dose, and monitor closely for adverse effects (including myopathy), during and in the 2 weeks following mifepristone treatment. Consider therapy modification

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pregabalin: May enhance the fluid-retaining effect of Antidiabetic Agents (Thiazolidinedione). Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

RifAMPin: May increase the metabolism of Antidiabetic Agents (Thiazolidinedione). Management: Consider alternatives to the concomitant use of rifampin with thiazolidinedione antidiabetic agents. Monitor patients receiving these combinations for decreased effects of the thiazolidinedione derivative. Consider therapy modification

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Sulfonylureas: Antidiabetic Agents (Thiazolidinedione) may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose adjustments in patients taking thiazolidinediones and monitor for hypoglycemia. Consider therapy modification

Sulfonylureas: DPP-IV Inhibitors may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Trimethoprim: May decrease the metabolism of Antidiabetic Agents (Thiazolidinedione). Monitor therapy

Adverse Reactions

Percentages as reported with combination product. Also see individual agents.

1% to 10%:

Endocrine & metabolic: Hypoglycemia (≤4%)

Neuromuscular & skeletal: Back pain (4%)

Respiratory: Nasopharyngitis (5%), upper respiratory tract infection (4%)

<1% (Limited to important or life-threatening): Severe arthralgia (FDA Safety Alert, Aug 28, 2015)

ALERT: U.S. Boxed Warning

Congestive heart failure:

Thiazolidinediones, including pioglitazone, cause or exacerbate congestive heart failure (CHF) in some patients. After initiation and after dose increases, monitor patients carefully for signs and symptoms of heart failure (eg, excessive, rapid weight gain; dyspnea, edema). If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of alogliptin/pioglitazone must be considered.

Alogliptin/pioglitazone is not recommended in patients with symptomatic heart failure. Initiation in patients with established New York Heart Association (NYHA) class III or IV heart failure is contraindicated.

Warnings/Precautions

Concerns related to adverse effects:

• Arthralgia: Severe and disabling arthralgia has been reported with DPP-4 inhibitor use; onset may occur within one day to years after treatment initiation and may resolve with discontinuation of therapy. Some patients may experience a recurrence of symptoms if DPP-4 inhibitor therapy resumed. Discontinue use if severe joint pain results from DPP-4 inhibitor therapy.

• Bladder cancer: Clinical trial data suggest an increased risk of bladder cancer in patients exposed to pioglitazone; risk may be increased with duration of use. Avoid use in patients with active bladder cancer and consider risks versus benefits prior to initiating therapy in patients with a history of bladder cancer.

• Edema: Dose-related edema, including new-onset or exacerbation of existing edema, has been reported; use with caution in patients with edema or at risk for heart failure. Monitor for signs/symptoms of heart failure.

• Fractures: Increased incidence of bone fractures in females treated with pioglitazone; majority of fractures occurred in the lower limb and distal upper limb. Consider risk of fracture prior to initiation and during use. According to the American Diabetes Association guidelines, thiazolidinediones should be avoided in patients with fracture risk factors (ADA 2016a).

• Heart failure/cardiac effects: [US Boxed Warning]: Thiazolidinediones, including pioglitazone, may cause or exacerbate heart failure; closely monitor for signs and symptoms of heart failure (eg, rapid weight gain, dyspnea, edema), particularly after initiation or dose increases; if heart failure develops, treat accordingly and consider dose reduction or discontinuation of alogliptin and pioglitazone. Monitor patients for signs and symptoms of heart failure (eg, dyspnea, edema, excessive/rapid weight gain). Not recommended for use in any patient with symptomatic heart failure. Initiation of therapy is contraindicated in patients with NYHA class III or IV heart failure; if used in patients with NYHA class I or II (systolic) heart failure, initiate at lowest dosage and monitor closely. Alogliptin may be associated with increased risk of hospitalization due to heart failure. Use with caution in patients with a history of heart failure; consider discontinuation of therapy if heart failure develops.

• Hematologic effects: May decrease hemoglobin/hematocrit; effects may be related to increased plasma volume. Use with caution in patients with anemia.

• Hepatotoxicity: Cases of fatal and nonfatal hepatic failure have been reported in postmarketing surveillance. Baseline liver function tests (serum transaminases) are recommended to rule out underlying liver diseases. Use with caution in patients with abnormal serum transaminases. Monitor and promptly evaluate serum transaminase levels in patients with symptoms of hepatic injury (eg, fatigue, anorexia, jaundice, dark urine, and/or abdominal pain). In patients with clinically significant transaminase elevations and/or persistent or worsening elevations, therapy should be interrupted. Therapy should only be resumed with caution in patients where an alternative cause of transaminase elevations has been determined.

• Hypersensitivity reactions: Rare hypersensitivity reactions, including anaphylaxis, angioedema, and/or severe dermatologic reactions such as Stevens-Johnson syndrome, have been reported in postmarketing surveillance; discontinue if signs/symptoms of hypersensitivity reactions occur. Use with caution if patient has experienced angioedema with other DPP-4 inhibitor use.

• Pancreatitis: Cases of acute pancreatitis have been reported with use. Monitor for signs/symptoms of pancreatitis; discontinue use immediately if pancreatitis is suspected and initiate appropriate management. Use with caution in patients with a history of pancreatitis as it is not known if this population is at greater risk.

• Weight gain: Dose-related weight gain observed with use; mechanism unknown but likely associated with fluid retention and fat accumulation.

Disease-related concerns:

• Diabetes mellitus (type 1): Not indicated for use in patients with type 1 diabetes mellitus (insulin dependent, IDDM) due to lack of efficacy in this population.

• Diabetic ketoacidosis (DKA): Not indicated for use in patients with DKA due to lack of efficacy in this patient population.

• Hepatic impairment: Safety and efficacy have not been established in severe hepatic dysfunction. Dosage adjustments are not required in mild or moderate hepatic dysfunction based on properties of individual components. Use with caution in patients with liver disease.

• Macular edema: Has been reported with thiazolidinedione use, including pioglitazone; some patients with macular edema presented with blurred vision or decreased visual acuity, and most had peripheral edema at time of diagnosis. Patients should be seen by an ophthalmologist if any visual symptoms arise during therapy and all diabetic patients should have regular eye exams.

• Renal impairment: Use with caution in patients with moderate renal dysfunction; dosing adjustment required. Not recommended in patients with severe renal dysfunction or end-stage renal disease (ESRD); appropriately adjusted dosage of individual components may be considered.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Premenopausal/anovulatory females: Use with caution in premenopausal, anovulatory women; may result in a resumption of ovulation, increasing the risk of pregnancy. Adequate contraception is recommended during therapy.

Other warnings/precautions:

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

Monitoring Parameters

HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2016b]), serum glucose; signs and symptoms of heart failure; renal function (prior to initiation of therapy then annually or more frequent if necessary); liver enzymes (ALT, AST, alkaline phosphatase, and total bilirubin) prior to initiation in all patients (continue routine periodic monitoring during treatment in patients with liver disease or suspected liver disease); routine ophthalmic exams are recommended; patients reporting visual deterioration should have a prompt referral to an ophthalmologist and consideration should be given to discontinuing pioglitazone; signs/symptoms of bladder cancer (dysuria, macroscopic hematuria, dysuria, urinary urgency).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Refer to individual agents.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, rhinitis, rhinorrhea, pharyngitis, or back pain. Have patient report immediately to prescriber signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), painful urination, hematuria, change in amount of urine passed, bone pain, loss of strength and energy, angina, vision changes, signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, increased hunger, or sweating), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), joint pain, or signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating, and advising patients.

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