^ Important Dosage And Administration Information
^ Hepatic Effects
There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking pioglitazone or alogliptin, although some of the reports contain insufficient information necessary to establish the probable cause [see Adverse Reactions (6.2)].
In glycemic control trials of alogliptin 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.
Patients with type 2 diabetes mellitus may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (ALT, aspartate aminotransferase [AST], alkaline phosphatase and total bilirubin) and assessing the patient is recommended before initiating alogliptin and pioglitazone tablets therapy. In patients with abnormal liver tests, alogliptin and pioglitazone tablets should be initiated with caution.
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 (serum ALT greater than three times the ULN) and if abnormal liver tests persist or worsen, alogliptin and pioglitazone tablets should be interrupted, and an investigation done to establish the probable cause. Alogliptin and pioglitazone tablets should not be restarted in these patients without another explanation for the liver test abnormalities.
^ Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Manufactured for Padagis® Minneapolis, MN 55427 www.padagis.com
All trademarks are the property of their respective owners ALS333 R7
1B000 RC PH2 Rev 06-24
1
^ Description
Alogliptin and pioglitazone tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes mellitus: alogliptin and pioglitazone.
^ Coadministration With Strong Cyp2c8 Inhibitors
The maximum recommended dosage of alogliptin and pioglitazone tablets is 25 mg of alogliptin and 15 mg of pioglitazone once daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
^ 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 the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving alogliptin and pioglitazone tablets. If bullous pemphigoid is suspected, alogliptin and pioglitazone tablets should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
^ 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.
^ Overdosage
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.
In the event of an overdose, contact the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.
^3 Dosage Forms And Strengths
^ Pediatric Use
Safety and effectiveness of alogliptin and pioglitazone tablets in pediatric patients have not been established.
Alogliptin and pioglitazone tablets are not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures and urinary bladder tumors [see Warnings and Precautions (5.1, 5.5, 5.6, 5.7)].
^ Strong Cyp2c8 Inhibitors
An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the concentration-time curve [AUC]) and half-life of pioglitazone. Therefore, the maximum recommended dosage of alogliptin and pioglitazone tablets is 25 mg of alogliptin and 15 mg of pioglitazone once daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].
^4 Contraindications
Alogliptin and pioglitazone tablets are contraindicated in patients with:
^ Animal Toxicology And/or Pharmacology
Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone (approximately 11, one, and two times the MRHD for mice, rats and dogs, respectively, based on mg/m2). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg (approximately 35 times the MRHD based on mg/m2). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately four times the MRHD based on mg/m2), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the MRHD based on mg/m2).
^ How Supplied/storage And Handling
Alogliptin and pioglitazone tablets are available in the following strengths and packages:
25 mg/15 mg tablet: yellow, round, biconvex and film-coated with both “A/P” and “25/15” printed on one side, available in:
25 mg/30 mg tablet: peach, round, biconvex and film-coated with both “A/P” and “25/30” printed on one side, available in:
25 mg/45 mg tablet: red, round, biconvex, film-coated and with both “A/P” and “25/45” printed on one side, available in:
12.5 mg/30 mg tablet: pale peach, round, biconvex and film-coated with both “A/P” and “12.5/30” printed on one side, available in:
^ 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.
^ 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 pioglitazone tablets [see Drug Interactions (7.1)].
^ 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 pioglitazone tablets, assess for other potential causes for the event and institute alternative treatment for diabetes. 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 pioglitazone tablets.
^Principal Display Panel - Mg/ Mg Tablet Bottle Label
NDC 45802-499-65 Rx Only
Alogliptinand PioglitazoneTablets25 mg/45 mg
DISPENSE WITHMEDICATION GUIDE
30 Tablets
Padagis®
0
^ Recommended Dosage And Administration
Recommended Starting Dosage Based on Current Regimen
Individualize the starting dosage of alogliptin and pioglitazone tablets based on the patient's current regimen and the available strengths of alogliptin and pioglitazone tablets (see Table 1).
Dosage Titration for Additional Glycemic Control
Titrate the alogliptin and pioglitazone tablets dosage gradually, as needed, after assessing therapeutic response and tolerability, up to a maximum dosage of 25 mg of alogliptin and 45 mg of pioglitazone once daily.
^ Insulin Secretagogues And Insulin
Insulin and insulin secretagogues are known to cause hypoglycemia. Coadministration of alogliptin and pioglitazone tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue and insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.8)].
^Principal Display Panel - Mg/ Mg Tablet Bottle Label
NDC 45802-260-65 Rx Only
Alogliptinand PioglitazoneTablets12.5 mg/30 mg
DISPENSE WITHMEDICATION GUIDE
30 Tablets
Padagis®
^ Clinical Studies
The effectiveness of alogliptin and pioglitazone tablets has been established based on four adequate and well-controlled Phase 3 trials of alogliptin and pioglitazone as adjunct to diet to improve glycemic control in adult patients with type 2 diabetes mellitus.
In patients with type 2 diabetes mellitus, treatment with alogliptin and pioglitazone produced clinically meaningful and statistically significant improvements in A1C compared to either alogliptin or pioglitazone alone. As is typical for trials of agents to treat type 2 diabetes mellitus, the mean reduction in A1C with alogliptin and pioglitazone appears to be related to the degree of A1C elevation at baseline.
^ Topiramate
A decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate [see Clinical Pharmacology (12.3)]. The clinical relevance of this decrease is unknown; however, when alogliptin and pioglitazone tablets and topiramate are used concomitantly, monitor patients for adequate glycemic control.
^6 Adverse Reactions
The following serious adverse reactions are described below or elsewhere in the prescribing information:
^ 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 pioglitazone tablets.
After initiation of alogliptin and pioglitazone tablets, patients should be observed for signs and symptoms of pancreatitis. If pancreatitis is suspected, alogliptin and pioglitazone tablets should promptly be discontinued and appropriate management should be initiated.
^ Females And Males Of Reproductive Potential
Discuss the potential for unintended pregnancy with premenopausal women as therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some anovulatory women.
^ Cyp2c8 Inducers
An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with alogliptin and pioglitazone tablets, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of alogliptin and pioglitazone tablets (25 mg of alogliptin and 45 mg of pioglitazone) [see Clinical Pharmacology (12.3)].
^1 Indications And Usage
Alogliptin and pioglitazone tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
^Warning: Congestive Heart Failure
^Principal Display Panel - Mg/ Mg Tablet Bottle Label
NDC 45802-402-65 Rx Only
Alogliptinand PioglitazoneTablets25 mg/30 mg
DISPENSE WITHMEDICATION GUIDE
30 Tablets
Padagis®
^ Recommended Dosage For Patients With Renal Impairment
^ Mechanism Of Action
Alogliptin and pioglitazone tablets combine two antihyperglycemic agents: alogliptin and pioglitazone.
^Principal Display Panel - Mg/ Mg Tablet Bottle Label
NDC 45802-351-65 Rx Only
Alogliptinand PioglitazoneTablets25 mg/15 mg
DISPENSE WITHMEDICATION GUIDE
30 Tablets
Padagis®
^ Recommendations For Congestive Heart Failure
Starting Dosage in Patients with NYHA Class I or II Congestive Heart Failure
For patients with preexisting NYHA Class I or II congestive heart failure, the recommended starting dosage of alogliptin and pioglitazone tablets is 25 mg of alogliptin and 15 mg of pioglitazone [see Boxed Warning and Warnings and Precautions (5.1)].
Monitoring for Fluid Retention and Dosage Modifications for Congestive Heart Failure
After initiation of alogliptin and pioglitazone tablets or with dosage increase, monitor patients carefully for adverse reactions related to fluid retention as has been seen with pioglitazone (e.g., weight gain, edema and signs and symptoms of congestive heart failure).
If congestive heart failure develops while taking alogliptin and pioglitazone tablets, consider discontinuation of alogliptin and pioglitazone tablets or dosage reduction of pioglitazone in alogliptin and pioglitazone tablets [see Boxed Warning and Warnings and Precautions (5.1)].