Alogliptin and Pioglitazone

ALOGLIPTIN AND PIOGLITAZONE- alogliptin benzoate and pioglitazone hydrochloride tablet, film coated
Perrigo New York Inc

WARNING: CONGESTIVE HEART FAILURE

  • Thiazolidinediones, including pioglitazone, which is a component of alogliptin and pioglitazone tablets, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1)].
  • After initiation of alogliptin and pioglitazone tablets and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea and/or edema). If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone in alogliptin and pioglitazone tablets must be considered [see Warnings and Precautions (5.1)].
  • Alogliptin and pioglitazone tablets are not recommended in patients with symptomatic heart failure [see Warnings and Precautions (5.1)].
  • Initiation of alogliptin and pioglitazone tablets in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

1.1 Monotherapy and Combination Therapy

Alogliptin and pioglitazone tablets are indicated 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 [see Clinical Studies (14)].

Important Limitations of Use

Alogliptin and pioglitazone tablets are not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.

2 DOSAGE AND ADMINISTRATION

2.1 Recommendations for All Patients

Alogliptin and pioglitazone tablets should be taken once daily and can be taken with or without food. The tablets must not be split before swallowing.

The recommended starting dose for alogliptin and pioglitazone tablets:

  • for patients inadequately controlled on diet and exercise is 25 mg/15 mg or 25 mg/30 mg,
  • for patients inadequately controlled on metformin monotherapy is 25 mg/15 mg or 25 mg/30 mg,
  • for patients on alogliptin who require additional glycemic control is 25 mg/15 mg or 25 mg/30 mg,
  • for patients on pioglitazone who require additional glycemic control is 25 mg/15 mg, 25 mg/30 mg or 25 mg/45 mg as appropriate based upon current therapy,
  • for patients switching from alogliptin coadministered with pioglitazone, alogliptin and pioglitazone tablets may be initiated at the dose of alogliptin and pioglitazone based upon current therapy,
  • for patients with congestive heart failure (NYHA Class I or II) is 25 mg/15 mg.

The alogliptin and pioglitazone tablets dose can be titrated up to a maximum of 25 mg/45 mg once daily based on glycemic response as determined by hemoglobin A1c (A1C).

After initiation of alogliptin and pioglitazone tablets or with dose 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) [see Boxed Warning and Warnings and Precautions (5.1)].

2.2 Patients with Renal Impairment

No dose adjustment of alogliptin and pioglitazone tablets is necessary for patients with mild renal impairment (creatinine clearance [CrCl] ≥60 mL/min).

The dose of alogliptin and pioglitazone tablets is 12.5 mg/15 mg, 12.5 mg/30 mg or 12.5 mg/45 mg once daily for patients with moderate renal impairment (CrCl ≥30 to <60 mL/min).

Alogliptin and pioglitazone tablets are not recommended for patients with severe renal impairment or ESRD [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Coadministration of pioglitazone and alogliptin 6.25 mg once daily based on individual requirements may be considered in these patients.

Because there is a need for dose adjustment based upon renal function, assessment of renal function is recommended prior to initiation of alogliptin and pioglitazone tablets therapy and periodically thereafter.

2.3 Coadministration with Strong CYP2C8 Inhibitors

Coadministration of pioglitazone and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately three-fold. Therefore, the maximum recommended dose of alogliptin and pioglitazone tablets is 25 mg/15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

  • 25 mg/15 mg tablets are yellow, round, biconvex, and film-coated, with both “A/P” and “25/15” printed on one side.
  • 25 mg/30 mg tablets are peach, round, biconvex, and film-coated, with both “A/P” and “25/30” printed on one side.
  • 25 mg/45 mg tablets are red, round, biconvex, and film-coated, with both “A/P” and “25/45” printed on one side.
  • 12.5 mg/15 mg tablets are pale yellow, round, biconvex, and film-coated, with both “A/P” and “12.5/15” printed on one side.
  • 12.5 mg/30 mg tablets are pale peach, round, biconvex, and film-coated, with both “A/P” and “12.5/30” printed on one side.
  • 12.5 mg/45 mg tablets are pale red, round, biconvex, and film-coated, with both “A/P” and “12.5/45” printed on one side.

4 CONTRAINDICATIONS

History of a serious hypersensitivity reaction to alogliptin or pioglitazone, components of alogliptin and pioglitazone tablets, such as anaphylaxis, angioedema or severe cutaneous adverse reactions.

Do not initiate in patients with NYHA Class III or IV heart failure [see Boxed Warning].

5 WARNINGS AND PRECAUTIONS

5.1 Congestive Heart Failure

Consider the risks and benefits of alogliptin and pioglitazone 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 congestive heart failure. Patients should be advised of the characteristic symptoms of congestive heart failure and should be instructed to immediately report such symptoms. If congestive heart failure develops, it should be managed according to current standards of care and consider discontinuation of alogliptin and pioglitazone tablets.

Alogliptin

In the EXAMINE trial which enrolled patients with type 2 diabetes 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.

Pioglitazone

Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure [see Boxed Warning, Contraindications (4) and Adverse Reactions (6.1)].

5.2 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, acute pancreatitis was reported in six (0.2%) patients treated with alogliptin 25 mg and two (<0.1%) patients treated with active comparators or placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes and high cardiovascular (CV) risk), acute pancreatitis was reported in ten (0.4%) patients treated with alogliptin and in seven (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.

5.3 Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin. 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 [see Adverse Reactions (6.3)]. 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.

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