1.1 Monotherapy and Combination Therapy

NESINA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings [see Clinical Studies (14)].

1.2 Limitation of Use

NESINA should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

2.1 Recommended Dosing

The recommended dose of NESINA is 25 mg once daily.

NESINA may be taken with or without food.

2.2 Patients with Renal Impairment

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

The dose of NESINA is 12.5 mg once daily for patients with moderate renal impairment (CrCl ≥30 to <60 mL/min).

The dose of NESINA is 6.25 mg once daily for patients with severe renal impairment (CrCl ≥15 to <30 mL/min) or with end-stage renal disease (ESRD) (CrCl <15 mL/min or requiring hemodialysis). NESINA may be administered without regard to the timing of dialysis. NESINA has not been studied in patients undergoing peritoneal dialysis [see Clinical Pharmacology (12.3)].

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

5.1 Pancreatitis

There have been postmarketing reports of acute pancreatitis in patients taking NESINA. After initiation of NESINA, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, NESINA should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using NESINA.

5.2 Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with NESINA. These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue NESINA, assess for other potential causes for the event and institute alternative treatment for diabetes [see Adverse Reactions (6.2)]. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with NESINA.

5.3 Hepatic Effects

There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking NESINA, although some of the reports contain insufficient information necessary to establish the probable cause [see Adverse Reactions (6.2)]. In randomized controlled studies, serum alanine aminotransferase (ALT) elevations greater than three times the upper limit of normal (ULN) were observed: 1.3% in alogliptin-treated patients and 1.5% in all comparator-treated patients.

Patients with type 2 diabetes may have fatty liver disease, 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 and assessing the patient before initiating NESINA therapy is recommended. In patients with abnormal liver tests, NESINA 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 and if abnormal liver tests persist or worsen, NESINA should be interrupted and investigation done to establish the probable cause. NESINA should not be restarted in these patients without another explanation for the liver test abnormalities.

5.4 Use with Medications Known to Cause Hypoglycemia

Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with NESINA.

5.5 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with NESINA or any other antidiabetic drug.

6.1 Clinical Studies 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 clinical practice.

Approximately 8500 patients with type 2 diabetes have been treated with NESINA in 14 randomized, double-blind, controlled clinical trials with approximately 2900 subjects randomized to placebo and approximately 2200 to an active comparator. The mean exposure to NESINA was 40 weeks with more than 2400 subjects treated for more than one year. Among these patients, 63% had a history of hypertension, 51% had a history of dyslipidemia, 25% had a history of myocardial infarction, 8% had a history of unstable angina and 7% had a history of congestive heart failure. The mean duration of diabetes was seven years, the mean body mass index (BMI) was 31 kg/m2 (51% of patients had a BMI ≥30 kg/m2), and the mean age was 57 years (24% of patients ≥65 years of age).

Two placebo-controlled monotherapy trials of 12 and 26 weeks of duration were conducted in patients treated with NESINA 12.5 mg daily, NESINA 25 mg daily and placebo. Four placebo-controlled add-on combination therapy trials of 26 weeks duration were also conducted: with metformin, with a sulfonylurea, with a thiazolidinedione and with insulin.

Four placebo-controlled and one active-controlled trials of 16 weeks up through two years in duration were conducted in combination with metformin, in combination with pioglitazone and with pioglitazone added to a background of metformin therapy.

Three active-controlled trials of 52 weeks in duration were conducted in patients treated with pioglitazone and metformin, in combination with metformin and as monotherapy compared to glipizide.

In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse events was 66% in patients treated with NESINA 25 mg compared to 62% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse events was 4.7% with NESINA 25 mg compared to 4.5% with placebo or 6.2% with active comparator.

Adverse reactions reported in ≥4% of patients treated with NESINA 25 mg and more frequently than in patients who received placebo are summarized in Table 1.

 

Hypoglycemia

Hypoglycemic events were documented based upon a blood glucose value and/or clinical signs and symptoms of hypoglycemia.

In the monotherapy study, the incidence of hypoglycemia was 1.5% in patients treated with NESINA compared to 1.6% with placebo. The use of NESINA as add-on therapy to glyburide or insulin did not increase the incidence of hypoglycemia compared to placebo. In a monotherapy study comparing NESINA to a sulfonylurea in elderly patients, the incidence of hypoglycemia was 5.4% with NESINA compared to 26% with glipizide (Table 2).

* Adverse reactions of hypoglycemia were based on all reports of symptomatic and asymptomatic hypoglycemia; a concurrent glucose measurement was not required; intent-to-treat population. † Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level or loss of consciousness or seizure.
Table 2. Incidence and Rate of Hypoglycemia* in Placebo and Active-Controlled Studies when NESINA Was Used as Add-On Therapy to Glyburide, Insulin, Metformin, Pioglitazone or Compared to Glipizide
Add-On to Glyburide (26 Weeks)	NESINA 25 mg + Glyburide	Placebo + Glyburide
	N=198	N=99
Overall (%)	19 (9.6)	11 (11.1)
Severe (%)†	0	1 (1)
Add-On to Insulin (± Metformin) (26 Weeks)	NESINA 25 mg + Insulin (± Metformin)	Placebo + Insulin (± Metformin)
	N=129	N=129
Overall (%)	35 (27)	31 (24)
Severe (%)†	1 (0.8)	2 (1.6)
Add-On to Metformin (26 Weeks)	NESINA 25 mg + Metformin	Placebo + Metformin
	N=207	N=104
Overall (%)	0	3 (2.9)
Severe (%)†	0	0
Add-On to Pioglitazone (± Metformin or Sulfonylurea) (26 Weeks)	NESINA 25 mg + Pioglitazone	Placebo + Pioglitazone
	N=199	N=97
Overall (%)	14 (7.0)	5 (5.2)
Severe (%)†	0	1 (1)
Compared to Glipizide (52 Weeks)	NESINA 25 mg	Glipizide
	N=222	N=219
Overall (%)	12 (5.4)	57 (26)
Severe (%)†	0	3 (1.4)
Add-On to Metformin (26 Weeks)	NESINA 25 mg	Metformin 500 mg twice daily
	N=112	N=109
Overall (%)	2 (1.8)	2 (1.8)
Severe (%)†	0	0
Add-On to Metformin Compared to Glipizide (52 Weeks)	NESINA 25 mg + Metformin	Glipizide + Metformin
	N=877	N=869
Overall (%)	12 (1.4)	207 (23.8)
Severe (%)†	0	以下是“全球医药”详细资料

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