KAZANO SIDE EFFECTS

Last updated on MDtodate: 10/6/2022

SIDE EFFECTS

The following serious adverse reactions are described below or elsewhere in the prescribing information:

• Pancreatitis
• Heart Failure
• Hypersensitivity Reactions
• Hepatic Effects
• Severe and Disabling Arthralgia
• Bullous Pemphigoid

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 Hydrochloride

Over 2700 patients with type 2 diabetes have received alogliptin coadministered with metformin in four large, randomized, double-blind controlled clinical trials. The mean exposure to KAZANO was 58 weeks, with more than 1400 subjects treated for more than one year. These included two 26 week placebo-controlled studies, one 52 week active control study and an interim analysis of a 104 week active-controlled study. In the KAZANO arm, the mean duration of diabetes was approximately six years, the mean body mass index (BMI) was 31 kg/m² (56% of patients had a BMI ≥30 kg/m²) and the mean age was 55 years (18% of patients ≥65 years of age).

In a pooled analysis of these four controlled clinical studies, the overall incidence of adverse reactions was 74% in patients treated with KAZANO compared to 75% treated with placebo. Overall discontinuation of therapy due to adverse reactions was 6.2% with KAZANO compared to 1.9% in placebo, 6.4% in metformin and 5.0% in alogliptin.

Adverse reactions reported in ≥4% of patients treated with KAZANO 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 Patients Treated with KAZANO and More Frequently Than in Patients Receiving Either Alogliptin, Metformin or Placebo

	Number of Patients (%)
	KAZANO* N=2794	Alogliptin† N=222	Metformin‡ N=1592	Placebo N=106
Upper respiratory tract infection	224 (8.0)	6 (2.7)	105 (6.6)	3 (2.8)
Nasopharyngitis	191 (6.8)	7 (3.2)	93 (5.8)	2 (1.9)
Diarrhea	155 (5.5)	4 (1.8)	105 (6.6)	3 (2.8)
Hypertension	154 (5.5)	5 (2.3)	96 (6.0)	6 (5.7)
Headache	149 (5.3)	11 (5.0)	74 (4.6)	3 (2.8)
Back pain	119 (4.3)	1 (0.5)	72 (4.5)	1 (0.9)
Urinary tract infection	116 (4.2)	4 (1.8)	59 (3.7)	2 (1.9)
*KAZANO – includes data pooled for patients receiving alogliptin 25 and 12.5 mg combined with various dose of metformin †Alogliptin – includes data pooled for patients receiving alogliptin 25 and 12.5 mg ‡Metformin – includes data pooled for patients receiving various doses of metformin

 

Hypoglycemia

In a 26 week, double-blind, placebo-controlled study of alogliptin in combination with metformin, the number of patients reporting hypoglycemia was 1.9% in the alogliptin 12.5 mg with metformin HCl 500 mg, 5.3% in the alogliptin 12.5 mg with metformin HCl 1000 mg, 1.8% in the metformin HCl 500 mg and 6.3% in the metformin HCl 1000 mg treatment groups.

In a 26 week placebo-controlled study 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 with metformin and 2.9% in the placebo treatment groups.

In a 52 week, active-controlled, double-blind study of alogliptin once daily as add-on therapy to the combination of pioglitazone 30 mg and metformin compared to the titration of pioglitazone 30 mg to 45 mg and metformin, the number of patients reporting hypoglycemia was 4.5% in the alogliptin 25 mg with pioglitazone 30 mg and metformin group versus 1.5% in the pioglitazone 45 mg with metformin group.

In an interim analysis conducted in a 104-week, double-blind, active-controlled study 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

A total of 14,778 patients with type 2 diabetes participated in 14 randomized, double-blind, controlled clinical trials of whom 9052 subjects were treated with alogliptin, 3469 subjects were treated with placebo and 2257 were treated with an active comparator. The mean duration of diabetes was seven years, the mean body mass index (BMI) was 31 kg/m² (49% of patients had a BMI ≥30 kg/m²), and the mean age was 58 years (26% of patients ≥65 years of age). The mean exposure to alogliptin was 49 weeks with 3348 subjects treated for more than one year.

In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse reactions was 73% in patients treated with alogliptin 25 mg compared to 75% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse reactions was 6.8% with alogliptin 25 mg compared to 8.4% with placebo or 6.2% with active comparator.

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: Adverse Reactions Reported in ≥4% Patients Treated with Alogliptin 25 mg and More Frequently Than in Patients Given Placebo in Pooled Studies

	Number of Patients (%)
	Alogliptin 25 mg N=6447	Placebo N=3469	Active Comparator N=2257
Nasopharyngitis	309 (4.8)	152 (4.4)	113 (5.0)
Upper Respiratory Tract Infection	287 (4.5)	121 (3.5)	113 (5.0)
Headache	278 (4.3)	101 (2.9)	121 (5.4)

 

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 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 study 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 Hydrochloride

Table 3: Most Common Adverse Reactions (≥5%) in a Placebo-Controlled Clinical Study of Metformin Monotherapy*

Adverse Reaction	Metformin Monotherapy (n=141)	Placebo (n=145)
	% of Patients
Diarrhea	53.2	11.7
Nausea/vomiting	25.5	8.3
Flatulence	12.1	5.5
Asthenia	9.2	5.5
Indigestion	7.1	4.1
Abdominal discomfort	6.4	4.8
Headache	5.7	4.8
*Reactions that were more common in metformin than placebo-treated patients

 

Laboratory Abnormalities

Alogliptin And Metformin Hydrochloride

No clinically meaningful differences were observed among treatment groups regarding hematology, serum chemistry or urinalysis results.

Metformin Hydrochloride

Metformin may lower serum vitamin B12 concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on KAZANO, and any apparent abnormalities should be appropriately investigated and managed .

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use. 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

Acute pancreatitis, hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria and severe cutaneous adverse reactions, including Stevens-Johnson syndrome, hepatic enzyme elevations, fulminant hepatic failure, severe and disabling arthralgia and bullous pemphigoid, rhabdomyolysis, diarrhea, constipation, nausea, and ileus.

Metformin

Cholestatic, hepatocellular, and mixed hepatocellular liver injury.