"The U.S. Food and Drug Administration today approved Farxiga (dapaglifozin) tablets to improve glycemic control, along with diet and exercise, in adults with type 2 diabetes.
Type 2 diabetes affects about 24 million people and accounts for "...
The following serious adverse reactions are described below or elsewhere in the prescribing information:
- Pancreatitis [see WARNINGS AND PRECAUTIONS]
- Heart Failure [see WARNINGS AND PRECAUTIONS]
- Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
- Hepatic Effects [see WARNINGS AND PRECAUTIONS]
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 (%)|
|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 v arious 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
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.
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
|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)|
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.
Table 3: Most Common Adverse Reactions ( ≥ 5%) in
a Placebo-Controlled Clinical Study of Metformin Monotherapy *
|Adverse Reaction||Metformin Monotherapy
|% of Patients|
|*Reactions that were more common in metformin than placebo-treated patients|
Alogliptin And 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 [see WARNINGS AND PRECAUTIONS].
The following adverse reactions have been identified during the postmarketing use of alogliptin. 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.
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, acute pancreatitis, diarrhea, constipation, nausea, and ileus [see WARNINGS AND PRECAUTIONS]
Read the Kazano (alogliptin and metformin hcl tablets) Side Effects Center for a complete guide to possible side effects
Alogliptin is primarily renally excreted.Cytochrome (CYP) P450-related metabolism is negligible. No significant drug-drug interactions were observed with the CYP-substrates or inhibitors tested or with renally excreted drugs [see CLINICAL PHARMACOLOGY].
Carbonic Anhydrase Inhibitors
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate and induce nonanion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with metformin, as the risk of lactic acidosis may increase.
Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of KAZANO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
The Use Of Metformin With Other Drugs
Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs and isoniazid. When such drugs are administered to a patient receiving KAZANO, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving KAZANO, the patient should be observed closely for hypoglycemia.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 4/25/2016
Additional Kazano Information
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