Date of approval.
Date of revision.
Pioglitazone Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the direction of your physician.
Warning: Congestive Heart Failure
Thiazolidinediones, including pioglitazone, are at risk of causing or worsening congestive heart failure in some patients (see [Precautions]). Patients should be monitored closely for signs and symptoms of heart failure (including abnormally rapid weight gain, dyspnea, and/or edema) when starting this drug and when doses are increased. If these signs and symptoms occur, the patient should be managed according to standard heart failure treatment protocols and the drug must be discontinued or the dose reduced.
This product is contraindicated in patients with heart failure (see [Contraindications] and [Precautions]).
Drug Name]
Generic name: Pioglitazone Hydrochloride Tablets
English name: Pioglitazone Hydrochloride Tablets
Hanyu Pinyin: Yansuan Bigelietong Pian
Ingredients
The main ingredient of this product is pioglitazone hydrochloride. Its chemical name is: (±) 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]phenylmethyl}-2,4-thiazolidinedione hydrochloride.
Its structural formula is as follows
Molecular formula: C19H20N2O3S-HCl
Molecular weight: 392.89
【Properties】.
This product is a white or off-white tablet with indentations.
Indications
Type 2 diabetes mellitus
This product is used only in patients with presumed insulin resistance who have received the following therapies without adequate effect
1 1) Using diet therapy and/or exercise therapy only
2) Using diet therapy and/or exercise therapy plus sulfonylureas
3) Use of diet therapy and/or exercise therapy plus alpha-glucosidase inhibitors
4) Use of diet therapy and/or exercise therapy plus biguanides
2) Use of diet therapy and/or exercise therapy plus insulin preparations
<Precautions regarding indications>
This product should only be used in patients who have been clearly diagnosed with diabetes mellitus. It should be noted that in addition to diabetes, there are diseases with diabetes-like symptoms such as abnormal glucose tolerance and positive urine sugar (renal diabetes, geriatric abnormalities of glucose tolerance, thyroid abnormalities, etc.).
Specification
30mg (based on C19H20N2O3S)
Dosage and Administration
1 Recommended use for all patients
Take orally, once a day.
The recommended starting dose for patients without congestive heart failure is 15mg or 30mg once a day.
The recommended starting dose for patients with congestive heart failure (NYHA class I and II) is 15 mg once a day.
The dose may be increased gradually from 15 mg once a day to a maximum dose of 45 mg once a day depending on the change in glycosylated hemoglobin (HbA1c) test blood glucose.
Patients should be closely monitored for adverse effects associated with fluid retention (e.g., weight gain, edema), as well as signs and symptoms of congestive heart failure, after initial administration or dose increase.
Liver function tests (serum alanine and aspartate aminotransferases, alkaline phosphokinase, and total bilirubin) are required prior to initial administration of this product. Routine periodic liver function tests are not recommended if the patient does not have liver disease while taking this product. Patients with abnormal liver function tests prior to administration of this product or patients with abnormal liver function detected during administration of this product should take appropriate measures as described in Warnings and Precautions.
2 Combined administration with insulin secretion promoter or insulin
If a patient develops hypoglycemia when this product is combined with an insulin-promoting agent (e.g., sulfonylurea), the dose of the insulin-promoting agent should be reduced.
If a patient develops hypoglycemic symptoms when this product is combined with insulin, the dose of insulin should be reduced by 10% to 25%, and the insulin dosage should be further adjusted according to the patient’s individual blood glucose response.
<Precautions regarding dosage>
1. It has been reported that female patients have a higher chance of edema, so the starting dose for female patients is 15mg once a day, and attention should be paid to observe whether edema occurs.
2.After increasing the dose from 30mg once a day to 45mg once a day, it has been reported that patients have a higher chance of edema, therefore, when increasing the dose to 45mg, attention should be paid to observe whether edema occurs.
3. When this product is used in combination with insulin preparations, there are reports of a higher incidence of edema in patients, so it is appropriate to start with 15mg once a day. The dose should be increased with caution and careful observation of edema and signs and symptoms of heart failure.
4. Usually elderly patients have reduced physiological function, so it is appropriate to start with 15mg once a day.
[Adverse reactions] According to foreign literature.
According to the results of a clinical trial conducted in Japan, among 1368 patients who took pioglitazone 15mg, 30mg or 45mg once a day, 364 patients (26.6%) experienced adverse reactions including abnormal laboratory test values. The incidence of edema was higher in female patients and in combination with insulin [the incidence of edema when this product was used alone and in combination with other hypoglycemic agents other than insulin: 3.9% (26/665) in men and 11.2% (72/643) in women; the incidence of edema when combined with insulin: men: 13.6% (3/22) and 28.9% ( 11/38)]. Moreover, patients with diabetic complications were more likely to develop edema compared to those without diabetic complications [the proportions of patients with retinopathy, with diabetic neuropathy, and with diabetic nephropathy who developed edema were: 10.4% (44/422), 11.4% (39/342), and 10.6% (30/282), respectively]. In addition, the incidence of hypoglycemia increased when combined with insulin [the proportions of hypoglycemia occurring when this product was used alone and when combined with other hypoglycemic agents other than insulin and when combined with insulin were: 0.7% (9/1308) and 33.3% (20/60), respectively]. The results of post-marketing monitoring of actual administration (as of December 2009) showed that 556 patients (16.3%) out of 3421 patients experienced adverse reactions (including abnormal laboratory test values). The following adverse reactions to this product occurred in the clinical trials described above, in post-marketing surveillance results, or in spontaneous reports.
(1) Adverse reactions of clinical significance
(1) Because of the possibility of developing or aggravating heart failure, close observation should be made during the administration of this product. If signs/symptoms such as edema, sudden weight gain and heart failure (shortness of breath, palpitations, increased cardiothoracic ratio, pleural effusion, etc.) occur, appropriate measures such as discontinuation of the drug and administration of medullary diuretics should be taken. Patients with combined heart disease are more likely to have heart failure when taking this product or when combining it with insulin, and therefore patients should be closely monitored for signs of heart failure (refer to items [Caution in use] and [Important precautions]).
(2) Because the increase in circulating plasma volume may cause edema (8.2%, 112/1368 cases), close observation should be made. When edema occurs, take appropriate measures such as reducing the dose or discontinuing the drug. If symptoms do not improve after these measures, consider giving a medullary diuretic (furosemide, etc.) if necessary, depending on the situation. Edema is more common in female patients, patients who are taking insulin in combination with insulin or patients with diabetic complications, and it has also been reported when the dose is increased from 30mg once a day to 45mg. For such patients, special attention should be paid to the occurrence of edema (refer to [precautions concerning dosage]).
3) Hepatic dysfunction or jaundice (<0.1%) may accompany significant elevations of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP). Therefore, in patients with potential liver dysfunction, liver function tests should be performed periodically if necessary. Appropriate measures such as discontinuation of medication should be taken if abnormalities occur.
4) When combined with other hypoglycemic drugs, hypoglycemic symptoms sometimes occur (<0.1~5%). In case of hypoglycemia, this product or the hypoglycemic drug used in combination should be handled with caution such as reducing the dose or suspending the medication. When hypoglycemic symptoms occur with this product, sucrose is usually given, but when hypoglycemic symptoms occur in combination with α-glucosidase inhibitors, glucose should be given. The incidence of hypoglycemic symptoms is higher when combined with insulin.
5) Some features of rhabdomyolysis may occur (frequency of occurrence is unknown), such as muscle pain, weakness, increased phosphocreatine kinase (CK (CPK)), and increased myoglobin in blood and urine. Once this occurs, the drug should be discontinued and appropriate measures should be taken.
6) Cases of recurrence of gastric ulcer have been reported.
7) Bladder cancer: No association between cumulative dose or cumulative duration of ACTOS exposure and bladder cancer was detected in some studies, including the 10-year observational study in the United States, but an association was detected in other studies. The inconsistent results and limitations of these studies lead to an inability to interpret the observational data and thus to conclude that ACTOS may be associated with an increased risk of bladder tumors. There are insufficient data to determine whether pioglitazone is a tumor promoter in bladder cancer.
(2) Other adverse reactions
More than 5% (inclusive) 0.1% to less than 5% Less than 0.1% Frequency unknown 1) Blood Note 1) Anemia, leukopenia or thrombocytopenia 2) Cardiovascular system Increased blood pressure, increased cardiothoracic ratio Note 2), abnormal ECG Note 2), palpitations, chest pressure or facial flushing 3) Allergic reactions Note 3) Rash, eczema, pruritus 4) Digestive system Nausea, vomiting, gastric upset, heartburn, abdominal pain bloating, diarrhea, constipation, hyperphagia or hypophagia 5) LiverNote 4) Elevated AST, ALT, ALP or γ-GTP 6) Psychoneurological system Dizziness, hobbling, headache, sleepiness, malaise, weakness or numbness 7) Elevated other lactate dehydrogenase (LDH) and creatinase (CK (CPK))Note 5) Elevated blood urea nitrogen (BUN) and potassium, decreased total protein and blood calcium, decreased Increased body weight, increased urine protein, shortness of breath arthralgia, tremor, rapid decline in blood glucose with worsening fracture of diabetic retinopathyNote 6) Note 1) Regular blood tests (1 every 3 months or so).
(Note 2) Refer to <Important precautions> in (2).
(Note 3) The product should be discontinued at this time.
Note 4) Frequency of occurrence: AST (GOT) elevation 0.86% (11/1272 cases), ALT elevation 0.94% (12/1276 cases), ALP elevation 0.47% (6/1272 cases), γ-GTP elevation 0.95% (12/1263 cases)
(Note 5) Sometimes, elevated LDH (5.63%, 71/1261 cases) and elevated CK (CPK) (5.00%, 61/1221 cases) were observed closely when abnormalities occurred, such as review.
(Note 6) An increased incidence of fractures in female patients has been reported in clinical studies abroad.
In randomized, double-blind, controlled clinical trials of ACTOS conducted abroad, more than 8,500 patients with type 2 diabetes mellitus were treated with this product, including in the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive ) in which 2,605 patients with type 2 diabetes and macrovascular disease were treated. In these clinical trial studies, more than 6,000 patients were treated for 6 months or longer, 4,500 patients were treated for 1 year or longer, and 3,000 patients were treated for at least 2 years.
In the six placebo-controlled monotherapy trials of 16 to 26 weeks and the combined treatment trials of 16 to 24 weeks, the incidence of patients withdrawing from the trials due to adverse drug events was 4.5% in the drug group and 5.8% in the control group. The incidence of adverse events leading to patient withdrawal was lower in the PROactive arm (1.5%) than in the placebo arm (3.0%), and the most common adverse event leading to withdrawal from the trial was related to poor glycemic control.
In the PROactive trial, the incidence of patient withdrawal due to adverse events was 9.0% and 7.7% in the product and placebo groups, respectively. Congestive heart failure was the most common serious adverse event causing patients to withdraw from the trial, with an incidence of 1.3% in the PROactive arm compared with 0.6% in the placebo arm.
Common Adverse Events: 16-Week to 26-Week Monotherapy Trials
The incidence and types of common adverse events reported in the three 16-week to 26-week placebo-controlled monotherapy clinical trials are shown in Table 1. The table lists adverse events that occurred at an incidence of >5% and were more common in the product group than in the placebo group. These adverse events were not related to the dose of this product administered.
Table 1. three 16-week to 26-week placebo-controlled monotherapy trials.
Reported incidence > 5% and incidence of adverse events higher in the Benadryl group than in the placebo group Event name Placebo N=259 Benadryl N=606 Patients (%) Patients (%) Upper respiratory tract infection 8.513.2 Headache 6.99.1 Sinusitis 4.66.3 Muscle pain 2.75.4 Pharyngitis 0.85.1 Common adverse events: 16-week to 24-week combined medication treatment trials
The incidence and types of common adverse events reported in therapeutic clinical trials of this product in combination with sulfonylureas are shown in Table 2. The incidence >5% and those adverse events that were more common in the highest dose group of this product are listed in the table.
Table 2. 16-week to 24-week clinical trials of combined treatment with this product and sulfonylureas 16-week placebo-controlled trials, reported incidence >5% and incidence of adverse events higher in the Benzedrine 30 mg + sulfonylurea group than in other groups Event name Placebo + sulfonylurea
N=187 Benadryl 15mg+sulfonylurea
N=184 Benadryl 30mg+sulfonylurea
N=189 patients (%) patients (%) patients (%) patients (%) edema 2.11.612.7 headache 3.74.35.3 gastrointestinal gas 0.52.76.3 weight gain 02.75.3
24-week uncontrolled double-blind trial, reported incidence>5% and incidence of adverse events in the Benadryl 45mg+sulfonylurea group over the Benadryl 30mg+sulfonylurea group Event name Benadryl 30mg+sulfonylurea
N=351 Benadryl 45mg + sulfonylurea N=351 patients (%) patients (%) hypoglycemia 13.415.7 edema 10.523.1 upper respiratory tract infection 12.314.8 weight gain 9.113.4 urinary tract infection 5.76.8 Note: the terms peripheral edema, generalized edema, sunken edema, and fluid retention are unified by “edema”. Summary.
The incidence and types of common adverse events reported in clinical trials combining this product with metformin are shown in Table 3. The incidence >5% and the more common adverse events in the highest dose group are listed in the table.
Table 3. 16-week to 24-week placebo-controlled clinical trials of this product in combination with metformin treatment at 16 weeks
Reported incidence >5% and incidence of adverse events that were higher in the Benadryl + metformin group than in the placebo + metformin group Event name Placebo + metformin
N=160 Benadryl 30 mg + metformin
N=168 patients (%) patients (%) edema 2.56.0 headache 1.96.0
24-week uncontrolled double-blind study
Reported incidence >5% and incidence of adverse events in the Benadryl 45mg + metformin group than in the Benadryl 30mg + metformin group Event name Benadryl 30mg + metformin
N=411 Benadryl 45mg+metformin
N=416 Patients (%) Patients (%) Upper respiratory tract infection 12.413.5 Edema 5.813.9 Headache 5.45.8 Weight gain 2.96.7 Note: The terms peripheral edema, generalized panniculitis, sunken edema and fluid retention are uniformly summarized as “edema”.
The incidence and types of common adverse events reported in clinical trials of this product in combination with insulin are shown in Table 4. The incidence of adverse events >5% and those more common at the highest dose of this product are listed in the table.
Table 4. 16-week to 24-week placebo-controlled clinical trials of this product in combination with insulin treatment
Reported incidence >5% and incidence of adverse events higher in the 30mg+insulin group than in the placebo+insulin group Event name Placebo+insulin
N=187 Benadryl 15mg+insulin
N=191 Benadryl 30mg+insulin
N=188 patients (%) patients (%) patients (%) hypoglycemia 4.87.915.4 edema 7.012.617.6 upper respiratory tract infection 9.68.414.9 headache 3.23.16.9 weight gain 0.55.26.4 back pain 4.32.15.3 dizziness 3.72.65.3 gastrointestinal gas 1.63.75.3
24-week uncontrolled double-blind study
Reported incidence>5% and incidence of adverse events in the Benadryl 45mg+insulin group over the Benadryl 30mg+insulin group Event name Benadryl 30mg+insulin
N=345 Benadryl 45mg+insulin
N=345 patients (%) patients (%) hypoglycemia 43.547.8 edema 22.026.1 weight gain 7.213.9 urinary tract infection 4.98.7 diarrhea 5.55.8 back pain 3.86.4 elevated blood creatinine phosphokinase 4.65.5 sinusitis 4.65.5 hypertension 4.15.5 note: peripheral edema, generalized pannic edema, sunken edema, and fluid The terms edema, generalized edema, sunken edema, and fluid retention are summarized uniformly under the term “edema”.
The common adverse events and types of adverse events reported in the PROactive trial are listed in Table 5, and those that occurred at an incidence of >5% and were more common in the product group than in the placebo group.
Table 5. PROactive trial: reported incidence >5% and more common in the product group than in the placebo group. Event name Placebo
N=2633 Benadryl
N=2605 Patients (%) Patients (%) Hypoglycemia 18.827.3 Edema 15.326.7 Heart failure 6.18.1 Extremity pain 5.76.4 Back pain 5.15.5 Chest pain 5.05.1 The mean follow-up period for patients was 34.5 months.
Congestive heart failure: The incidence of adverse events associated with congestive heart failure during the 16-week to 24-week combined clinical trial with sulfonylureas, the 16-week to 24-week clinical trial with insulin, and the 16-week to 24-week clinical trial with metformin are shown in Table 6. no fatal adverse events occurred.
Table 6. congestive heart failure emergency adverse events in patients treated with this product in combination with a sulfonylurea or placebo in combination with a sulfonylurea Event name Placebo-controlled trial (16 weeks) Non-controlled double-blind trial (24 weeks) Placebo
+ sulfonylureas
N=187 Benadryl 15mg
+ sulfonylurea
N=184 Benadryl 30mg
+ sulfonylurea
N=189 Benadryl 30mg
+Sulfonylurea
N=351 Benadryl 45mg
+sulfonylurea
N=351 patient (%) patient (%) patient (%) patient (%) patient (%) patient (%) at least one incident of congestive heart failure2 (1.1%)001 (0.3%)6 (1.7%) admission to hospital2 (1.1%)0002 (0.6%)
Patients treated with this product in combination with insulin or placebo in combination with insulin Placebo-controlled trial (16 weeks) Non-controlled double-blind trial (24 weeks) Event name Placebo
+ insulin
N=187 Benadryl 15mg
+ insulin
N=191 Benadryl 30mg
+ insulin
N=188Phenobarbital 30mg + insulin
+ insulin
N=345Phenobarbital 45mg
+ insulin
N=345 patients (%) patients (%) patients (%) patients (%) patients (%) patients (%) at least one incident of congestive heart failure 02 (1.0%)2 (1.1%)3 (0.9%)5 (1.4%) admission to hospital 02 (1.0%)1 (0.5%)1 (0.3%)3 (0.9%)
Patients treated with this product in combination with metformin or placebo in combination with metformin Event name Placebo-controlled study (16 weeks) Non-controlled double-blind study (24 weeks) Placebo
+ metformin
N=160 this product 30mg
+Metformin
N=168 Benadryl 30mg
+Metformin
N=411 Benadryl 45mg
+Metformin
N=416 patients (%) patients (%) patients (%) patients (%) patients (%) at least one incident of congestive heart failure 01 (0.6%) 01 (0.2%) admission to hospital 01 (0.6%) 01 (0.2%) patients with type 2 diabetes mellitus complicated by congestive heart failure (NYHA class II or early class III) were randomized to 24 weeks of each of the following on a double-blind basis this product or gliphenylurea, where the daily dose of this product was 30 mg to 45 mg (n=262) and the daily dose of gliphenylurea was 10 mg to 15 mg (n=256). The incidence of adverse events associated with congestive heart failure in this trial is summarized in Table 7.
Table 7. Sudden onset of congestive heart failure in patients with concurrent congestive heart failure (NYHA class II or III) treated with this product or gliphenylurea Event name of the event This product
N=262 Glibenclamide
N=256 Patients (%) Patients (%) Death from cardiovascular causes (post-determination outcome)
5 (1.9%)6 (2.3%) Hospital admission due to worsening congestive heart failure (post adjudication)26 (9.9%)12 (4.7%) Emergency department visit due to congestive heart failure (post adjudication)
4 (1.5%)3 (1.2%) Patients experienced worsening congestive heart failure during the trial
35 (13.4%)21 (8.2%) Hospital admissions for congestive heart failure during the PROactive trial are shown in Table 8.
Table 8. sudden-onset congestive heart failure adverse events in the PROactive trial Event name Placebo
N=2633 This product
N=2605 patients (%) patients (%) at least one hospital admission for congestive heart failure events 108 (4.1%) 149 (5.7%) lethal 22 (0.8%) 25 (1.0%) hospital admission, non-lethal 86 (3.3%) 124 (4.7%) Cardiovascular safety: in the PROactive trial, 5238 patients with a history of combined macrovascular disease Nearly all patients (95%) were taking concomitant cardiovascular medications (e.g., beta-blockers, ACE inhibitors, angiotensin 2 receptor antagonists, and cardiovascular drugs). beta-blockers, ACE inhibitors, angiotensin 2 receptor antagonists, calcium channel blockers, nitrates, diuretics, aspirin, statins, and clofibrate). At baseline, the mean age of the patients was 62 years, the mean duration of diabetes was 9.5 years, the mean HbA1c was 8.1%, and the mean follow-up was 34.5 months.
The primary objective of the study was to examine the effect of this product on mortality and the incidence of macrovascular events in patients with type 2 diabetes who are at high risk of developing macrovascular events. The primary efficacy variable was time to first event for any of the cardiovascular composite endpoints, which included all-cause death, nonfatal myocardial infarction (MI) (including resting myocardial infarction), stroke, acute coronary syndrome, cardiac intervention (including coronary artery bypass grafting or percutaneous coronary intervention), major lower extremity great vessel dissection above the ankle, and bypass surgery or revascularization of the lower extremity. revascularization. At least one adverse event occurred in 514 patients (19.7%) in the product group and in 572 patients (21.7%) in the placebo group (hazard ratio 0.90; 95% confidence interval: 0.80, 1.02; p=0.10).
At 3 years into the trial, there was no statistically significant difference in first-ever cardiovascular adverse events between the product and placebo groups, but no increase in mortality or overall large-vessel adverse event rates was found in the product group. The incidence of first-occurrence adverse events associated with the primary trial endpoint and the total number of each adverse event are shown in Table 9.
Table 9. first adverse event and total number of adverse events for cardiovascular-related events trial endpoints Type of cardiovascular event Placebo
N=2633 This product
N=2605 First event n (%) Total events n First event n (%) Total events n Any adverse event 575 (21.7) 900 514 (19.7) 803 Death from all causes 122 (4.6) 186110 (4.2) 177 Non-fatal myocardial infarction (MI) 118 (4.5) 157105 (4.0) 131 Stroke 96(3.6)11976(2.9)92Acute coronary syndrome63(2.4)7842(1.6)65Cardiac surgery (CABG/PCI)101(3.8)240101(3.9)195Lower extremity great vessel dissection13(0.6)289(0.3)28Lower extremity revascularization57(2.2)9271(2.7) 115CABG = coronary artery bypass grafting; PCI = percutaneous intervention
Weight gain: When this product is administered alone or in combination with other hypoglycemic agents, dose related weight gain occurs. The mechanism of weight gain is not known, but is likely related to the combined effects of fluid retention and fat accumulation.
Tables 10 and 11 summarize the weight changes in the 16-week to 26-week randomized, double-blind monotherapy trial and the 16 to 24-week combination therapy trial with other drugs, as well as in the PROactive trial, for the product and placebo groups.
Table 10. Weight change (kg) relative to baseline during the randomized, double-blind clinical trials Control group
(placebo) Benadryl
15 mg of Benadryl
30mg Benadryl
45mg median
(25th/75th
(Percentile) Median
(25th/75th
(Percentile) Median
(25th/75th
Median (percentile)
(25th/75th
Percentile) Monotherapy
(16 weeks to 26 weeks) -1.4(-2.7/0.0)
N=2560.9(-0.5/3.4)
N=791.0(-0.9/3.4)
N=1882.6(0.2/5.4)
N=79 Combined medication treatment
(16 weeks to 24 weeks) Sulfonylureas -0.5 (-1.8/0.7)
N=1872.0(-0.2/3.2)
N=1833.1(1.1/5.4)
N=5284.1(1.8/7.3)
N=333Metformin-1.4(-3.2/0.3)
N=160N/A0.9(-1.3/3.2)
N=5671.8(-0.9/5.0)
N=407Insulin0.2(-1.4/1.4)
N=1822.3(0.5/4.3)
N=1903.3(0.9/6.3)
N=5224.1(1.4/6.8)
N=338
Table 11. median ratio of weight change in patients in the placebo group to patients in the placebo group at double-blind treatment in the PROactive trial placebo median (25th/75th percentile) median (25th/75th percentile) weight change relative to basal status at the last visit (kg) -0.5(-3.3,2.0)
N=2581+3.6(0.0,7.5)
N=2560 Note: The median duration of exposure to this product and placebo was 2.7 years.
Edema: Edema occurring on this product will reversibly improve with discontinuation of this product. Edema usually does not require hospital admission unless congestive heart failure is also present. The frequency and type of edema that occurred during the clinical study of this product are shown in Table 12.
Table 12. Adverse events of edema occurring in patients taking this product Placebo Benadryl 15 mg Benadryl 30 mg Benadryl 45 mg Patient (%) Patient (%) Patient (%) Patient (%) Patient (%) Monotherapy (16 weeks to 26 weeks)3 (1.2%)
N=2592 (2.5%)
N=8113(4.7%)
N=27511 (6.5%)
N=169 Combined medication treatment
(16 weeks to 24 weeks) Sulfonylureas4(2.1%)
N=1873(1.6%)
N=18461(11.3%)
N=54,081(23.1%)
N=351Metformin4(2.5%)
N=160N/A34(5.9%)
N=57958(13.9%)
N=416 insulin13(7.0%)
N=18724(12.6%)
N=191109(20.5%)
N=53390(26.1%)
N=345 Note: The terms peripheral edema, generalized edema, sunken edema, and fluid retention are summarized uniformly as “edema”.
Table 13: Edema Adverse Events in the PROactive Trial Placebo
N=2633 This product
N=2605 patients (%) patients (%) 419 (15.9%) 712 (27.3%) Note: The terms peripheral edema, generalized edema, sunken edema, and fluid retention are summarized consistently as “edema”.
Hepatic effects: To date, there is no evidence of hepatotoxicity in the database of controlled clinical trials of this product. A specially designed randomized, double-blind, 3-year trial was conducted to compare the incidence of ACTOS and gliphenylurea serum ALT elevation to three times the upper limit of normal when the basal therapy was a combination of metformin and insulin. The test was conducted every 8 weeks for the first 48 weeks of the trial and then every 12 weeks. ALT values greater than three times the upper limit of normal reference were observed in 3/1051 (0.3%) patients in the Benzedrine group and 9/1046 (0.9%) patients in the Gliphenylurea group. To date, none of the patients in the controlled clinical trial data have experienced serum ALT greater than three times the upper reference value or total bilirubin greater than twice the upper reference value, and no patient has experienced severe drug-induced reciprocal superimposed liver damage.
Hypoglycemia: In clinical trials of this product, hypoglycemic adverse events were reported by investigators based on clinical judgment without the need for a confirmed diagnosis by end-point glucose testing.
In the 16-week clinical trial with sulfonylureas, the reported incidence of hypoglycemic events in the 30 mg group of this product was 3.7% compared to 0.5% in the placebo group. In the 16-week clinical trial with insulin addition, the reported incidence of hypoglycemic events was 7.9% in the 15 mg group, 15.4% in the 30 mg group, and 4.8% in the placebo group.
In the 24-week combination with sulfonylurea clinical trial and the 24-week combination with insulin clinical trial, the reported incidence of hypoglycemic events was higher in the Benadryl 45 mg group than in the Benadryl 30 mg group, at (15.7% vs. 13.4%) and (47.8% vs. 43.5%) in the two trials, respectively.
In these four trials, three patients in the 30 mg group within the 24-week combined clinical trial with insulin were admitted to the hospital with hypoglycemia (0.9%). An additional 14 patients reported severe hypoglycemia (defined as a hypoglycemic event in which the patient’s daily activities were significantly affected) that did not require hospital admission. These patients were treated with either Benadryl 45 mg in combination with a sulfonylurea (n=2) or Benadryl 30 mg or Benadryl 45 mg in combination with insulin (n=12).
Bladder cancer: In a 2-year carcinogenicity study, tumors were found in the bladder of male rats.
In addition, 14/2605 (0.54%) patients randomly assigned to the ACTOS group and 5/2633 (0.19%) patients randomly assigned to the placebo group were diagnosed with bladder cancer during the 3-year PROactive clinical trial. After excluding patients who had been taking the drug for less than a year at the time of diagnosis of bladder cancer, six cases (0.23%) in the ACTOS group and two cases (0.08%) in the placebo group were diagnosed with bladder cancer. After completion of the trial, most patients were observed for up to 10 additional years with little additional exposure to ACTOS. During the 13-year PROactive and observational follow-up period, there was no difference in the incidence of bladder cancer between patients randomly assigned to the ACTOS or placebo groups (HR=1.00; [95% CI: 0.59-1.72]).
In observational studies, there were differences in outcomes related to bladder cancer risk in patients taking ACTOS; some studies found no association between increased bladder cancer risk and ACTOS, while others found an association between the two.
In a large 10-year prospective observational cohort study conducted in the United States, patients who had taken ACTOS did not have a statistically significant increased risk of bladder cancer compared with patients who had never taken ACTOS (HR = 1.06; [95% CI: 0.89-1.26]).
A retrospective cohort study of data from the United Kingdom found a statistically significant association between ACTOS use and bladder cancer (HR:1.63; [95% CI: 1.22-2.19]).
Macular edema: There are foreign post-marketing reports of the occurrence or exacerbation of (diabetic) macular edema with vision loss with the administration of thiazolidinediones, including pioglitazone, but the frequency of occurrence is very rare. It is not clear whether macular edema is directly related to the administration of pioglitazone. If a patient develops vision loss, the physician should consider the possibility that it is macular edema. Patients with diabetes should receive regular routine eye examinations by an ophthalmologist. In addition to this, patients with diabetes should be examined by an ophthalmologist promptly whenever they develop any kind of visual symptoms, regardless of ongoing treatment or other physical examination abnormalities.
Fractures: In a foreign randomized clinical trial of patients with type 2 diabetes (mean duration of disease 9.5 years), researchers noted an increased incidence of fractures in women taking pioglitazone. During a mean follow-up period of 34.5 months, the incidence of fractures in female patients in the pioglitazone group was 5.1% (44/870) compared with only 2.5% (23/905) in the placebo group. This difference appeared one year after the start of treatment and persisted throughout the study. The fractures that occurred in the female patients were non-vertebral fractures, including lower and distal upper extremities. The incidence of fractures in male patients treated with pioglitazone was 1.7% (30/1735), which was not significantly increased compared with 2.1% (37/1728) in the placebo group. Patients treated with pioglitazone, especially female patients, should consider the risk of fracture and take care to assess and maintain bone health according to current standards of care.
Contraindications] (Contraindicated in the following patients)
Patients with heart failure or a history of heart failure [In animal studies, there is a potential for compensatory changes in cardiac weight associated with an increase in circulating plasma volume. Heart failure or exacerbation of heart failure has been reported in clinical cases].
Patients with severe ketosis, diabetic coma or pre-coma, or type 1 diabetes [hyperglycemia must be rapidly corrected with intravenous fluids and insulin].
Patients with severe hepatic dysfunction [this product is primarily metabolized in the liver and has the potential to cause accumulation].
Patients with severe renal dysfunction.
Patients with severe infections, pre- and post-surgery, or severe trauma [insulin injections are necessary to control blood glucose, and therefore administration of this product is not appropriate].
Patients with a history of hypersensitivity to the ingredients of this product.
Pregnant women or women at risk of pregnancy [refer to [Pregnancy and Lactation]].
This product is contraindicated in patients with a current or prior history of bladder cancer or in patients with unexplained sarcoid hematuria.
Precautions]
Use with caution (use with caution in the following patients)
(1) For the following patients or conditions.
(1) Patients with heart disease, such as myocardial infarction, angina pectoris, cardiomyopathy and hypertensive heart disease, which may cause heart failure [concomitant increase in circulating plasma volume has the potential to induce heart failure] (refer to [Important Precautions] and [Clinically Significant Adverse Reactions]).
(2) Hepatic or renal dysfunction (refer to [Contraindication]).
3) Pituitary insufficiency or adrenal insufficiency [may cause hypoglycemia].
(4) Malnutrition, starvation, irregular diet, inadequate dietary intake or debilitated state [may cause hypoglycemia].
(5) Intense muscle exercise [may cause hypoglycemia].
(6) Excessive alcohol consumption [may cause hypoglycemia].
(7) Elderly patients (refer to [Geriatric use] item).
(2) Patients who are using other glucose-lowering drugs (refer to [Drug Interactions] and [Clinically Significant Adverse Reactions] items).
2. Important precautions
(1) Because the increase in circulating plasma volume may lead to edema and induce or aggravate heart failure for a short period of time, the following conditions should be observed (refer to [Contraindications] and [Caution in use])
(i) This product should not be used in patients with heart failure or a history of heart failure.
(ii) Close observation should be made after taking this product. If edema, sudden weight gain, or symptoms of heart failure occur, appropriate measures such as discontinuation of the drug and administration of a medullary diuretic (furosemide, etc.) should be taken.
(iii) Patients should be instructed to pay attention to the occurrence of edema, sudden weight gain or change in symptoms while taking this product. If any of these abnormal symptoms occur, discontinue the drug immediately and consult a physician.
(2) It may cause abnormal electrocardiogram and increase in cardiothoracic ratio, and should be observed with due care; check the electrocardiogram regularly and take cautious measures such as reducing the dose or temporarily stopping the drug if abnormalities are found (refer to [other adverse reactions]).
(3) When this product is used in combination with other hypoglycemic drugs, it may cause hypoglycemic symptoms. When used in combination with these drugs, patients should be fully informed of the symptoms of hypoglycemia and how to deal with them, and be reminded to pay attention to the symptoms of hypoglycemia (refer to [Drug Interactions] and [Clinically Significant Adverse Reactions]).
(4) This product should only be used for patients who have not achieved adequate results with basic diabetes therapy such as diet therapy and/or exercise therapy.
(5) This product should only be used in patients with presumed insulin resistance. The rough criteria for determining insulin resistance are Body Mass Index (BMI kg/m2) greater than or equal to 24; or fasting whole blood insulin secretion level greater than or equal to 5 mU/mL.
(6) Blood glucose and urine sugar should be checked regularly during the administration of this product to confirm its efficacy. If the satisfactory effect is not achieved after 3 months of administration, it should be promptly changed to other drugs.
(7) During the period of administration, the following situations may occur: no longer need to continue the medication; need to reduce the dose; or the therapeutic effect is reduced or not effective due to the patient’s lack of moderation or co-infection. Therefore, attention should be paid to dietary intake, weight changes, blood sugar, and the presence of infections. Attention should be paid to making frequent judgments about the need to continue medication, the dose to be taken and the choice of medication, etc.
(8) Since rapid decline in blood sugar may be accompanied by aggravation of diabetic retinopathy. Cases have been reported when this product is used, so diabetic retinopathy should be closely monitored.
(9) The safety of combining this product with α-glucosidase inhibitors at a daily dose of 45 mg has not been established (little clinical experience with this product).
(10) The safety of combining this product with α-glucosidase inhibitors and sulfonylureas has not been established (an increasing incidence of adverse reactions has been observed in clinical trials).
(11) The safety of combining 45 mg of this product with biguanides in one day has not been established (little clinical experience with this drug). If a patient experiences vision loss, the physician should consider the possibility of macular edema.
(12) The risk of bladder cancer in patients taking pioglitazone cannot be completely excluded. The risk of bladder cancer should be fully explained to patients or their families before treatment is started. Patients must consult their physician immediately when any symptoms of hematuria, urinary urgency, or painful urination occur.
(13) Regular check-ups, such as urine tests, should be performed during the course of pioglitazone administration. If abnormalities are observed, appropriate measures should be taken. In addition, observation should be continued after stopping pioglitazone.
3. Precautions for use
When the drug is delivered to the patient: the drug in the aluminum-plastic blister package (PVC/aluminum foil) should be instructed to remove it from the aluminum-plastic blister (PVC/aluminum foil) package before taking it [there have been reports of serious complications such as mediastinitis due to perforation of the esophageal mucosa by accidental puncture of the hard, sharp-edged part of the aluminum-plastic blister (PVC/aluminum foil) package].
4. Other precautions
(1) In a 24-month trial of oral administration by the tube feeding method in rats and mice, bladder tumors developed in the male rat ≥3.6 mg/kg/day group.
(2) An increase in the number and size of colonic tumors has been reported in familial adenomatous polyposis (FAP) mouse models after oral administration of the similar drugs troglitazone or rosiglitazone.
(3) The occurrence or aggravation of (diabetic) macular edema has been reported with the application of thiazolidinediones such as pioglitazone. When patients experience a sharp decrease in visual acuity, macular edema should be considered as a possibility.
Pregnant women and nursing mothers use]
(1) Contraindicated in pregnant women or women at risk of pregnancy.
(2) Avoid use in nursing mothers, but stop breastfeeding if you have to use the drug.
For children]
The safety and efficacy of the drug for children have not been established. Due to the lack of long-term safety data, this product is not recommended for use in pediatric patients.
Geriatric use]
Usually the elderly have reduced physiological functions and should be administered with caution, for example, starting with 15 mg once a day and closely monitoring for adverse reactions during administration.
There was no significant difference in peak pioglitazone blood concentrations in healthy elderly subjects compared to younger subjects, but the AUC value increased by approximately 21%. The mean half-life values of pioglitazone endpoints were longer in older subjects (approximately 10 hours) compared to younger subjects (approximately 7 hours). These changes were not to the extent that they were determined to be clinically relevant.
[Drug Interactions].
Table 14 Precautions for combined use (caution should be exercised when this product is combined with the following drugs)
Drug name and other signs, symptoms, management, mechanism, etc. Hypoglycemic agents
*Sulfonylureas
Glimepiride, glibenclamide, gliclazide, toluenesulfonylurea, etc.
*Sulfonamides
Glipizide
*Biguanide drugsNote 1)
Metformin hydrochloride, butorphanol hydrochloride
*Naglinide
*Miglinide
*α-glucosidase inhibitors
Voglibose, acarbose, etc.
*Insulin preparations *When this product is combined with hypoglycemic agents in the left column, hypoglycemic symptoms may occur and should be administered with care and caution, e.g. when combined with either of these drugs, a low dose should be considered to start.
*When hypoglycemic symptoms occur in combination with α-glucosidase inhibitors, sucrose should be given instead of glucose.
Combination with glucose-lowering drugs and drugs that enhance or reduce the hypoglycemic effect of glucose-lowering drugs
*Drugs that enhance the hypoglycemic effect of glucose-lowering drugs
β-blockers, salicylic acid preparations, monoamine oxidase inhibitors, the
hyperlipidemia treatment drugs of beta derivatives, warfarin, etc.
*Drugs that reduce the hypoglycemic effect of hypoglycemic drugs
If this product is added to the left side of the combination of epinephrine, adrenocorticotropic hormone, thyroid hormone, etc., attention should be paid to the precautions for the combination of glucose-lowering drugs in [Precautions], and the effect on the improvement of insulin resistance of this product should be fully noted.
CYP2C8 inducers such as rifampicin have been reported to reduce the AUC of this product by 54% when combined with rifampicin. CYP2C8 inhibitors such as gemfibrozil have been reported to cause a 3-fold increase in AUC when combined with gemfibrozil. Because of potential dose-related adverse effects, pioglitazone dosage needs to be reduced when this product is combined with gemfibrozil, with the recommended maximum dose being 15 mg a day. reduced exposure to pioglitazone and its active metabolites has been found with concomitant administration of pioglitazone and topiramate. The clinical relevance of this change is not known; however, patients are monitored for adequate glycemic control when ACTOS and topiramate are administered concomitantly. Note 1) Refer to item [[Important Precautions] (9)]
[Drug overdose].
There is a lack of information on drug overdose in humans. In case of drug overdose, appropriate supportive treatment should be given according to the clinical manifestations of the patient.
Pharmacology and Toxicology
Pharmacological effects
Pioglitazone is a thiazolidinedione oral antidiabetic drug, which is a highly selective peroxisome proliferator-activated receptor (PPAR) agonist, and controls blood glucose levels by improving peripheral and hepatic insulin sensitivity. Its main mechanism of action is to activate PPAR nuclear receptors in insulin-activated tissues such as fat, skeletal muscle and liver, thereby regulating the transcription of insulin-responsive genes and controlling the production, transport and utilization of blood glucose.
Toxicological studies
Repeated dosing toxicity: Pioglitazone (equivalent to 11, 1 and 2 times the maximum clinically recommended dose, respectively, converted to body surface area) was found to be cardiologically enlarged in mice (100 mg/kg), rats (≥4 mg/kg) and dogs (3 mg/kg) given repeatedly by mouth. In a 1-year oral administration trial in rats, animals in the 160 mg/kg/day (equivalent to 35 times the maximum clinically recommended dose by body surface area) group experienced significant cardiac failure, resulting in animal mortality associated with the administration. Cardiac enlargement was seen in monkeys given pioglitazone orally at doses ≥8.9 mg/kg (equivalent to 4 times the maximum clinically recommended dose, converted to body surface area) for 13 weeks, but no cardiac enlargement was seen at doses up to 32 mg/kg (equivalent to 13 times the maximum clinically recommended dose, converted to body surface area) for 52 weeks of administration.
Genotoxicity: Pioglitazone Ames test, mammalian cell forward mutation test (CHO/HPRT and AS52/XPRT), in vitro cytogenetic test in CHL cells, in vitro DNA synthesis test and in vivo micronucleus test were all negative.
Reproductive toxicity: No toxic effects were observed in pregnant rats given pioglitazone 20 mg/kg (approximately 5 times the clinical dose of 45 mg based on body surface area conversion) during the organogenesis phase, but delayed delivery and reduced fetal viability were observed at doses of 40 and 80 mg/kg (approximately ≥9 times the clinical dose of 45 mg). No toxic effects were observed in pregnant rabbits given pioglitazone at 80 mg/kg (approximately 35 times the clinical dose of 45 mg) during organogenesis, but reduced fetal viability was seen at 160 mg/kg (approximately 69 times the clinical dose of 45 mg). In rats administered orally during late gestation and lactation at doses ≥10 mg/kg (twice the clinical dose based on body surface area), delayed development (decreased body weight) was observed in the pups after birth.
Pioglitazone can be secreted into rat milk, but it is not known whether it is secreted into human milk.
Carcinogenicity: In a 2-year carcinogenicity test in rats administered orally at doses up to 63 mg/kg/day (14 times the clinical dose of 45 mg based on body surface area), no administration-induced tumors were observed in organs other than the bladder in male rats. Benign and/or malignant migratory cell tumors were seen in male rats at doses ≥4 mg/kg/day (equivalent to a clinical dose of 45 mg based on body surface area). The mechanism of bladder tumor development in male rats is suspected to be related to irritation and proliferation caused by urinary tract stones. In a 2-year study completed in 2009 on the mechanism of reduction of urinary stones in male rats by dietary acidification, it was found that dietary acidification reduced but did not eliminate proliferative changes in the bladder and that the presence of stones exacerbated the proliferative response induced by pioglitazone, but was not considered to be the primary cause of proliferation. The relevance of the results for the development of bladder tumors in male rats to humans cannot be ruled out.
In a 2-year carcinogenicity test in mice, orally administered doses up to 100 mg/kg/day (equivalent to 11 times the clinical dose of 45 mg, converted to body surface area), no administration-induced tumors were observed.
Pharmacokinetics
Blood concentration
In healthy adult men, the prodrug and its metabolites I-VI (M-I to M-VI) were detected in the blood when the product was administered orally, with M- II to M- IV being the active metabolites.
The blood concentrations of prodrugs and active metabolites in healthy adult men (8), at a single oral dose of pioglitazone 30 mg on an empty stomach, are shown in the table below.
Blood concentrations in healthy adult men
30mg on an empty stomach (8 cases)
Peak concentration reached
(Cmax)
(mg/mL) Time to peak
(Tmax)
(h) Area under the curve
(AUC0~336h)
(mg-h/mL) Half-life
(T1/2)
(h) Prodrug 1.4±0.21.8±0.411.6±2.25.4±1.7 Metabolite-II
(M-II) 0.04±0.024.8±2.50.4±0.3 – Metabolite-III
(M-III) 0.3±0.011.5±2.112.8±2.125.0±4.7 Metabolite-IV
(M-IV) 0.6±0.114.8±4.029.5±4.523.8±2.7 (mean±standard deviation)
R1R2 prodrug H3C-H2C-H-metabolite-II
(M-II) H3C-H2C-HO-metabolite-III
(M-III) H3C-OC-H-metabolite-IV
(M-IV) H3C
＞HC-
HO
H-metabolite-V
(M-V) HOOC-H2C-H-metabolite-VI
(M-VI) HOOC-H-
Time
In healthy adult men (8 cases), a single dose of pioglitazone 30 mg was administered either on an empty stomach or after a meal, and there were no significant differences in the pharmacokinetic parameters of the prodrug, except for the prolonged Tmax of the prodrug; therefore, the effect of feeding on drug metabolism was considered to be minimal. The hypoglycemic effect was observed experimentally in Wistar obese rats, and the results showed that the activities of M-II to M-IV were lower than those of the prodrugs.
2. Excretion in urine
The main urinary excretion of pioglitazone in healthy adult men (14 cases) was M-IV to M-VI after a single dose of 30mg on an empty stomach, and the cumulative urinary excretion rate was about 30% at 48h after taking the drug.
3. Blood concentration after multiple doses
In healthy adult men (6 cases), pioglitazone 30mg was taken once a day for 9 days (stopped the next day), and the blood concentration of the prodrug and all active metabolites (prodrug + M-II to M-IV) reached a steady state at 6-7 days, so it was considered that there was no accumulation of the drug after repeated administration.
4. Blood concentration when combined with sulfonylureas
In patients with type 2 diabetes who were using sulfonylureas (glibenclamide, gliclazide), the blood concentrations of prodrugs and all active metabolites (prodrugs + M-II to M-IV) in combination with pioglitazone 30 mg once a day for 7 days were similar to those in patients with type 2 diabetes who were using diet therapy only. In addition, no effect on changes in the drug-time curve and protein binding of sulfonylureas was observed.
5. Blood concentrations in combination with α-glucosidase inhibitors
The blood concentrations of prodrugs and all active metabolites (prodrugs + M-II to M-IV) in type 2 diabetic patients on voglibose combined with pioglitazone 30 mg once a day were similar to those in type 2 diabetic patients on diet therapy alone or in combination with sulfonylureas.
6. Blood concentrations in combination with metformin
Blood concentrations of prodrugs and all active metabolites (prodrugs + M-II to M-IV) in healthy adult males (14 subjects) on multiple doses of metformin, combined with pioglitazone 30 mg once a day, were similar to those in healthy adult males (14 subjects) on pioglitazone alone.
7. Special Populations
Dosing in patients with renal insufficiency
The serum clearance half-lives of pioglitazone, M-III and M-IV were not altered in patients with moderate renal impairment (creatinine clearance of 30-50 mL/min) and severe renal impairment (creatinine clearance <30 mL/min) compared to subjects with normal renal function. Therefore, dose adjustment is not required in patients presenting with renal impairment.
Dosing in patients with hepatic insufficiency
The mean peak serum pioglitazone and total pioglitazone (pioglitazone, M-III and M-IV) concentrations were reduced to 45% in subjects with impaired hepatic function (CTP class B/C) compared to normal subjects, but the mean AUC values were not altered. Therefore, no dose adjustment is required for patients with concomitant development of hepatic injury.
Cases of hepatic failure after administration of this product have been reported after marketing, and subjects with serum ALT values >2.5 times (upper reference limit) have been excluded from clinical trials, so please use with caution in patients with liver disease.
8. Other
For the metabolism of pioglitazone, a variety of cytochrome P450 isoenzymes 1A1, 1A2, 2C8, 2C9, 2C19, 2D6 and 3A4 are involved. Pioglitazone has little effect on the metabolic activity of human cytochrome P450 isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 expressing microsomes (in vitro experiment).
Storage
Avoid light, store at room temperature.
Packaging
1. polyvinyl chloride/aluminum foil, plus polyester/aluminum/polyethylene composite film bag: 7 tablets/plate x 1 plate/bag/box, 7 tablets/plate x 2 plates/bag/box, 7 tablets/plate x 3 plates/bag/box, 15 tablets/plate x 1 plate/bag/box, 15 tablets/plate x 2 plates/bag/box.
2. HDPE bottle for oral solid medicine: 30 tablets/bottle/box, 60 tablets/bottle/box, 90 tablets/bottle/box.
[Expiration date
12 months
【Execution standard
【Approval number】 State Drug Certificate H20110048
【Manufacturer】
Company Name: Jiangsu Deyuan Pharmaceutical Co.
Production Address: No. 29 Changjiang Road, Lianyungang Economic and Technological Development Zone
Postal Code: 222047
Telephone number: 0518-82340786
Fax number: 0518-82340788
Web address: http://www.pharmdy.com