Approval date: November 29, 2010
Date of revision: December 20, 2010; February 16, 2011; January 16, 2013; March 07, 2013; January 04, 2018; January xx, 2020
Pioglitazone Metformin Tablets (15mg/500mg) Instructions
Please read the instructions carefully and use under the guidance of a physician
Warning: congestive heart failure and lactic acidosis
Congestive heart failure
Thiazolidinediones, including pioglitazone (one of the components of this product), are at risk of causing or worsening congestive heart failure in some patients (refer to [Precautions] Pioglitazone Hydrochloride).
Patients should be monitored closely for signs and symptoms of heart failure (e.g., rapid weight gain, dyspnea, and/or edema) after starting this product or increasing the dose. If heart failure develops, it should be managed according to standard heart failure treatment protocols and the product must be discontinued or the dose reduced (see [PRECAUTIONS] Pioglitazone Hydrochloride).
This product is not recommended for use in patients with symptomatic heart failure and is contraindicated in patients with New York Heart Association (NYHA) Class III or IV heart failure (refer to [Contraindications] and [Precautions] Pioglitazone Hydrochloride).
Lactic acidosis
Death, hypothermia, hypotension, and intractable slow arrhythmias due to metformin-associated lactic acidosis have been reported post-marketing. Symptoms include mental depression, muscle aches, dyspnea, sleepiness, and abdominal pain. Test abnormalities include elevated blood lactate concentrations, anion gap acidosis, and increased lactate: metformin-induced lactic acidosis is manifested by elevated blood lactate concentrations (greater than 5 mmol/L), anion gap acidosis (without signs of ketonuria or ketonemia), increased lactate:pyruvate ratio, increased pyruvate ratio, and plasma metformin concentrations usually greater than 5 mcg/mL. (Refer to [ Precautions]).
Risk factors for metformin-associated lactic acidosis include renal injury, co-administration with certain drugs, old age (65 years or older), comparative radiological studies, surgical and other operations, hypoxic states, excessive alcohol intake, and liver injury. Information on how to reduce the risk of metformin-associated lactic acidosis and manage these high-risk groups is detailed in the full instructional information (refer to [Dosage] [Contraindications] [Precautions] [Drug Interactions]).
If metformin-associated lactic acidosis is suspected, discontinue this product immediately and receive routine supportive care in a hospital. Immediate hemodialysis is recommended (refer to [Precautions]).
[Drug Name].
Generic name: Pioglitazone Metformin Tablets (15mg/500mg)
English name: Pioglitazone Hydrochloride and Metformin Hydrochloride Tablets (15mg/500mg)
Hanyu Pinyin: Bigelietong Erjiashuanggua Pian (15mg/500mg)
【Ingredients】.
This product is a compound preparation, the main ingredients of which are pioglitazone hydrochloride and metformin hydrochloride.
Pioglitazone Hydrochloride
Chemical name: (±) 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]phenylmethyl}-2,4-thiazolidinedione hydrochloride
Chemical structure formula.
Molecular formula: C19H20N2O3S-HCl
Molecular weight: 392.89
Metformin hydrochloride
Chemical name: 1,1-dimethylbiguanide hydrochloride
Chemical structure formula
Molecular formula: C4H11N5-HCl
Molecular weight: 165.63
Properties
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
This product is indicated for use in patients with type 2 diabetes currently treated with the combination of pioglitazone hydrochloride and metformin hydrochloride or in patients with type 2 diabetes with poor glycemic control after treatment with metformin hydrochloride alone, on the basis of dietary control and exercise.
Important limitations on use.
Pioglitazone exerts its hypoglycemic effect only in the presence of endogenous insulin. This product should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it is not effective in these conditions.
Caution must be exercised when using this product in patients with liver disease (refer to [Precautions]).
Specification
Each tablet contains Pioglitazone Hydrochloride 15mg (in pioglitazone) and Metformin Hydrochloride 500mg.
Dosage]
Recommended Dosage.
The treatment of type 2 diabetes should be individualized according to effectiveness and tolerability and should not exceed the maximum recommended daily dose of pioglitazone 45mg and metformin hydrochloride 2550mg. metformin above 2000mg is better tolerated when used in three divided doses a day.
The starting dose of this product is selected based on the patient’s current pioglitazone and/or metformin dosage. Patients should be monitored closely for adverse effects related to fluid retention, such as weight gain, edema, and signs or symptoms of congestive heart failure, when starting this product or increasing the dose.
Liver function tests (e.g., serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be performed prior to initiation of this product. Patients without liver disease do not require routine periodic liver function tests during treatment with this product. For patients with abnormal liver function tests before or during the use of this product, refer to [Precautions] for appropriate measures.
This product may be given in divided one-day doses and may be taken with food to reduce gastrointestinal side effects associated with metformin hydrochloride.
1. Starting dosage for those with poor glycemic control on metformin alone
Based on the usual starting dose of pioglitazone of 15-30 mg/day, the product can be started at 15 mg/500 mg (1 tablet) once or twice a day, and the dose will be gradually increased according to the assessment of treatment response.
2. The starting dose for those who have already been treated with pioglitazone hydrochloride and metformin hydrochloride combination therapy and switch to this product
This product may be started at 15 mg/500 mg (1 tablet) depending on the amount of metformin tablets and pioglitazone tablets previously taken. This product should be taken with meals to reduce gastrointestinal adverse effects caused by metformin.
For patients with renal disease
Assess renal function before starting this product and monitor regularly after dosing.
This product is contraindicated in patients with eGFR below 45 mL/min/1.73 m2.
Use with potent CYP2C8 inhibitors
Concomitant use of pioglitazone (a component of this product) and the potent CYP2C8 inhibitor gemfibezil results in an approximately 3-fold increase in pioglitazone exposure. Therefore, when this product is used with gemfibezil or other potent CYP2C8 inhibitors, the recommended maximum dose is one tablet per day.
Iodinated Contrast Imaging Discontinuation of Dosing
For patients with an eGFR between 45 and 60 mL/min/1.73m2; a history of liver disease, alcoholism, or heart failure; or patients who will receive intra-arterial iodinated contrast, this product must be discontinued at the time of or before the start of the iodinated contrast imaging examination. Forty-eight hours after the imaging examination, eGFR should be re-evaluated and the product can be restarted if renal function is stable.
[Adverse reactions].
As reported in foreign literature.
Clinical trial experience
Due to different clinical trial conditions, the incidence of adverse reactions in clinical trials of one drug cannot be directly compared with the incidence of other drugs, nor can it reflect the incidence of actual use.
Pioglitazone
More than 8,500 patients with type 2 diabetes were taking pioglitazone in randomized, double-blind, controlled clinical trials, including 2,605 patients with type 2 diabetes with macroangiopathy treated with pioglitazone in prospective clinical trials. More than 6,000 patients in these trials took pioglitazone for at least 6 months, more than 4,500 patients took pioglitazone for at least 1 year, and more than 3,000 patients took pioglitazone for at least 2 years.
In the six pooled 16- to 26-week placebo-controlled monotherapy and 16- to 24-week additional combination trials, the incidence of withdrawal from the trials due to adverse events was 4.5% and 5.8% in the pioglitazone and control groups, respectively. The most common adverse event leading to withdrawal from the trial was associated with poor glycemic control, although the incidence of such events was lower in the pioglitazone group (1.5%) than in the placebo group (3.0%).
In the prospective trial, the dropout rates due to adverse events were 9.0% and 7.7% in the pioglitazone and placebo groups, respectively. Congestive heart failure was the most common adverse event leading to withdrawal from the trial, with an incidence of 1.3% and 0.6% in the pioglitazone and placebo groups, respectively.
Common adverse reactions: 16- to 26-week monotherapy trials
The types and incidence of common adverse reactions in the three pooled pioglitazone 16- to 26-week placebo-controlled monotherapy trials are shown in Table 1. The adverse reactions reported in the table were more common in the pioglitazone group than in the placebo group, and the incidence was higher than 5%. None of these adverse reactions were dose related to pioglitazone.
Table 1. three pooled 16- to 26-week placebo-controlled clinical pioglitazone dosing trials alone: adverse reactions were more common in the pioglitazone group than in the placebo group and occurred at an incidence of >5%. Percentage of patients (%) Placebo n=259 Pioglitazone n=606 Upper respiratory tract infection 8.513.2 Headache 6.99.1 Sinusitis 4.66.3 Myalgia 2.75.4 Pharyngitis 0.85.1
Common adverse reactions: 16 to 24 week coadministration trial
The incidence and types of common adverse reactions in the pioglitazone plus metformin combination trial are shown in Table 2. adverse reactions reported in the table were more common in the pioglitazone group than in the placebo group and occurred at a rate higher than 5%.
Table 2. 16- to 24-week clinical trial of pioglitazone plus metformin combination 16-week placebo-controlled trial
Adverse reactions pioglitazone + metformin group more common than placebo + metformin group and incidence higher than 5% percent of patients (%) placebo + metformin n=160 pioglitazone 30 mg + metformin n=168 edema 2.56.0 headache 1.96.0 24-week uncontrolled double-blind trial
Adverse effects were more frequent in the pioglitazone 45 mg + metformin group than in the pioglitazone 30 mg + metformin group, and the incidence was higher than 5% percent of patients (%) pioglitazone 30 mg + metformin n=411 pioglitazone 45 mg + metformin n=416 upper respiratory tract infection 12.413.5 edema 5.813.9 headache 5.45.8 weight gain 2.96. 7 Note: Peripheral edema, systemic edema and fluid retention are indicated as “edema”.
Common Adverse Reactions: 24-Week Clinical Trial of Pioglitazone Metformin Tablets
The incidence and type of adverse reactions in a 24-week double-blind controlled clinical trial in which pioglitazone metformin tablets were administered twice daily (n=600) to patients whose blood glucose was not adequately controlled by diet and exercise are shown in Table 3.
Table 3. adverse reactions reported in a 24-week double-blind clinical trial in patients with inadequate glycemic control by diet and exercise on pioglitazone metformin tablets twice daily (incidence of pioglitazone metformin tablets adverse reactions ≥ 5%) Percentage of patients (%) Pioglitazone metformin tablets 15/850 mg
2 times daily
N=201 pioglitazone
15mg
2 times daily
N=190 Metformin
850mg
2 times a day
N=209 Diarrhea 9.02.615.3 Headache 5.52.64.8 The reported adverse reactions for abdominal pain in the 24-week trial were 2.0% in the pioglitazone metformin tablet group, 1.6% in the pioglitazone monotherapy group and 3.3% in the metformin monotherapy group.
Common adverse reactions: prospective trials
The incidence and types of common adverse reactions in prospective trials are shown in Table 4. reported adverse reactions were higher in the pioglitazone group than in the placebo group and occurred in >5% of cases.
Table 4. prospective trial: adverse reactions pioglitazone group was higher than the placebo group and the incidence was >5% Percentage of patients (%) placebo n=2633 pioglitazone n=2605 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 reactions associated with congestive heart failure in the 16- to 24-week increased metformin co-administration trial is shown in Table 5. there were no fatal events.
Table 5. incidence of congestive heart failure (CHF) adverse events in patients on pioglitazone or placebo + metformin % of patients (%) placebo-controlled trial (16 weeks) uncontrolled double-blind trial (24 weeks) placebo + metformin n=160 pioglitazone 30 mg + metformin n=168 pioglitazone 30 mg + metformin n=411 pioglitazone 45 mg + Metformin n=416 at least 1 incident congestive heart failure 01 (0.6%) 01 (0.2%) hospitalization 01 (0.6%) 01 (0.2%)
Table 6. congestive heart failure (CHF) acute adverse reactions pioglitazone/placebo+sulfonylurea Percentage of patients (%) placebo-controlled trial (16 weeks) uncontrolled double-blind trial (24 weeks) placebo+sulfonylurea n=187 pioglitazone 15 mg+sulfonylurea n=184 pioglitazone 30 mg+sulfonylurea
n=189 pioglitazone 30mg+sulfonylurea n=351 pioglitazone 45mg+sulfonylurea n=351 at least 1 incident of congestive heart failure 2 (1.1%) 001 (0.3%) 6 (1.7%) hospitalization 2 (1.1%) 0002 (0.6%) pioglitazone/placebo+insulin % of patients (%) placebo-controlled trial (16 weeks) uncontrolled double-blind Trial (24 weeks) placebo + insulin n=187 pioglitazone 15 mg + insulin n=191 pioglitazone 30 mg + insulin n=188 pioglitazone 30 mg + insulin n=345 pioglitazone 45 mg + insulin n=345 at least 1 incident of congestive heart failure 02 (1.0%) 2 (1.1%) 3 (0.9%) 5 (1.4%) Hospitalization 02 (1.0%) 1 (0.5%) 1 (0.3%) 3 (0.9%) Pioglitazone/placebo + metformin Percentage of patients (%) Placebo-controlled trial (16 weeks) Non-controlled double-blind trial (24 weeks) Placebo + metformin n=160 Pioglitazone 30 mg + metformin
n=168 pioglitazone 30 mg + metformin n=411 pioglitazone 45 mg + metformin n=416 at least 1 incident of congestive heart failure 01 (0.6%) 01 (0.2%) hospitalization 01 (0.6%) 01 (0.2%)
Table 7. acute CHF adverse reactions after pioglitazone or glibenclamide in patients with NYHA class II or III congestive heart failure Patient percent (%) Pioglitazone n=262 Glibenclamide n=256 death due to cardiovascular adverse reactions5 (1.9%) 6 (2.3%) overnight hospitalization due to worsening CHF26 (9.9%) 12 (4.7%) Emergency room visits due to CHF4 (1.5%)3 (1.2%) Progression of CHF course in patients in the trial35 (13.4%)21 (8.2%)
Hospitalizations resulting from congestive heart failure events that occurred during the prospective trial are shown in Table 8.
Table 8. acute CHF adverse reactions in the prospective trial Patient percent (%) placebo n=2633 pioglitazone n=2605 at least 1 hospitalized congestive heart failure event 108 (4.1%) 149 (5.7%) fatal 22 (0.8%) 25 (1.0%) hospitalized, non-fatal 86 (3.3%) 124 (4.7%)
Cardiovascular safety
A total of 5238 patients with type 2 diabetes were tested in the prospective trial, of which 2605 patients with macrovascular disease were randomized into the pioglitazone group, administered up to 45 mg/day, and a total of 2633 in the placebo group for standard care. Almost all trial patients (95%) were taking cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins, or fibrates). The mean age of the patients was 62 years, the mean history of diabetes was 9.5 years, and the mean HbA1c was 8.1%. The mean follow-up period was 34.5 months.
The primary objective of this trial was to examine the effect of pioglitazone on mortality and the incidence of macrovascular disease in type 2 diabetic patients with a high risk of macrovascular events. The primary pharmacodynamic variable was time to first event of any cardiovascular composite endpoint, including all-cause death, nonfatal myocardial infarction (MI) including painless infarction, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, amputation of the thigh above the ankle, bypass surgery, or leg revascularization. 514 patients in the pioglitazone group (19.7%) and 572 ( 21.7%) of patients in the placebo group had at least 1 event in the primary composite endpoint (HR 0.90; 95% CI: 0.80, 1.02; p=0.10).
Although there was no significant difference in the three-year incidence of first events between the pioglitazone and placebo groups in this combination, there was no increase in mortality in the pioglitazone group or in the total macrovascular event rate. The first-time incidence of events for the primary composite endpoint and all individual events are shown in Table 9.
Table 9. prospective trial: number of first and total events for each component of the cardiovascular composite endpoint cardiovascular events placebo n=2633 pioglitazone n=2605 first events n (%) total events n first events n (%) total events n any events 572 (1.7) 900514 (19.7) 803 all-cause death 122 (4.6) 186110 (4.2) 177 Nonfatal heart attack (MI) 118 (4.5) 157105 (4.0) 131 Stroke 96 (3.6) 11976 (2.9) 92 Acute coronary syndrome 63 (2.4) 7842 (1.6) 65 Cardiac intervention (CABG/PCI) 101 (3.8) 240101 (3.9) 195 Thigh amputation 15 (0.6) 289 (0.3) 28 Leg revascularization 57 (2.2) 9271 (2.7) 115
Weight gain
Dose-dependent weight gain occurs when pioglitazone is administered alone or in combination with other antidiabetic drugs. The mechanism of weight gain has not been clarified, but may be related to the combined effects of fluid retention and fat accumulation.
Tables 10, 11, and 12 summarize weight changes in the 16- to 26-week randomized double-blind pioglitazone monotherapy and 16- to 24-week combination trials, prospective trials, and the 24-week pioglitazone metformin tablet trial.
Table 10. weight change from baseline in randomized double-blind clinical trials (kg) Control (placebo) pioglitazone 15 mg pioglitazone 30 mg pioglitazone 45 mg median
(25th, 75th percentile) Median
(25th, 75th percentile) Median
(25th, 75th percentile) Median
(25th, 75th percentile) Monotherapy
(16 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 drug therapy (16-24 weeks) sulfonylurea -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=407 Insulin 0.2 (-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 change in body weight of patients in the pioglitazone group versus the placebo group during double-blind dosing in the prospective trial Placebo pioglitazone median
(25th, 75th percentile) Median
(25th, 75th percentile) Change from baseline to final follow-up (kg) -0.5 (-3.3, 2.0) N=2581+3.6 (0.0, 7.5) N=2560 Note: The median exposure for pioglitazone versus placebo was 2.7 years.
Table 12. Weight change from baseline after pioglitazone metformin tablets in a double-blind clinical trial in patients with ineffective glycemic control by diet and exercise (Kg) Pioglitazone metformin tablets 15/850 mg
Pioglitazone twice daily
15mg
2 times daily metformin
850mg
Median 2 times daily
(25th, 75th percentile) Median
(25th, 75th percentile) Median
(25th, 75th percentile) Change from baseline to final follow-up (kg) 1.00 (-1.0, 3.0) N=1981.35 (-0.7, 4.1) N=178-1.00 (-2.6, 0.4) N=203
Edema
Edema caused by taking pioglitazone can recover after stopping the medication. Edema usually does not require hospitalization unless there is concomitant congestive heart failure.
In the 24-week pioglitazone metformin tablet trial, the adverse effects of edema were 3.0% in the pioglitazone metformin tablet group, 4.2% in the pioglitazone alone group, and 1.4% in the metformin alone group.
The incidence and types of edema adverse reactions seen in clinical observations of pioglitazone are shown in Table 13.
Table 13. edema adverse reactions in patients taking pioglitazone Patient percentage (%) placebo pioglitazone 15 mg pioglitazone 30 mg pioglitazone 45 mg alone (16 to 26 weeks) 3 (1.2%) n=2592 (2.5%) n=8113 (4.7%) n=27511 (6.5%) n=169 combination (16 to 24 weeks) Sulfonylurea 4 (2.1%) n=1873 (1.6%) n=18461 (11.3%) n=54,081 (23.1%) n=351 Metformin 4 (2.5%) n=160 N/A34 (5.9%) n=57,958 (12.9%) n=416 Insulin 13 (7.0%) n=18,724 (12.6%) n= 191109 (20.5%) n=53390 (26.1%) n=345
Table 14. percentage of patients with edema adverse reactions in prospective trials (%) placebo n=2633 pioglitazone n=2605419 (15.9%) 712 (27.3%) liver effects
To date, there is no evidence of pharmacologic hepatotoxicity in the pioglitazone clinical controlled trials database. A randomized, double-blind, three-year trial comparing pioglitazone and glibenclamide in combination with metformin and insulin, respectively, was specifically designed to assess the incidence of serum ALT elevations above 3 times the upper limit of the normal range, measured every 8 weeks for the first 48 weeks of the trial and every 12 weeks thereafter. Three in 10,051 (0.3%) and nine in 10,046 (0.9%) patients in the pioglitazone and glibenclamide groups, respectively, had ALT values 3 times above the upper limit of the normal range. No patients in the pioglitazone controlled clinical trial had an increase in serum ALT 3 times above the upper limit of the normal range or total bilirubin 2 times above the upper limit of the normal range, both of which are predictive of severe drug-related liver injury.
Hypoglycemia
Hypoglycemic adverse reactions based on clinical judgment of observers and not requiring confirmation by finger prick glucose testing have been reported in pioglitazone clinical trials.
In the 16-week sulfonylurea combination trial, the incidence of hypoglycemia was 3.7% in the pioglitazone 30 mg group and 0.5% in the placebo group. In the 16-week trial in combination with insulin, the reported incidence of hypoglycemia was 7.9% in the pioglitazone 15 mg group, 15.4% in the pioglitazone 30 mg group, and 4.8% in the placebo group.
The incidence of hypoglycemia was higher in the 24-week trial in combination with sulfonylurea and in the 24-week trial in combination with insulin in the pioglitazone 45 mg than in the pioglitazone 30 mg group (15.7% vs 13.4% and 47.8% vs 43.5%, respectively).
Three patients in the four trials were hospitalized for hypoglycemia. All 3 patients were from the 24-week pioglitazone 30 mg co-administered insulin trial (0.9%). Another 14 patients reported severe hypoglycemia (defined as interference with the patient’s daily activities), but did not require hospitalization. These patients took pioglitazone 45 mg + sulfonylurea (n=2) or pioglitazone 30 mg or 45 mg + insulin (n=12).
Bladder tumors
In a 2-year carcinogenicity study, tumors were found in the bladders of male rats. In addition, 14/2605 (0.54%) patients randomly assigned to the pioglitazone hydrochloride tablet 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 pioglitazone hydrochloride tablet 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 pioglitazone hydrochloride tablets. 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 pioglitazone hydrochloride tablets (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 pioglitazone hydrochloride tablets; some studies found no association between increased bladder cancer risk and pioglitazone hydrochloride tablets, 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 pioglitazone hydrochloride tablets (ACTOS) did not have a statistically significant increased risk of bladder cancer compared with patients who had never taken them (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 pioglitazone hydrochloride tablet use and bladder cancer (HR: 1.63; [95% CI: 1.22-2.19]).
Associations between cumulative dose or cumulative duration of pioglitazone hydrochloride tablet exposure and bladder cancer were not detected in some studies, including the 10-year observational study in the United States, but they were detected in other studies. The inconsistent results and limitations of these studies lead to inability to interpret the observational data and thus to draw conclusions.
Pioglitazone hydrochloride tablets may be associated with an increased risk of bladder tumors. There are insufficient data to determine whether pioglitazone is a tumor promoter for bladder cancer.
Metformin Hydrochloride
In a double-blind clinical trial of metformin in patients with type 2 diabetes, 141 patients were treated with metformin (maximum dose of 2550 mg/day) and 145 patients received placebo. The rate of adverse reactions in patients in the metformin group was higher than 5%, and the incidence of adverse reactions in the metformin group was higher than in the placebo group, as shown in Table 15. 6% of patients in the metformin group in this trial discontinued the drug due to diarrhea.
Table 15. most common adverse reactions in a placebo-controlled clinical trial of metformin monotherapy (>5.0%) adverse reactions metformin alone
N=141 Placebo
N=145 Percentage of patients (%) Diarrhea 53.211.7 Nausea/vomiting 25.58.3 Flatulence 12.15.5 Weakness 9.25.5 Dyspepsia 7.14.1 Abdominal pain 6.44.8 Headache 5.74.8
Laboratory abnormalities
Hematologic effects
Pioglitazone may cause a decrease in hemoglobin levels and erythrocyte pressure volume. In placebo-controlled monotherapy studies, patients in the pioglitazone group had a 2% to 4% decrease in mean hemoglobin values compared with a -1% to +1% change in the mean hemoglobin values in the placebo group. These changes occurred during the first 4 to 12 weeks of treatment and remained flat thereafter. These changes may be related to the increased plasma volume caused by pioglitazone, which has not been found to be clinically hematologically significant.
Vitamin B12 concentration
Metformin decreases serum vitamin B12 concentrations. Annual hematologic testing is recommended for patients taking this product, and significant abnormalities should be investigated and managed appropriately.
Serum creatine phosphokinase
In the serum creatine phosphokinase (CPK) test specified in the pioglitazone clinical trial protocol, 9 pioglitazone-treated patients (0.2%) had elevated CPK exceeding 10 times the upper limit of normal (values of 2150 to 11400 IU/L), which was not seen in the comparison group. Six of these patients continued pioglitazone therapy, two patients had CPK elevations on the last day of dosing, and one patient discontinued pioglitazone because of CPK elevations. All of these elevations were recovered with no clinically significant sequelae. The relationship of these events to pioglitazone dosing is unclear.
Postmarketing Studies
The following adverse reactions were identified in post-marketing use of pioglitazone after approval. Because these reactions were voluntarily reported from populations of variable size, it is generally not possible to estimate their incidence with certainty and to assess the causality of the remaining drug exposures.
Pioglitazone
New onset or worsening of diabetic macular edema with vision loss
Fatal and non-fatal liver failure
Post-marketing reports of patients who developed congestive heart failure on pioglitazone, independent of the presence of prior cardiac disease or concomitant insulin use.
Unusual weight gain beyond that observed in general clinical trials has been reported in post-marketing dosing experience. These patients should be evaluated for fluid retention and volume-related events such as extensive edema and congestive heart failure.
Metformin
Cholestasis, hepatocellular and mixed hepatocellular liver injury.
[Contraindicated].
1. confirmed New York Heart Association (NYHA) heart failure class III or IV.
2. severe renal impairment (eGFR less than 45 mL/min/1.73m2).
3. known hypersensitivity to pioglitazone, metformin or any other component of the product
4. Contraindicated in patients with metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.
5. This product is contraindicated in patients with a current or prior history of bladder cancer or in patients with unexplained hematuria of the naked eye.
[Precautions].
Congestive Heart Failure
Pioglitazone.
As with other thiazolidinediones, pioglitazone alone or in combination with other antidiabetic drugs can cause dose-dependent fluid retention, most commonly when combined with insulin. Fluid retention may cause or worsen heart failure. Patients who are using this product should be observed for signs and symptoms of congestive heart failure. If congestive heart failure occurs, care should be provided according to current standards and discontinuation or dose reduction should be considered.
Lactic acidosis
Metformin hydrochloride.
Lactic acidosis
Post-marketing lactic acidosis events have been reported in association with metformin, including fatal events. These events begin with mild, ill-defined symptoms such as depression, muscle aches, abdominal pain, dyspnea, or increased drowsiness; however, hypothermia, hypotension, and intractable tardive dyskinesia accompanying severe acidosis can occur. Metformin-associated lactic acidosis is manifested by increased blood lactate concentrations (above 5 mmol/L), anion-gap acidosis (without ketonuria or ketonemia symptoms), and increased lactate: increased pyruvate ratios and plasma metformin concentrations usually above 5 mcg/mL. Metformin decreases lactate uptake by the liver, causing increased lactogenic blood concentrations, which leads to an increased risk of lactic acidosis, especially in patients at risk. especially in at-risk patients.
If metformin-associated lactic acidosis is suspected, routine supportive care should be received in the hospital and the product should be discontinued immediately. Immediate hemodialysis is recommended for correction of lactate and removal of accumulated metformin in patients diagnosed with lactic acidosis or highly suspected lactic acidosis (metformin hydrochloride is dialyzable and has a clearance rate of 170 mL/min under good hematologic conditions). The outcome of hemodialysis is usually symptom reversal and recovery.
Educate patients and their families about the symptoms of lactic acidosis and instruct them to discontinue the product and inform their physicians of the symptoms if they become relevant.
For each known or possible risk factor for metformin-associated lactic acidosis, risk reduction and management is recommended as follows.
Renal injury
Postmarketing metformin-associated lactic acidosis events have occurred primarily in patients with significant renal injury. Because metformin is primarily excreted renally, the risk of metformin accumulation and the risk of metformin-associated lactic acidosis increases with the severity of renal injury. Clinical recommendations based on the patient’s renal function include the following.
Test eGFR values prior to initiation of this product.
Patients with an eGFR below 45 mL/min/1.73 m2 are contraindicated from using this product.
Test eGFR values at least once a year in all patients taking this product. Patients at increased risk of renal injury (e.g., elderly) should have their renal function checked frequently.
Drug Interactions
Concomitant use of this product with other specific drugs that may increase the risk of metformin-related lactic acidosis: drugs that impair renal function, drugs that cause significant hematologic changes, drugs that interfere with acid-base balance or increase metformin accumulation (e.g., cationic drugs). Therefore, more frequent monitoring of such patients should be considered.
Patients over 65 years of age
The risk of metformin-associated lactic acidosis increases with the age of the patient. Older patients are more likely to have hepatic, renal, or cardiac impairment than younger patients, and therefore renal function should be evaluated more frequently in older patients.
Comparative radiological studies
The use of intravascular iodinated contrast agents in patients treated with metformin leads to a dramatic decrease in renal function, as well as the development of lactic acidosis. In patients with an eGFR between 45 and 60 mL/min/1.73m2; with a history of liver disease, alcoholism, or heart failure; or who will receive intra-arterial iodinated contrast, the product must be discontinued at the time of or before the start of the iodinated contrast imaging examination. The eGFR should be re-evaluated 48 hours after the imaging examination; if renal function is stable, the product may be restarted.
Surgery and other operations
Food and water fasting during surgery or other operations may increase the risk of volume failure, hypotension, and renal injury. This product should be temporarily discontinued when patients are restricted from eating and drinking.
Hypoxic Conditions
Several post-marketing events have occurred with metformin-associated lactic acidosis due to acute congestive heart failure (particularly with inadequate perfusion and oxygenation). Cardiovascular failure (shock), acute myocardial infarction, sepsis, and other conditions with inadequate blood oxygenation are associated with lactic acidosis and may cause prerenal azotemia. In the event of such events, the product should be discontinued immediately.
Excessive alcohol intake
Alcohol amplifies the effects of metformin on lactate metabolism, which may increase the risk of metformin-associated lactic acidosis. Patients are warned not to consume excessive amounts of alcohol while taking this product.
Liver Injury
Cases of metformin-associated lactic acidosis have been reported in patients with liver injury. This may be due to impaired lactate clearance resulting in higher blood lactate concentrations. Therefore, avoid the use of this product in patients with clinical signs or laboratory indications of liver disease.
Edema
In clinical controlled trials of pioglitazone, patients using pioglitazone developed more edema than those using placebo in a dose-related manner. New onset as well as worsening edema was similarly reported in post-marketing investigations.
Use this product with caution in patients with edema. This is because thiazolidinediones, including pioglitazone, can cause fluid retention and consequent congestive heart failure or worsening. This product should be used with caution in patients at risk for congestive heart failure. Care should be taken to monitor patients using this product for signs or indications of congestive heart failure.
Hypoglycemia
Concomitant use of insulin or other antidiabetic drugs (especially insulinotropic agents such as sulfonylureas) in patients using this product may cause hypoglycemia. To reduce the risk of hypoglycemia, it may be necessary to reduce the dose of the concomitant antidiabetic drug. Inadequate calorie intake or intense exercise without calorie supplementation may also cause hypoglycemia. Elderly patients, frail or malnourished patients, adrenal or pituitary insufficiency, and alcoholics are particularly susceptible to hypoglycemia. Elderly patients and patients taking beta-adrenergic blockers may have difficulty detecting the onset of hypoglycemia.
Hepatic effects
There have been post-marketing reports of fatal or non-fatal hepatic failure events in patients taking pioglitazone, although the information in these reports is insufficient to assess the causative agent. To date, there is no evidence of pharmacologic hepatotoxicity in the pioglitazone clinical controlled trials database.
Patients with type 2 diabetes may have heart disease such as fatty liver or sudden congestive heart failure (both conditions may cause abnormal liver function tests), as well as other types of liver disease (most of which can be treated or controlled). Therefore, liver function tests (AST, ALT, alkaline phosphate and total bilirubin) are recommended and evaluated prior to the use of this product.
This product should be started with caution in patients with abnormal liver function tests.
Patients with symptoms of liver injury (including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice) should have immediate liver function tests. In clinical trials, if a patient develops an abnormal liver function test (ALT ≥ 3 times the upper limit of the reference range), the product should be discontinued and the possible cause of the disease should be investigated. Patients with abnormal liver function tests with no other explanation should not be restarted on this product.
Patients with serum ALT greater than three times the upper limit of the reference range and serum total bilirubin greater than two times the reference range without an elective etiology are at risk of serious drug-related liver injury and should not be restarted on this product. Use this product with caution in patients with a low rise in serum ALT or bilirubin and a reference causative agent.
Bladder tumors
The risk of bladder cancer cannot be completely excluded in patients taking pioglitazone. The risk of bladder cancer should be fully explained to patients or their families before treatment is started. Patients must consult their doctor immediately when any symptoms of hematuria, urinary urgency, or painful urination occur. 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.
Fracture
According to foreign literature, a total of 5238 patients with type 2 diabetes were tested in prospective positive clinical trials, of which 2605 patients with macroangiopathy were randomized into the pioglitazone group, administered up to 45 mg/day, and a total of 2633 in the placebo group for standard care. During a follow-up period of a mean of 34.5 months, the incidence of fractures was 5.1% (44/870) in women in the pioglitazone group and 2.5% (23/905) in the placebo group. This difference was observed in the first year of treatment and throughout the trial thereafter. The majority of fractures observed in female patients were non-vertebral fractures, including lower ribs and distal upper extremities. There was no increase in fracture rates in men in the pioglitazone group compared to the placebo group (1.7% vs 2.1%). Patients on pioglitazone should be considered for fracture risk, especially in women. Care should be taken to assess and maintain bone health when using this product according to current standards of care.
Macular edema
Macular edema has been reported in post-marketing diabetic patients taking pioglitazone or other thiazolidinediones. Some patients present with blurred vision or decreased vision, but others are diagnosed during routine eye examinations.
Most patients have peripheral edema at the time of diagnosis of macular edema. In some patients, macular edema resolved after discontinuation of thiazolidinediones.
Patients with diabetes should receive regular eye examinations according to current standards of care. Any diabetic patient reporting visual symptoms should be referred to ophthalmology immediately, whether these symptoms are discovered while taking medications or during a physical examination.
Vitamin B12 concentration
It has been reported in the foreign literature that in a 29-week controlled clinical trial of metformin, approximately 7% of patients experienced a decrease in normal serum vitamin B12 concentrations to below normal levels after metformin administration with no clinical manifestations. This decrease may be due to interference with the uptake of B12 from the B12 endogenous factor complex; however, such decreases are rarely associated with anemia and recover quickly after discontinuation of metformin or vitamin B12 supplementation. It is recommended that patients who are taking this product have annual hematology tests and any abnormalities should be investigated and managed. Some patients, such as those with inadequate vitamin B12 or calcium intake/absorption, exhibit a tendency to fall below normal vitamin B12 concentrations. For these patients, routine serum vitamin B12 measurements are recommended at 2-3 year intervals.
Large vessel lesions
No clinical trials have demonstrated a decreased risk of macrovascular disease with the use of this product.
[For Pregnant and Lactating Women].
Pregnant women.
This product is contraindicated in patients who are planning to become pregnant or are already pregnant.
There are limited dosing data associated with this product or pioglitazone in pregnant women to determine the drug-related risk of major congenital defects or miscarriage. Published studies of metformin use during pregnancy have not reported a clear association between metformin and the risk of major congenital defects or miscarriage. There is a risk that maternal and fetal diabetes may be difficult to control during pregnancy.
The predicted risk of major congenital defects is 6-10% in preconception diabetic women with HbA1c>7% and up to 20-25% in preconception diabetic women with HbA1c >10%, according to the relevant literature. The predicted risk of miscarriage in the pre-pregnancy diabetic population has not been determined. In the general US population, the predicted risks of major congenital defects and miscarriage in women with clinically confirmed pregnancies are 2 to 4% and 15 to 20%, respectively.
Poor glycemic control during pregnancy increases the risk of maternal diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, stillbirth, and delivery complications. Poor glycemic control increases the risk of major congenital defects, stillbirth, and morbidity associated with macrosomia in the fetus.
Published data from postmarketing studies do not report a clear association between metformin administration during pregnancy and major congenital defects, miscarriage, and adverse maternal or fetal outcomes. However, because of methodological limitations, including small sample sizes and inconsistent comparison subgroups, these studies could not determine the absence of risks associated with metformin.
Lactating Women.
Breastfeeding is not recommended during treatment with this product.
There is no information to suggest that this product or pioglitazone is present in human breast milk, has effects on the nursing infant, or affects milk production.
According to foreign literature, metformin is present in human milk at infant doses of approximately 0.11% to 1% of the maternal weight corrected dose, with a milk/plasma ratio range of 0.13 to 1.
Pediatric Use]
The safety and efficacy of this product for use in children have not been established.
Based on the adverse reactions observed in adults, including fluid retention, congestive heart failure, fractures and bladder cancer, this product is not recommended for use in pediatric patients.
[Geriatric Use].
Pioglitazone
In three pooled 16-26 week double-blind, placebo-controlled, monotherapy trials, 92 patients (15.2%) were ≥65 years of age and 2 patients (0.3%) were ≥75 years of age. 201 patients (18.7%) in the pioglitazone group were ≥65 years of age and 19 patients (1.8%) were ≥75 years of age in two pooled 16-24 week sulfonylurea combination trials. 2 pooled In the 16-24 week metformin combination trial, 155 (15.5%) patients in the pioglitazone group were ≥65 years of age and 19 (1.9%) were ≥75 years of age. 272 (25.4%) patients in the pioglitazone group were ≥65 years of age and 22 (2.1%) were ≥75 years of age in the 2 pooled 16-24 week insulin combination trials.
In the prospective trial, 1068 (41.0%) patients on pioglitazone were ≥65 years of age and 42 (1.6%) were ≥75 years of age.
There were no significant differences in pharmacokinetic parameters between older and younger patients in the pharmacokinetic studies conducted on pioglitazone.
Clinical differences in efficacy and safety between older patients (≥65 years) and younger patients were not determined, and conclusions were limited by the inadequate sample size of patients ≥75 years of age.
Metformin hydrochloride
Although other reported clinical experience has not identified differences in response to dosing between older and younger patients, clinical controlled trials of metformin did not include enough older patients to determine that response differences existed with younger patients. Typically, older patients with decreased hepatic, renal, and cardiac function and more frequent concomitant disease or treatment with other medications are at higher risk for lactic acidosis, and older patients should choose their doses carefully, generally selecting the lowest dose in the dose range to initiate dosing. Renal function should be evaluated more frequently in elderly patients.
[Drug Interactions].
Potent CYP2C8 inhibitors
CYP2C8 inhibitors (e.g., gemfibezil) significantly increase pioglitazone exposure (area under the serum concentration-time curve or AUC) and half-life (t1/2). Therefore, the maximum recommended daily dose of pioglitazone is 15 mg if gemfibezil or other potent CYP2C8 inhibitors are taken concurrently.
CYP2C8 inducers
CYP2C8 inducers (e.g., rifampin) may significantly reduce pioglitazone exposure (AUC). Therefore, if CYP2C8 inducers are taken or discontinued while taking pioglitazone, a change in diabetes therapy is required based on clinical response, but not exceeding the maximum recommended daily dose of pioglitazone of 45 mg.
Carbonic anhydrase inhibitors
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide, or dichloroanilide) frequently cause decreased serum bicarbonate or mediate nonionic gap, hyperchloremic metabolic acidosis. Concomitant administration of these drugs with this product increases the risk of lactic acidosis. Close monitoring of these patients should be considered.
Drugs that reduce metformin clearance
Concomitant administration of drugs that interfere with the renal tubular transport system involved in the renal clearance of metformin (e.g., organic cation transporter-2 [OCT2]/Reynolizine, vandetanib, dolutegravir, and multidrug and toxin efflux transport protein [MATE] inhibitors such as cimetidine) increases systemic exposure to metformin and increases the risk of lactic acidosis. Consider the risks and benefits when taking concomitantly.
Alcohol
Alcohol amplifies the effects of metformin on lactate metabolism. Patients should not consume excessive amounts of alcohol during the use of this product.
Insulin secretion or insulin
If a patient develops hypoglycemia while taking both this product and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.
If a patient develops hypoglycemia by taking this product and insulin at the same time, the dose of insulin should be reduced by 10% to 25%, and the insulin dose should be further adjusted according to the glycemic response and individual situation.
Medications that affect blood sugar control
A number of medications can cause hyperglycemia or lead to uncontrolled blood glucose, including thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, niacin, sympathomimetics, calcium channel blockers, and isoniazid. Patients taking this product with these drugs should be closely monitored for glycemic control. If a patient taking this product discontinues these drugs, the patient should be closely monitored for hypoglycemia.
Topiramate
A reduction in exposure to pioglitazone and its active metabolite is observed when pioglitazone and topiramate are taken concomitantly. The clinical relevance of this reduction is not known; however, patients should be monitored for adequate glycemic control when taking both this product and topiramate.
[Drug Overdose].
Pioglitazone
One case of overdose of pioglitazone was reported in a controlled clinical trial in a male patient who took 120 mg daily for 4 days and 180 mg daily for the next 7 days. the patient denied any clinical symptoms during this period.
When an overdose occurs, the patient should be treated appropriately according to the clinical symptoms and indications.
Metformin Hydrochloride
Overdose has been reported with metformin hydrochloride, including intake of more than 50 g. Hypoglycemic reactions have been reported in approximately 10% of patients, but a causal relationship between hypoglycemic reactions and metformin hydrochloride has not been established. Lactic acidosis occurred in approximately 32% of patients. In good hemodynamic conditions, the dialysis clearance of metformin can reach 170 mL/min. Therefore, in patients with suspected metformin overdose, the accumulated metformin in the body can be removed by hemodialysis.
Pharmacology and Toxicology
Pharmacological effects
This product is a compound preparation composed of pioglitazone and metformin.
Pioglitazone hydrochloride
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 insulin sensitivity in the periphery and liver. 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.
Metformin hydrochloride
Metformin reduces hepatic gluconeogenesis, inhibits intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Toxicological studies
No data are available on the non-clinical safety of pioglitazone metformin combination; the following data are derived from the results of studies of pioglitazone and metformin alone.
Pioglitazone hydrochloride
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 results were 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, oral administration of doses up to 63 mg/kg/day (14 times the clinical dose of 45 mg, based on body surface area) did not result in tumors 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 urinary tract stone induced irritation and hyperplasia. 2-year study of the mechanism of urinary tract stone reduction by dietary acidification in male rats revealed 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 administered orally at 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.
Metformin hydrochloride
Genotoxicity: In vitro Ames test, mouse lymphocyte mutation test, human lymphocyte chromosome aberration test, and in vivo micronucleus test in mice were all negative for metformin.
Reproductive toxicity: Oral administration of metformin to rats at doses up to 600 mg/kg/day (approximately 3 times the maximum daily recommended human clinical dose of 2000 mg based on body surface area) did not show effects on fertility in male and female rats.
Oral administration of metformin 600 and 140 mg/kg/day during organogenesis in pregnant rats and rabbits, respectively, did not show teratogenicity. The results of lactating rats showed that metformin hydrochloride could be secreted into milk and could reach the level in plasma.
Carcinogenicity: Metformin 900 mg/kg/day was given orally for 104 weeks in rats and 1500 mg/kg/day in mice for 91 weeks, which is approximately 4 times the maximum daily recommended human clinical dosage of 2000 mg based on body surface area, and no carcinogenicity was observed in mice and male rats, and benign interstitial uterine The incidence of benign mesometrial polyps increased in female rats at a dose of 900mg/kg/day.
Pharmacokinetics]
According to foreign literature, it is reported that
Absorption
In a bioequivalence test of pioglitazone metformin tablets 15mg/500mg in healthy subjects in fasted state, the area under the curve (AUC) and maximum blood concentration (Cmax) of pioglitazone and metformin in single-dose combination tablets were bioequivalent to the administration of pioglitazone 15mg with concomitant administration of metformin 500mg.
Food did not affect the AUC of metformin hydrochloride, but the mean peak serum concentration decreased by 28%. Food delayed the time to peak for both pioglitazone and metformin hydrochloride (1.9 hours for pioglitazone and 0.8 hours for metformin), and these changes were not clinically significant.
Recommend 0phimurium) pioglitazone
After once-daily administration of pioglitazone, both pioglitazone and its major active metabolites, M-II and M-IV, reached steady-state serum concentrations within 7 days. At steady state, M-III and M-IV reached serum concentrations greater than or equal to pioglitazone. At steady state, pioglitazone accounted for approximately 30-50% of the total pioglitazone peak serum concentrations (pioglitazone + active metabolites) and 20-25% of the total AUC in healthy subjects and patients with type 2 diabetes.
The Cmax, AUC, and trough serum concentration (Cmin) of pioglitazone, M-III, and M-IV increased proportionally with daily doses of 15 mg and 30 mg.
After oral administration of pioglitazone, pioglitazone reaches Tmax within 2 h. Food delays Tmax to 3-4 h, but does not change the degree of absorption (AUC).
Metformin hydrochloride
The absolute bioavailability of oral 500 mg metformin tablets in the fasted state is approximately 50-60%. A single dose of oral metformin tablets from 500 mg to 1500 mg indicates that blood concentrations do not increase proportionately with increasing doses, due to reduced absorption rather than a change in drug elimination. For the clinical generic dose and dosing regimen of metformin, steady-state plasma concentrations of metformin are achieved within 24 to 48 hours, typically less than 1 mcg/mL. In controlled clinical studies, even at the maximum dose, the maximum plasma concentration of metformin did not exceed 5 mcg/mL.
Food slightly delays and reduces the absorption of metformin, with an average Cmax reduction of approximately 40% and an AUC reduction of approximately 25%. The clinical relevance of these reductions is unclear.
Distribution
Pioglitazone
The mean apparent volume of distribution (Vd/F) of pioglitazone administered as a single dose was 0.63 ± 0.41 (mean ± standard deviation) L/kg body weight. Pioglitazone is extensively bound (>99%) to proteins in human serum, primarily serum albumin. Pioglitazone also binds to other serum proteins, but with low affinity. The metabolites M-III and M-IV also bind extensively (>98%) to serum albumin.
Metformin hydrochloride
Metformin is hardly bound to plasma proteins. With time action, metformin enters red blood cells.
Metabolism
Pioglitazone
Pioglitazone is metabolized primarily by hydroxylation and oxidation, with metabolites partially converted to glucosinolates or sulfate isomers. Metabolites M-III and M-IV are the main circulating active metabolites in humans.
In vitro data demonstrate the involvement of multiple CYP isoenzymes in pioglitazone metabolism, including CYP2C8, the relatively minor but additional contribution of CYP3A4, such as CYP1A1, which is predominantly extrahepatic. in vivo studies combining the potent CYP2C8 inhibitor gemfibrozil with pioglitazone have shown that pioglitazone is a CYP2C8 substrate. Measurements of urinary 6-beta hydroxycortisol in patients taking pioglitazone suggest that pioglitazone is not a strong CYP3A4 enzyme inducer.
Metformin hydrochloride
A single dose of metformin administered intravenously to healthy subjects demonstrated that metformin is excreted from the urine in its original form and is not metabolized by the liver (no metabolites were found in humans) or excreted by the bile.
Excretion and clearance
Pioglitazone
After oral administration, pioglitazone is detectable in the urine in approximately 15% to 30% of the total amount of pioglitazone. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It can be assumed that most of the pioglitazone taken orally is excreted in the bile in its original form or as a metabolite and finally in the feces.
The mean serum half-lives of pioglitazone and its metabolites (M-III and M-IV) are 3-7 hours and 16-24 hours, respectively, and the calculated apparent clearance of pioglitazone (CL/F) is 5-7 l/h.
Metformin hydrochloride
The renal clearance of metformin is approximately 3.5 times higher than creatinine clearance, suggesting that renal tubular secretion is the major route of metformin elimination. After oral administration, approximately 90% of the absorbed drug is eliminated by the kidneys within 24 hours, with a plasma elimination half-life of approximately 6.2 hours. The elimination half-life in whole blood is approximately 17.6 hours, suggesting that red blood cells may be a distribution compartment.
Special Populations
Renal insufficiency.
Pioglitazone: In patients with moderate (creatinine clearance 30-50 mL /min) to severe (creatinine clearance <30 mL /min) renal insufficiency, the serum elimination half-lives of pioglitazone, M-III and M-IV are the same as normal and no dose adjustment is required for patients with renal insufficiency.
Metformin hydrochloride: In patients with decreased renal function, the plasma and blood half-lives of metformin hydrochloride are prolonged and renal clearance is reduced.
Hepatic insufficiency.
Pioglitazone: The mean Cmax of pioglitazone and total pioglitazone (pioglitazone, M-III and M-IV) was reduced by approximately 45% and the mean AUC value was unchanged in subjects with hepatic insufficiency (Child-Turcotte-Pugh classification B/C) compared to healthy subjects. Therefore, no dose adjustment was required for patients with hepatic insufficiency.
Post-marketing reports and clinical studies of pioglitazone for hepatic failure generally exclude patients with serum transaminases greater than 2.5 times the upper limit of the reference range. Use this product with caution in patients with liver disease.
Metformin hydrochloride: Data from pharmacokinetic studies in subjects with hepatic insufficiency are not available.
Geriatric.
Pioglitazone: In healthy elderly subjects, pioglitazone Cmax did not change significantly, but AUC was elevated by approximately 21% compared to younger subjects. The mean half-life in older subjects (~10 hours) was similarly prolonged compared to younger subjects (~7 hours). These changes were not sufficient to be considered clinically relevant.
Metformin hydrochloride: Data from a limited controlled pharmacokinetic study in healthy elderly subjects showed decreased total plasma clearance, prolonged half-life, and increased Cmax compared to healthy young subjects. These data suggest that changes in renal function in the elderly result in altered metformin pharmacokinetics.
Children.
Pioglitazone: Pharmacokinetic data for children are not available. This product is not recommended for pediatric patients.
Metformin hydrochloride: Children with type 2 diabetes (12 to 16 years of age) with normal renal function who received a single dose of metformin tablets 500 mg orally with a meal had a geometric mean Cmax and AUC difference of less than 5% for metformin compared with healthy adults (20 to 45 years of age) who were sex-weight matched and had normal renal function.
Gender.
Pioglitazone: Mean Cmax and AUC values were increased by 20% to 60% in women compared to men. In controlled clinical trials, hemoglobin A1c (HbA1c) was reduced somewhat more in women than in men compared to baseline concentrations (mean HbA1c difference averaged 0.5%). To achieve good glycemic control, treatment should be individualized, but no dose adjustment is required for gender differences alone.
Metformin hydrochloride: Based on gender analysis (19 males and 16 females), there were no significant differences in metformin hydrochloride pharmacokinetic parameters between normal subjects and type 2 diabetic patients. In controlled clinical studies in type 2 diabetics, the hypoglycemic effect of metformin hydrochloride was comparable in males and females.
Ethnicity.
Pioglitazone: Pharmacokinetic data are not available for different races.
Metformin Hydrochloride: Pharmacokinetic studies of metformin hydrochloride by race have not been performed. In controlled clinical studies in patients with type 2 diabetes, the hypoglycemic effect of metformin hydrochloride was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).
Drug Interactions
No specific pharmacokinetic drug interaction trials were conducted for this product; pioglitazone and metformin were tested separately in such trials.
Pioglitazone.
Table 16: Effect of concomitant pioglitazone administration on systemic exposure to other drugs Concomitant drug pioglitazone
Dose (mg)* Change in drug and dose AUC + Change in Cmax + 45 mg (n=12) Warfarin ++ Initial daily dose and subsequent maintenance dose based on PT and INR values
Rapid value = 35±5% R-warfarin â3% R-warfarin â2% S-warfarin â1% S-warfarin á1% 45mg (n=12) Digoxin 0.200mg once daily (initial dose) and subsequently 0.250mg daily (maintenance dose, 7 days) á15% á17% 45mg daily for 21 days (n=35) Oral contraceptives Ethinyl estradiol (EE) 0.035mg + norethindrone (NE) 1mg, continuous 21 days EEâ11%EEâ13%NEá3%NEâ7%45mg (n=23) fexofenadine once 60mg twice daily, continuous 7 daysá30%á37%45mg (n=14) glipizide 5mg daily, continuous 7 daysâ3%â8% daily 45mg for 8 days (n=16) Metformin Day 8 1000mg, single dose â3%â5%45mg (n=21) Midazolam Day 15 7.5mg, single dose â26%â26%45mg (n=24) Ranitidine once 150mg twice daily for 7 days á1%â1% 45mg daily for 4 days (n= (n=24) Nifedipine extended-release tablets 30mg daily for 4 daysâ13%â17%45mg (n=25) Atorvastatin calcium 80mg daily for 7 daysâ14%â23%45mg (n=22) Theophylline 400mg once twice daily for 7 daysá2%â5%* represents daily dose for 7 days unless otherwise noted.
+% Percent change (concurrent/no concurrent other drugs and no change = 0%); á and â represent increase and decrease in exposure, respectively.
++ represents no clinically significant effect of pioglitazone on prothrombin time.
Table 17. Effect of concomitant medications on systemic exposure to pioglitazone Concomitant medications and doses Pioglitazone dose (mg) * change in AUC + change in Cmax + gemfibrozil 600 mg
2 times daily for 2 consecutive days (N=12) 15mg Single dose á3.2 times ++á6% ketoconazole 200mg
2 times daily for 2 consecutive days (N=28) 45mgá34%á14% Rifampicin 600mg
1 time daily for 5 days
(N=10) 30mg single dose â54%â5% fexofenadine 60mg
2 times a day for 7 days
N=2345mgâ1%0%Renitidine 150mg
Take 2 times daily for 4 days
(N=23) 45mgâ13%â16% Nifedipine Extended Release Tablets 30mg
1 time daily for 7 days
(N=23) 45mgâ5%â4% atorvastatin calcium 80mg
1 time daily for 7 days
(N=24) 45mgâ24%â31% Theophylline 400mg
2 times a day for 7 days
(N=22) 45mgâ4%â2% topiramate 96mg
2 times a day for 7 days§
(N=26) 30mg§â15%¶0%* represents 1 dose daily for 7 days, unless otherwise noted.
+ mean ratio (concomitant/not concomitant with other drugs and no change = 1x) % change (concomitant/not concomitant with other drugs and no change = 0%); á and â represent increase and decrease in exposure, respectively.
++ The half-life of pioglitazone increased from 8.3 to 22.7 hours in the concomitant presence of gemfibrozil.
§ indicates the duration of concomitant dosing from the highest twice-daily dose of topiramate on day 14 to the end of day 22 of the study.
¶
Further reduction in active metabolites; 60% for M-III and 16% for M-IV.
Metformin hydrochloride.
Table 18. effect of concomitant medication on systemic exposure to plasma metformin concomitant medication dose of concomitant medication * dose of metformin * geometric mean ratio
(ratio to concomitant/non-concomitant drugs) No effect = 1.00 AUC + Cmax No dose adjustment required below glibenclamide 5mg500mg§0.98++0.99++ furosemide 40mg850mg1.09++1.22++ nifedipine 10mg850mg1.161.21 propranolol 40mg850mg0.900 .94 Ibuprofen 400mg850mg1.05++1.07++ Drugs eliminated via renal tubules may increase metformin accumulation. Cimetidine 400mg850mg1.401.61 Carbonic anhydrase inhibitors may cause metabolic acidosis. Topiramate 100mg¶500mg¶1.25¶1.17* All metformin and co-administered drugs are single doses.
+AUC=AUC0-∞
++ arithmetic mean ratio
§¶ Metformin hydrochloride extended-release tablets 500mg
¶ When 100 mg topiramate every 12 h and 500 mg metformin every 12 h reach steady state; AUC=AUC0-12h
Table 19. effect of metformin on systemic exposure to concomitant drugs concomitant drugs dose geometric mean ratio of metformin dose
(ratio to concomitant/non-concomitant drugs) No effect = 1.00 AUC + Cmax No dose adjustment required below glibenclamide 5mg 500mg 0.78++ 0.63++ tachyphylaxis 40mg 850mg 0.87++ 0.69++ nifedipine 10mg 850mg 1.10§ 1.08 Onelolol 40mg 850mg 1.01§ 0.94 Ibuprofen 400mg850mg0.97¶1.01¶ Cimetidine 400mg850mg0.95§1.01* All metformin and co-administered drugs are single dose.
+AUC=AUC0-∞
+ + arithmetic mean ratio, p < 0.05
§ Reported AUC0-24hr
¶ Geometric mean ratio
【Storage】Sealed and stored below 25℃.
Package】In plastic bottles, 30 tablets/bottle, 60 tablets/bottle, 18 tablets/bottle, 14 tablets/bottle.
【Validity】18 months.
【Execution Standard
【Approval Number】State Drug Registration Number H20100180
[Drug marketing license holder
Name: Hangzhou Zhongmei Huadong Pharmaceutical Co.
Registered address: No. 866 Moganshan Road, Hangzhou, Xiangfu Bridge
Postal Code: 310011
Contact: 0571-89903388 (switchboard), 8008571016, 4009057136
Fax number: 0571-89903366
Website: www.eastchinapharm.com
【Manufacturing enterprise
Company name: Hangzhou Zhongmei Huadong Pharmaceutical Co.
Production Address: No. 866 Moganshan Road, Hangzhou, Xiangfu Bridge
Postal code: 310011
Contact: 0571-89903388 (switchboard), 8008571016, 4009057136
Fax number: 0571-89903366
Website: www.eastchinapharm.com