Sonias HD

Sonias HD ist als Ergänzung zu Diät und Bewegung zur Verbesserung der Blutzuckerkontrolle bei Erwachsenen mit Typ-2-Diabetes mellitus angezeigt, die bereits mit Thiazolidindion und Sulfonylharnstoff behandelt wurden oder die eine unzureichende Blutzuckerkontrolle an einem Thiazolidindion allein oder einem Sulfonylharnstoff allein aufweisen.

Wichtige Nutzungsbeschränkungen

Pioglitazon übt seine antihyperglykämische Wirkung nur in Gegenwart von endogenem Insulin aus. Sonias HD sollte nicht zur Behandlung von Typ-1-Diabetes oder diabetischer Ketoazidose angewendet werden, da dies in diesen Umgebungen nicht wirksam wäre.

Seien Sie bei Patienten mit Lebererkrankungen vorsichtig.

Empfehlungen für alle Patienten

Sonias HD sollte einmal täglich mit der ersten Hauptmahlzeit eingenommen werden.

Sonias HD-Tabletten sind als 30 mg Pioglitazon plus 2 mg Glimepirid oder 30 mg Pioglitazon plus 4 mg Glimepirid-Tablette erhältlich. Wenn die Therapie mit einer Kombinationstablette, die Pioglitazon und Glimepirid enthält, als angemessen erachtet wird, beträgt die empfohlene Anfangsdosis:

• 30 mg / 2 mg oder 30 mg / 4 mg einmal täglich und nach Bedarf nach der Beurteilung der Angemessenheit des therapeutischen Ansprechens und der Verträglichkeit schrittweise titriert
• für Patienten, die die Glimepirid-Monotherapie nicht ausreichend kontrolliert haben: 30 mg / 2 mg oder 30 mg / 4 mg einmal täglich und nach Bedarf nach Beurteilung der Angemessenheit des therapeutischen Ansprechens und der Verträglichkeit schrittweise titriert
• für Patienten, die die Pioglitazon-Monotherapie nicht ausreichend kontrolliert haben: 30 mg / 2 mg einmal täglich und nach Bedarf nach der Beurteilung der Angemessenheit des therapeutischen Ansprechens und der Verträglichkeit schrittweise titriert
• für Patienten, die von der Kombinationstherapie von Pioglitazon plus Glimepirid als separate Tabletten wechseln: Sonias HD sollte in Dosen eingenommen werden, die so nahe wie möglich an der bereits eingenommenen Dosis von Pioglitazon und Glimepirid liegen
• für Patienten, die derzeit eine andere Sulfonylharnstoff-Monotherapie erhalten oder von einer Kombinationstherapie mit Pioglitazon plus einem anderen Sulfonylharnstoff (z., Glyburid, Glipizid, Chlorpropamid, Tolbutamid, Acetohexamid): 30 mg / 2 mg einmal täglich und nach Beurteilung der Angemessenheit der therapeutischen Reaktion angepasst. Beobachten Sie Hypoglykämie ein bis zwei Wochen lang aufgrund des möglichen überlappenden Arzneimitteleffekts.
• Bei Patienten mit systolischer Dysfunktion sollte die niedrigste zugelassene Dosis von Sonias HD erst verschrieben werden, nachdem die Titration von 15 mg bis 30 mg Pioglitazon sicher vertragen wurde.

Überwachen Sie die Patienten nach Beginn von Sonias HD oder mit Dosiserhöhung sorgfältig auf Hypoglykämie und Nebenwirkungen im Zusammenhang mit Flüssigkeitsretention wie Gewichtszunahme, Ödeme sowie Anzeichen und Symptome einer Herzinsuffizienz.

Lebertests (Serum-Alanin- und Aspartat-Aminotransferasen, alkalische Phosphatase und Gesamtbilirubin) sollten vor Beginn von Sonias HD durchgeführt werden. Eine regelmäßige routinemäßige Überwachung der Lebertests während der Behandlung mit Sonias HD wird bei Patienten ohne Lebererkrankung nicht empfohlen. Patienten mit Lebertestanomalien vor Beginn von Sonias HD oder mit abnormalen Lebertests während der Einnahme von Sonias HD sollten wie unter Warnungen und Vorsichtsmaßnahmen beschrieben behandelt werden.

Gleichzeitige Anwendung mit einem Insulinsekretagogen oder Insulin

Wenn bei einem Patienten, dem Sonias HD und ein Insulinsekretagoge gleichzeitig verabreicht werden, eine Hypoglykämie auftritt, sollte die Dosis des Insulinsekretagogens reduziert werden.

Wenn bei einem Patienten, dem Sonias HD und Insulin gleichzeitig verabreicht werden, eine Hypoglykämie auftritt, sollte die Insulindosis um 10% bis 25% gesenkt werden. Weitere Anpassungen der Insulindosis sollten anhand der glykämischen Reaktion individualisiert werden.

Gleichzeitige Anwendung mit starken CYP2C8-Inhibitoren

Die gleichzeitige Anwendung von Pioglitazon und Gemfibrozil, einem starken CYP2C8-Inhibitor, erhöht die Pioglitazon-Exposition um das Dreifache. Daher beträgt die empfohlene Höchstdosis von Pioglitazon 15 mg täglich, wenn sie in Kombination mit Gemfibrozil oder anderen starken CYP2C8-Inhibitoren angewendet wird. Wenn Gemfibrozil oder andere CYP2C8-Inhibitoren gleichzeitig verabreicht werden müssen, sollten die Patienten auf einzelne Komponenten von Sonias HD umsteigen, da die Mindestdosis von Pioglitazon in Sonias HD 15 mg überschreitet Drogeninteraktionen und KLINISCHE PHARMAKOLOGIE].

Gleichzeitige Anwendung mit Colesevelam

Wenn Colesevelam zusammen mit Glimepirid verabreicht wird, wird die maximale Plasmakonzentration und die vollständige Exposition gegenüber Glimepirid verringert. Daher sollte Sonias HD mindestens vier Stunden vor dem Abblättern von Colesevelam verabreicht werden Drogeninteraktionen und KLINISCHE PHARMAKOLOGIE].

• Einleitung bei Patienten mit etablierter Herzinsuffizienz der NYHA-Klasse III oder IV.
• Anwendung bei Patienten mit bekannter Überempfindlichkeit gegen Pioglitazon, Glimepirid oder eine andere Komponente von Sonias HD
• Anwendung bei Patienten mit bekannter Vorgeschichte einer allergischen Reaktion auf Sulfonamidderivate.

Gemeldete Überempfindlichkeitsreaktionen mit Glimepirid umfassen Hautausschläge mit oder ohne Juckreiz sowie schwerwiegendere Reaktionen (z.Anaphylaxie, Angioödem, Stevens-Johnson-Syndrom, Atemnot)

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Congestive Heart Failure

Pioglitazone

Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when Sonias HD is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of Sonias HD must be considered.

Hypoglycemia

Glimepiride

All sulfonylureas, including glimepiride, a component of Sonias HD, can cause severe hypoglycemia. The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. These impairments may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death.

Patients must be educated to recognize and manage hypoglycemia. Use caution when initiating and increasing Sonias HD doses in patients who may be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, patients on other antidiabetic medications). Debilitated or malnourished patients and those with adrenal, pituitary, or hepatic impairment are particularly susceptible to the hypoglycemic action of glucose-lowering medications. Hypoglycemia is also more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when alcohol is ingested.

Early warning symptoms of hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking medications or other sympatholytic agents. These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia.

Hypersensitivity Reactions

Glimepiride

There have been postmarketing reports of hypersensitivity reactions in patients treated with glimepiride, a component of Sonias HD, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, promptly discontinue Sonias HD, assess for other potential causes for the reaction, and institute alternative treatment for diabetes.

Potential Increased Risk Of Cardiovascular Mortality With Sulfonylureas

Glimepiride

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups.

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2.5 times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glimepiride tablets and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

Hepatic Effects

Pioglitazone

There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking pioglitazone, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the pioglitazone-controlled clinical trial database to date.

Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating Sonias HD therapy. In patients with abnormal liver tests, Sonias HD should be initiated with caution.

Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than 3 times the upper limit of the reference range), Sonias HD treatment should be interrupted and investigation done to establish the probable cause. Sonias HD should not be restarted in these patients without another explanation for the liver test abnormalities.

Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury and should not be restarted on Sonias HD. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with Sonias HD can be used with caution.

Urinary Bladder Tumors Pioglitazone

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study. In addition, during the three year PROactive clinical trial, 14 patients out of 2605 (0.54%) randomized to pioglitazone and 5 out of 2633 (0.19%) randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and two (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR =1.00; [95% CI: 0.59–1.72]).

Findings regarding the risk of bladder cancer in patients exposed to pioglitazone vary among observational studies; some did not find an increased risk of bladder cancer associated with pioglitazone, while others did.

A large prospective 10-year observational cohort study conducted in the United States found no statistically significant increase in the risk of bladder cancer in diabetic patients ever exposed to pioglitazone, compared to those never exposed to pioglitazone (HR =1.06 [95% CI 0.89–1.26]).

A retrospective cohort study conducted with data from the United Kingdom found a statistically significant association between ever exposure to pioglitazone and bladder cancer (HR: 1.63; [95% CI: 1.22–2.19]).

Associations between cumulative dose or cumulative duration of exposure to pioglitazone and bladder cancer were not detected in some studies including the 10-year observational study in the U.S., but were in others. Inconsistent findings and limitations inherent in these and other studies preclude conclusive interpretations of the observational data.

Pioglitazone may be associated with an increase in the risk of urinary bladder tumors. There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors.

Consequently, Sonias HD should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with Sonias HD should be considered in patients with a prior history of bladder cancer.

Edema

Pioglitazone

In controlled clinical trials, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and is dose-related. In postmarketing experience, reports of new onset or worsening edema have been received.

Sonias HD should be used with caution in patients with edema. Because thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, Sonias HD should be used with caution in patients at risk for congestive heart failure. Patients treated with Sonias HD should be monitored for signs and symptoms of congestive heart failure.

Fractures

Pioglitazone

In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and persisted during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in the incidence of fracture was observed in men treated with pioglitazone (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with Sonias HD and attention should be given to assessing and maintaining bone health according to current standards of care.

Hemolytic Anemia

Glimepiride

Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because Sonias HD contains glimepiride, which belongs to the class of sulfonylurea agents, use caution in patients with G6PD deficiency and consider the use of a nonsulfonylurea alternative. There are also postmarketing reports of hemolytic anemia in patients receiving glimepiride who did not have known G6PD deficiency.

Macular Edema

Pioglitazone

Macular edema has been reported in postmarketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination.

Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione.

Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient’s underlying medications or other physical findings.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Sonias HD.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION).

• Inform patients that Sonias HD is not recommended for patients with symptoms of heart failure.
• Inform patients that patients with severe heart failure (NYHA Class III or IV) cannot start Sonias HD as the risks exceed the benefits in such patients.
• It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients should also be informed of the potential risks and advantages of Sonias HD and of alternative modes of therapy.
• Tell patients to promptly report any sign of macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer.
• Prior to initiation of Sonias HD therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Combination therapy of Sonias HD with other antihyperglycemic agents may also cause hypoglycemia.
• Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on Sonias HD should immediately report these symptoms to a physician.
• Tell patients to promptly stop taking Sonias HD and seek immediate medical advice if there is unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine as these symptoms may be due to hepatotoxicity.
• Inform female patients that treatment with pioglitazone, like other thiazolidinediones may result in an unintended pregnancy in some premenopausal anovulatory females due to its effect on ovulation.
• Patients should be told to take a single dose of Sonias HD once daily with the first main meal and instructed that any change in dosing should be made only if directed by their physician.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No animal studies have been conducted with Sonias HD. The following data are based on findings in studies performed with pioglitazone or glimepiride individually.

Pioglitazone

A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m²). Drug-induced tumors were not observed in any organ except for the urinary bladder of male rats. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m²). Urinary calculi with subsequent irritation and hyperplasia were postulated as the mechanism for bladder tumors observed in male rats. A two-year mechanistic study in male rats utilizing dietary acidification to reduce calculi formation was completed in 2009. Dietary acidification decreased but did not abolish the hyperplastic changes in the bladder. The presence of calculi exacerbated the hyperplastic response to pioglitazone but was not considered the primary cause of the hyperplastic changes.

The relevance to humans of the bladder findings in the male rat cannot be excluded.

A two-year carcinogenicity study was also conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m²). No drug-induced tumors were observed in any organ.

Pioglitazone hydrochloride was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay.

No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone hydrochloride daily prior to and throughout mating and gestation (approximately nine times the maximum recommended human oral dose based on mg/m²).

Glimepiride

Studies in rats at doses of up to 5000 parts per million (ppm) in complete feed (approximately 340 times the maximum recommended human dose, based on surface area) for 30 months showed no evidence of carcinogenesis. In mice, administration of glimepiride for 24 months resulted in an increase in benign pancreatic adenoma formation that was dose-related and was thought to be the result of chronic pancreatic stimulation. No adenoma formation in mice was observed at a dose of 320 ppm in complete feed, or 46 − 54 mg/kg body weight/day. This is about 35 times the maximum human recommended dose of 8 mg once daily based on surface area.

Glimepiride was non-mutagenic in a battery of in vitro and in vivo mutagenicity studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis and mouse micronucleus test).

There was no effect of glimepiride on male mouse fertility in animals exposed up to 2500 mg/kg body weight (>1,700 times the maximum recommended human dose based on surface area). Glimepiride had no effect on the fertility of male and female rats administered up to 4000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area).

Use In Specific Populations

Pregnancy

Risk Summary

Limited data with Sonias HD or pioglitazone in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are clinical considerations related to fetal and neonatal adverse reactions and drug discontinuation if glimepiride is used during pregnancy. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

No adverse developmental effects were observed when pioglitazone was administered to pregnant rats and rabbits during organogenesis at exposures up to 5-and 35-times the 45 mg clinical dose, respectively, based on the body surface area. Administration of glimepiride to pregnant rats and rabbits during organogenesis induced maternal hypoglycemia and also increased fetal mortality at doses 50 (rats) and 0.1-times (rabbits) the 8 mg clinical dose, respectively, based on body surface area.

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20% respectively.

Clinical Considerations

Disease-associated Maternal and/or Embryo/fetal Risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

Fetal/Neonatal Adverse Reaction

Neonates of women with gestational diabetes, who are treated with sulfonylureas during pregnancy, may be at increased risk for neonatal intensive care unit admission, and may develop respiratory distress, hypoglycemia, birth injury, and be large for gestational age. Prolonged severe hypoglycemia, lasting 4-10 days, has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery and has been reported with the use of agents with a prolonged half-life. Observe newborns for symptoms of hypoglycemia and respiratory distress and manage accordingly.

Dose Adjustments During Pregnancy and the Postpartum Period

Due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a sulfonylurea at the time of delivery, Sonias HD should be discontinued at least two weeks before expected delivery.

Data

Animal Data

Pioglitazone and Glimepiride

Animal reproduction studies were not conducted with the combined products in Sonias HD. The following data are based on studies conducted with the individual components of Sonias HD.

Pioglitazone

Glimepiride

Fetal deaths occurred in rats and rabbits administered glimepiride during the period of organogenesis at doses 50-times (rats) and 0.1-times (rabbits) the 8 mg clinical dose, based on body surface area. This fetotoxicity, observed only at doses inducing maternal hypoglycemia, is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride and has been similarly noted with other sulfonylureas.

Lactation

Risk Summary

There is no information regarding the presence of pioglitazone or glimepiride in human milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone and glimepiride are present in rat milk; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Sonias HD and any potential adverse effects on the breastfed infant from Sonias HD or from the underlying maternal condition.

Data

During pre-and postnatal studies in rats, glimepiride was present in lactational milk and in serum of nursing rat pups. Offspring exposed to high levels of glimepiride during lactation developed skeletal abnormalities (shortening, thickening and bending of the humerus) during the postnatal period.

Females And Males Of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some anovulatory women.

Pediatric Use

Safety and effectiveness of Sonias HD in pediatric patients have not been established.

Sonias HD is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors.

Glimepiride

The pharmacokinetics, efficacy and safety of glimepiride have been evaluated in pediatric patients with type 2 diabetes as described below. Glimepiride is not recommended in pediatric patients because of its adverse effects on body weight and hypoglycemia.

The pharmacokinetics of a 1 mg single dose of glimepiride was evaluated in 30 patients with type 2 diabetes (male = 7; female = 23) between ages 10 and 17 years. The mean (±SD) AUC (0-last) (339±203 ng•hr/mL), Cmax (102±48 ng/mL) and t_1/2 (3.1±1.7 hours) for glimepiride were comparable to historical data from adults (AUC (0-last) 315±96 ng•hr/mL, Cmax 103±34 ng/mL and t_1/2 5.3±4.1 hours).

The safety and efficacy of glimepiride in pediatric patients was evaluated in a single-blind, 24week trial that randomized 272 patients (8 to 17 years of age) with type 2 diabetes to glimepiride (n=135) or metformin (n=137). Both treatment-naïve patients (those treated with only diet and exercise for at least two weeks prior to randomization) and previously treated patients (those previously treated or currently treated with other oral antidiabetic medications for at least three months) were eligible to participate. Patients who were receiving oral antidiabetic agents at the time of study entry discontinued these medications before randomization without a washout period. Glimepiride was initiated at 1 mg, and then titrated up to 2, 4 or 8 mg (mean last dose 4 mg) through Week 12, targeting a self monitored fasting fingerstick blood glucose <126 mg/dL. Metformin was initiated at 500 mg twice daily and titrated at Week 12 up to 1000 mg twice daily (mean last dose 1365 mg).

After 24 weeks, the overall mean treatment difference in HbA1c between glimepiride and metformin was 0.2%, favoring metformin (95% confidence interval -0.3% to +0.6%).

Based on these results, the trial did not meet its primary objective of showing a similar reduction in HbA1c with glimepiride compared to metformin.

The profile of adverse reactions in pediatric patients treated with glimepiride was similar to that observed in adults.

Hypoglycemic events documented by blood glucose values <36 mg/dL were observed in 4% of pediatric patients treated with glimepiride and in 1% of pediatric patients treated with metformin. One patient in each treatment group experienced a severe hypoglycemic episode (severity was determined by the investigator based on observed signs and symptoms).

Geriatric Use

To minimize the risk of hypoglycemia, the initial dosing, dose increments, and maintenance dosage of Sonias HD should be conservative. During initiation of Sonias HD therapy and any subsequent dose adjustments, geriatric patients should be observed carefully for hypoglycemia.

Pioglitazone

A total of 92 patients (15.2%) treated with pioglitazone in the three pooled 16-to 26-week double-blind, placebo-controlled, monotherapy trials were ≥65 years old and two patients (0.3%) were ≥75 years old. In the two pooled 16-to 24-week add-on to sulfonylurea trials, 201 patients (18.7%) treated with pioglitazone were ≥65 years old and 19 (1.8%) were ≥75 years old. In the two pooled 16-to 24-week add-on to metformin trials, 155 patients (15.5%) treated with pioglitazone were ≥65 years old and 19 (1.9%) were ≥75 years old. In the two pooled 16to 24-week add-on to insulin trials, 272 patients (25.4%) treated with pioglitazone were ≥65 years old and 22 (2.1%) were ≥75 years old. In PROactive, 1068 patients (41.0%) treated with pioglitazone were ≥65 years old and 42 (1.6%) were ≥75 years old.

In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients.

Although clinical experiences have not identified differences in effectiveness and safety between the elderly (≥65 years) and younger patients, these conclusions are limited by small sample sizes for patients ≥75 years old.

Glimepiride

In clinical trials of glimepiride, 1053 of 3491 patients (30%) were ≥65 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

There were no significant differences in glimepiride pharmacokinetics between patients with type 2 diabetes ≤65 years (n=49) and those >65 years (n=42).

Glimepiride is substantially excreted by the kidney. Elderly patients are more likely to have renal impairment. In addition, hypoglycemia may be difficult to recognize in the elderly. Use caution when initiating Sonias HD and increasing the dose of Sonias HD in this patient population.

Renal Impairment

To minimize the risk of hypoglycemia, the initial dosing, dose increments and maintenance dosage of Sonias HD should be conservative. During initiation of Sonias HD therapy and any subsequent dose adjustments, these patients should be observed carefully for hypoglycemia.

A multiple-dose titration study was conducted in 16 patients with type 2 diabetes and renal impairment using doses ranging from 1 mg to 8 mg daily for three months. Baseline creatinine clearance ranged from 10 to 60 mL/min. The pharmacokinetics of glimepiride were evaluated in the multiple-dose titration study and the results were consistent with those observed in patients enrolled in a single-dose study. In both studies, the relative total clearance of glimepiride increased when kidney function was impaired. Both studies also demonstrated that the elimination of the two major metabolites was reduced in patients with renal impairment.

The following serious adverse reactions are discussed elsewhere in the labeling:

• Congestive Heart Failure
• Hypoglycemia
• Edema
• Fractures
• Hemolytic Anemia

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The adverse events reported in at least 5% of patients in the controlled 16-week clinical studies between placebo plus a sulfonylurea and pioglitazone (15 mg and 30 mg combined) plus sulfonylurea treatment arms were upper respiratory tract infection (15.5% and 16.6%), accidental injury (8.6% and 3.5%), and combined edema/peripheral edema (2.1% and 7.2%), respectively.

The incidence and type of adverse events reported in at least 5% of patients in any combined treatment group from the 24-week study comparing pioglitazone 30 mg plus a sulfonylurea and pioglitazone 45 mg plus a sulfonylurea are shown in Table 1; the rate of adverse events resulting in study discontinuation between the two treatment groups was 6% and 9.7%, respectively.

Table 1. Adverse Events that Occurred in ≥5% of Patients in Any Treatment Group During the 24-Week Study

In US double-blind studies, anemia was reported in ≤2% of patients treated with pioglitazone plus a sulfonylurea.

Pioglitazone

Over 8500 patients with type 2 diabetes have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with pioglitazone in the PROactive clinical trial. In these trials, over 6000 patients have been treated with pioglitazone for six months or longer, over 4500 patients have been treated with pioglitazone for one year or longer, and over 3000 patients have been treated with pioglitazone for at least two years.

In six pooled 16-to 26-week placebo-controlled monotherapy and 16-to 24-week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with pioglitazone and 5.8% for comparator-treated patients. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with pioglitazone than with placebo (3.0%).

In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with pioglitazone and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with pioglitazone and 0.6% of patients treated with placebo.

Common Adverse Events: 16-to 26-Week Monotherapy Trials

A summary of the incidence and type of common adverse events reported in three pooled 16to 26-week placebo-controlled monotherapy trials of pioglitazone is provided in Table 2. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo. None of these adverse events were related to the pioglitazone dose.

Table 2. Three Pooled 16-to 26-Week Placebo-Controlled Clinical Trials of Pioglitazone Monotherapy: Adverse Events Reported at an Incidence >5% and More Commonly in Patients Treated with Pioglitazone than in Patients Treated with Placebo

A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 3. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo.

Table 3. PROactive Trial: Incidence and Types of Adverse Events Reported in >5% of Patients Treated with Pioglitazone and More Commonly than Placebo

Congestive Heart Failure

A summary of the incidence of adverse events related to congestive heart failure is provided in Table 4 for the 16-to 24-week add-on to sulfonylurea trials, for the 16-to 24-week add-on to insulin trials, and for the 16-to 24-week add-on to metformin trials. None of the events were fatal.

Table 4. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF)

Patients with type 2 diabetes and NYHA class II or early class III congestive heart failure were randomized to receive 24 weeks of double-blind treatment with either pioglitazone at daily doses of 30 mg to 45 mg (n=262) or glyburide at daily doses of 10 mg to 15 mg (n=256). A summary of the incidence of adverse events related to congestive heart failure reported in this study is provided in Table 5.

Table 5. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in Patients with NYHA Class II or IIICongestive Heart Failure Treated with Pioglitazone or Glyburide

Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 6.

Table 6. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in PROactiveTrial

Cardiovascular Safety

In the PROactive trial, 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. Almost all patients (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins, and fibrates). At baseline, patients had a mean age of 62 years, mean duration of diabetes of 9.5 years, and mean HbA1c of 8.1%. Mean duration of follow-up was 34.5 months.

The primary objective of this trial was to examine the effect of pioglitazone on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, nonfatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass surgery or revascularization in the leg. A total of 514 (19.7%) patients treated with pioglitazone and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (hazard ratio 0.90; 95% Confidence Interval: 0.80, 1.02; p=0.10).

Although there was no statistically significant difference between pioglitazone and placebo for the three-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with pioglitazone. The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 7.

Table 7. PROactive: Number of First and Total Events for Each Component within theCardiovascular Composite Endpoint

Weight Gain

Dose-related weight gain occurs when pioglitazone is used alone or in combination with other antidiabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Tables 8 and 9 summarize the changes in body weight with pioglitazone and placebo in the 16-to 26-week randomized, double-blind monotherapy and 16-to 24-week combination add-on therapy trials and in the PROactive trial.

Table 8. Weight Changes (kg) from Baseline during Randomized, Double-Blind Clinical Trials

Table 9. Median Change in Body Weight in Patients Treated with Pioglitazone vsPatients Treated with Placebo During the Double-Blind Treatment Period in the PROactive Trial

Edema

Edema induced from taking pioglitazone is reversible when pioglitazone is discontinued. The edema usually does not require hospitalization unless there is coexisting congestive heart failure. A summary of the frequency and types of edema adverse events occurring in clinical investigations of pioglitazone is provided in Table 10.

Table 10. Adverse Events of Edema in Patients Treated with Pioglitazone

Table 11. Adverse Events of Edema in Patients in the PROactive Trial

Hepatic Effects

There has been no evidence of pioglitazone-induced hepatotoxicity in the pioglitazonecontrolled clinical trial database to date. One randomized, double-blind, 3-year trial comparing pioglitazone to glyburide as add-on to metformin and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than three times the upper limit of the reference range, measured every eight weeks for the first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1051 (0.3%) patients treated with pioglitazone and 9/1046 (0.9%) patients treated with glyburide developed ALT values greater than three times the upper limit of the reference range. None of the patients treated with pioglitazone in the pioglitazone-controlled clinical trial database to date have had a serum ALT greater than three times the upper limit of the reference range and a corresponding total bilirubin greater than two times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury.

Hypoglycemia

In the pioglitazone clinical trials, adverse events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick glucose testing.

In the 16-week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with pioglitazone 30 mg and 0.5% with placebo. In the 16-week add-on to insulin trial, the incidence of reported hypoglycemia was 7.9% with pioglitazone 15 mg, 15.4% with pioglitazone 30 mg, and 4.8% with placebo.

The incidence of reported hypoglycemia was higher with pioglitazone 45 mg compared to pioglitazone 30 mg in both the 24-week add-on to sulfonylurea trial (15.7% versus 13.4%) and in the 24-week add-on to insulin trial (47.8% versus 43.5%).

Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were receiving pioglitazone 30 mg (0.9%) in the 24-week add-on to insulin trial. An additional 14 patients reported severe hypoglycemia (defined as causing considerable interference with patient’s usual activities) that did not require hospitalization. These patients were receiving pioglitazone 45 mg in combination with sulfonylurea (N=2) or pioglitazone 30 mg or 45 mg in combination with insulin (N=12).

Urinary Bladder Tumors

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study. During the three year PROactive clinical trial, 14 patients out of 2605 (0.54%) randomized to pioglitazone and 5 out of 2633 (0.19%) randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and two (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR =1.00; 95% CI: 0.59-1.72).

Glimepiride

Adverse events that occurred in controlled clinical trials with placebo and glimepiride monotherapy, other than hypoglycemia, included: headache (7.8% and 8.2%), accidental injury (3.4% and 5.8%), flu syndrome (4.4% and 5.4%), nausea (3.4% and 5.0%) and dizziness (2.4% and 5.0%), respectively.

Hypoglycemia

In a randomized, double-blind, placebo-controlled monotherapy trial of 14 weeks duration, patients already on sulfonylurea therapy underwent a 3-week washout period then were randomized to glimepiride 1 mg, 4 mg, 8 mg or placebo. Patients randomized to glimepiride 4 mg or 8 mg underwent forced-titration from an initial dose of 1 mg to these final doses, as tolerated. The overall incidence of possible hypoglycemia (defined by the presence of at least one symptom that the investigator believed might be related to hypoglycemia; a concurrent glucose measurement was not required) was 4% for glimepiride 1 mg, 17% for glimepiride 4 mg, 16% for glimepiride 8 mg and 0% for placebo. All of these events were self-treated.

In a randomized, double-blind, placebo-controlled monotherapy trial of 22 weeks duration, patients received a starting dose of either 1 mg glimepiride or placebo daily. The dose of glimepiride was titrated to a target fasting plasma glucose of 90 −150 mg/dL. Final daily doses of glimepiride were 1, 2, 3, 4, 6 or 8 mg. The overall incidence of possible hypoglycemia (as defined above for the 14-week trial) for glimepiride versus placebo was 19.7% vs. 3.2%. All of these events were self-treated.

Weight Gain

Glimepiride, like all sulfonylureas, can cause weight gain.

Allergic Reactions

In clinical trials, allergic reactions, such as pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occurred in less than 1% of glimepiride-treated patients. These may resolve despite continued treatment with glimepiride. There are postmarketing reports of more serious allergic reactions (e.g., dyspnea, hypotension, shock).

Laboratory Tests

Elevated Serum Alanine Aminotransferase (ALT)

In 11 pooled placebo-controlled trials of glimepiride, 1.9% of glimepiride-treated patients and 0.8% of placebo-treated patients developed serum ALT greater than two times the upper limit of the reference range.

Laboratory Abnormalities

Pioglitazone

Hematologic Effects

Pioglitazone may cause decreases in hemoglobin and hematocrit. In placebo-controlled monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone compared with a mean change in hemoglobin of -1% to +1% in placebo-treated patients. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume associated with pioglitazone therapy and are not likely to be associated with any clinically significant hematologic effects.

Creatine Phosphokinase

During protocol-specified measurement of serum creatine phosphokinase (CPK) in pioglitazone clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in nine (0.2%) patients treated with pioglitazone (values of 2150 to 11400 IU/L) and in no comparator-treated patients. Six of these nine patients continued to receive pioglitazone, two patients were noted to have the CPK elevation on the last day of dosing and one patient discontinued pioglitazone due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to pioglitazone therapy is unknown.

Postmarketing Experience

Pioglitazone

• New onset or worsening diabetic macular edema with decreased visual acuity.
• Fatal and nonfatal hepatic failure.

Postmarketing reports of congestive heart failure have been reported in patients treated with pioglitazone, both with and without previously known heart disease and both with and without concomitant insulin administration.

In postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure.

Glimepiride

• Serious hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson Syndrome
• Hemolytic anemia in patients with and without G6PD deficiency
• Impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, which may progress to liver failure.
• Porphyria cutanea tarda, photosensitivity reactions and allergic vasculitis
• Leukopenia, agranulocytosis, aplastic anemia, and pancytopenia
• Thrombocytopenia (including severe cases with platelet count less than 10,000/mcL) and thrombocytopenic purpura
• Hepatic porphyria reactions and disulfiram-like reactions
• Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH), most often in patients who are on other medications or who have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone

Pioglitazon

Während kontrollierter klinischer Studien wurde ein Fall einer Überdosierung mit Pioglitazon berichtet. Ein männlicher Patient nahm vier Tage lang 120 mg pro Tag und sieben Tage lang 180 mg pro Tag ein. Der Patient bestritt während dieser Zeit alle klinischen Symptome.

Im Falle einer Überdosierung sollte eine geeignete unterstützende Behandlung entsprechend den klinischen Anzeichen und Symptomen des Patienten eingeleitet werden.

Glimepirid

Eine Überdosierung von Glimepirid kann wie bei anderen Sulfonylharnstoffen zu schwerer Hypoglykämie führen. Leichte Hypoglykämie-Episoden können mit oraler Glukose behandelt werden. Schwere hypoglykämische Reaktionen stellen medizinische Notfälle dar, die eine sofortige Behandlung erfordern. Schwere Hypoglykämie mit Koma, Anfall oder neurologischer Beeinträchtigung kann mit Glucagon oder intravenöser Glucose behandelt werden. Eine fortgesetzte Beobachtung und eine zusätzliche Kohlenhydrataufnahme können erforderlich sein, da die Hypoglykämie nach einer offensichtlichen klinischen Erholung erneut auftreten kann.

Absorption und Bioverfügbarkeit:

Sonias HD

Bioäquivalenzstudien wurden nach einer Einzeldosis der Sonias HD 30 mg / 2 mg- und 30 mg / 4 mg-Tabletten und gleichzeitiger Anwendung von Pioglitazon (30 mg) und Glimepirid (2 mg oder 4 mg) unter Fastenbedingungen bei gesunden Probanden durchgeführt.

Basierend auf der Fläche unter der Kurve (AUC) und der maximalen Konzentration (Cmax) von Pioglitazon und Glimepirid waren Sonias HD 30 mg / 2 mg und 30 mg / 4 mg bioäquivalent zu Pioglitazon 30 mg, das gleichzeitig mit Glimepirid (2 mg oder 4 mg) verabreicht wurde mg).

Das Essen veränderte die systemische Exposition von Glimepirid oder Pioglitazon nach Verabreichung von Sonias HD nicht. Das Vorhandensein von Nahrungsmitteln veränderte die Zeit bis zur maximalen Serumkonzentration (Tmax) von Glimepirid oder Pioglitazon und Cmax von Pioglitazon nicht signifikant. Bei Glimepirid war jedoch ein Anstieg der Cmax um 22% zu verzeichnen, wenn Sonias HD zusammen mit einer Mahlzeit verabreicht wurde.

Pioglitazon

Nach einmal täglicher Verabreichung von Pioglitazon werden innerhalb von sieben Tagen Steady-State-Serumkonzentrationen sowohl von Pioglitazon als auch seiner aktiven Hauptmetaboliten M-III (Keto-Derivat von Pioglitazon) und M-IV (Hydroxylderivat von Pioglitazon) erreicht. Im Steady-State erreichen M-III und M-IV Serumkonzentrationen, die gleich oder größer als die von Pioglitazon sind. Im Steady-State macht Pioglitazon sowohl bei gesunden Probanden als auch bei Patienten mit Typ-2-Diabetes etwa 30% bis 50% der maximalen Gesamt-Pioglitazon-Serumkonzentrationen (Pioglitazon plus aktive Metaboliten) und 20% bis 25% der gesamten AUC aus

Die Cmax-, AUC- und Talspiegel im Serum (Cmin) für Pioglitazon und M-III und M-IV stiegen proportional mit verabreichten Dosen von 15 mg und 30 mg pro Tag.

Nach oraler Verabreichung von Pioglitazon betrug Tmax von Pioglitazon innerhalb von zwei Stunden. Lebensmittel verzögern Tmax auf drei bis vier Stunden, verändern jedoch nicht das Absorptionsgrad (AUC).

Glimepirid

Studien mit oralen Einzeldosen von Glimepirid bei gesunden Probanden und mit mehreren oralen Dosen bei Patienten mit Typ-2-Diabetes zeigten zwei bis drei Stunden nach der Dosis maximale Arzneimittelkonzentrationen (Cmax). Wenn Glimepirid zu den Mahlzeiten verabreicht wurde, waren die mittleren Cmax und AUC um 8% bzw. 9% verringert.

Glimepirid reichert sich nach Mehrfachdosierung nicht im Serum an. Die Pharmakokinetik von Glimepirid unterscheidet sich nicht zwischen gesunden Probanden und Patienten mit Typ-2-Diabetes. Die Clearance (CL / F) von Glimepirid nach oraler Verabreichung ändert sich über den Dosisbereich von 1 mg bis 8 mg nicht, was auf eine lineare Pharmakokinetik hinweist.

Bei gesunden Probanden betrugen die intra- und interindividuellen Variabilität der pharmakokinetischen Glimepiridparameter 15% bis 23% bzw. 24% bis 29%.

Verteilung

Pioglitazon

Das mittlere scheinbare Verteilungsvolumen (Vd / F) von Pioglitazon nach einmaliger Verabreichung beträgt 0,63 ± 0,41 (Mittelwert ± SD) L / kg Körpergewicht. Pioglitazon ist im Humanserum weitgehend proteingebunden (> 99%), hauptsächlich an Serumalbumin. Pioglitazon bindet auch an andere Serumproteine, jedoch mit geringerer Affinität. M-III und M-IV sind ebenfalls weitgehend an Serumalbumin gebunden (> 98%).

Glimepirid

Nach intravenöser (IV) Dosierung bei gesunden Probanden betrug Vd / F 8,8 l (113 ml / kg) und die Gesamtkörperclearance (CL) 47,8 ml / min. Die Proteinbindung war größer als 99,5%.

Stoffwechsel

Pioglitazon

Pioglitazon wird durch Hydroxylierung und Oxidation weitgehend metabolisiert; Die Metaboliten wandeln sich teilweise auch in Glucuronid- oder Sulfatkonjugate um. Die Metaboliten M-III und M-IV sind die wichtigsten zirkulierenden aktiven Metaboliten beim Menschen.

In vitro Daten zeigen, dass mehrere CYP-Isoformen am Metabolismus von Pioglitazon beteiligt sind, einschließlich CYP2C8 und in geringerem Maße CYP3A4 mit zusätzlichen Beiträgen einer Vielzahl anderer Isoformen, einschließlich des hauptsächlich extrahepatischen CYP1A1. In vivo Die Untersuchung von Pioglitazon in Kombination mit Gemfibrozil, einem starken CYP2C8-Inhibitor, zeigte, dass Pioglitazon ein CYP2C8-Substrat ist. Die bei mit Pioglitazon behandelten Patienten gemessenen 6ß-Hydroxycortisol / Cortisol-Verhältnisse im Urin zeigten, dass Pioglitazon kein starker CYP3A4-Enzyminduktor ist.

Glimepirid

Glimepirid wird durch oxidative Biotransformation entweder nach einer IV- oder oralen Dosis vollständig metabolisiert. Die Hauptmetaboliten sind das Cyclohexylhydroxymethylderivat (M1) und das Carboxylderivat (M2). CYP2C9 ist an der Biotransformation von Glimepirid zu M1 beteiligt. M1 wird durch ein oder mehrere zytosolische Enzyme weiter zu M2 metabolisiert. Bei Tieren besitzt M1 etwa ein Drittel der pharmakologischen Aktivität von Glimepirid, es ist jedoch unklar, ob M1 beim Menschen klinisch bedeutsame Auswirkungen auf den Blutzucker hat. M2 ist inaktiv.

Ausscheidung und Beseitigung

Pioglitazon

Nach oraler Verabreichung werden ungefähr 15% bis 30% der Pioglitazon-Dosis im Urin gewonnen. Die renale Elimination von Pioglitazon ist vernachlässigbar und das Medikament wird hauptsächlich als Metaboliten und deren Konjugate ausgeschieden. Es wird vermutet, dass der größte Teil der oralen Dosis entweder unverändert oder als Metaboliten in die Galle ausgeschieden und im Kot ausgeschieden wird.

Die mittlere Serumhalbwertszeit (t_1/2) von Pioglitazon und seinen Metaboliten (M-III und M-IV) liegen zwischen drei und sieben Stunden bzw. 16 bis 24 Stunden. Pioglitazon hat einen scheinbaren Abstand, CL / F, berechnet auf fünf bis sieben l / h.

Glimepirid

Wann ¹⁴C-Glimepirid wurde oral an drei gesunde männliche Probanden verabreicht, ungefähr 60% der gesamten Radioaktivität wurden innerhalb von sieben Tagen im Urin zurückgewonnen. M1 und M2 machten 80% bis 90% der im Urin zurückgewonnenen Radioaktivität aus. Das Verhältnis von M1 zu M2 im Urin betrug bei zwei Probanden ungefähr 3: 2 und bei einem Probanden 4: 1. Ungefähr 40% der gesamten Radioaktivität wurden im Kot zurückgewonnen. M1 und M2 machten ungefähr 70% (Verhältnis von M1 bis M2 betrug 1: 3) der im Kot zurückgewonnenen Radioaktivität aus. Es wurde kein Ausgangsarzneimittel aus Urin oder Kot gewonnen. Nach intravenöser Dosierung bei Patienten wurde keine signifikante biliäre Ausscheidung von Glimepirid oder seinem M1-Metaboliten beobachtet.

Nierenfunktionsstörung

Pioglitazon

Die Serumeliminationshalbwertszeit von Pioglitazon, M-III und M-IV bleibt bei Patienten mit mäßiger [Kreatinin-Clearance (CLcr) 30 bis 50 ml / min] und schwerer (CLcr <30 ml / min) Nierenfunktionsstörung im Vergleich unverändert zu Patienten mit normaler Nierenfunktion. Daher ist bei Patienten mit eingeschränkter Nierenfunktion keine Dosisanpassung erforderlich.

Glimepirid

In einer Einzeldosis, offene Studie Glimepirid 3 mg wurde Patienten mit milden verabreicht, mittelschwere und schwere Nierenfunktionsstörung, geschätzt von CLcr: Gruppe I bestand aus fünf Patienten mit leichter Nierenfunktionsstörung (CLcr> 50 ml / min) Gruppe II bestand aus 3 Patienten mit mittelschwerer Nierenfunktionsstörung (CLcr = 20 bis 50 ml / min) und Gruppe III bestand aus sieben Patienten mit schwerer Nierenfunktionsstörung (CLcr <20 ml / min). Obwohl die Glimepirid-Serumkonzentrationen mit abnehmender Nierenfunktion abnahmen, hatte Gruppe III eine 2,3-fach höhere mittlere AUC für M1 und eine 8,6-fach höhere mittlere AUC für M2 im Vergleich zu entsprechenden mittleren AUCs in Gruppe I. Die t_½ für Glimepirid änderte sich nicht, während das t_½ für M1 und M2 erhöht, wenn die Nierenfunktion abnimmt. Die mittlere Urinausscheidung von M1 plus M2 als Prozentsatz der Dosis verringerte sich von 44,4% für Gruppe I auf 21,9% für Gruppe II und 9,3% für Gruppe III

Leberfunktionsstörung

Pioglitazon

Im Vergleich zu gesunden Kontrollen weisen Patienten mit eingeschränkter Leberfunktion (Child-Turcotte-Pugh Grade B / C) eine durchschnittliche Cmax-Reduktion von ca. 45% und Gesamtpioglitazon (Pioglitazon, M-III und M-IV) Cmax auf, jedoch keine Änderung des Mittelwerts AUC-Werte. Daher ist bei Patienten mit Leberfunktionsstörung keine Dosisanpassung erforderlich.

Es gibt Postmarketing-Berichte über Leberversagen mit Pioglitazon, und klinische Studien haben im Allgemeinen Patienten mit Serum-ALT> 2,5-facher Obergrenze des Referenzbereichs ausgeschlossen.

Verwenden Sie Sonias HD bei Patienten mit Lebererkrankungen mit Vorsicht.

Glimepirid

Es ist nicht bekannt, ob eine Beeinträchtigung der Leber auf die Pharmakokinetik von Glimepirid vorliegt, da die Pharmakokinetik von Glimepirid bei Patienten mit Leberfunktionsstörung nicht ausreichend bewertet wurde.

Geriatrische Patienten

Pioglitazon

Bei gesunden älteren Probanden war die Cmax von Pioglitazon nicht signifikant unterschiedlich, aber die AUC-Werte waren ungefähr 21% höher als bei jüngeren Probanden. Der mittlere t_½ Pioglitazon war auch bei älteren Probanden (ca. 10 Stunden) im Vergleich zu jüngeren Probanden (ca. sieben Stunden) verlängert. Diese Änderungen hatten keine Größenordnung, die als klinisch relevant angesehen werden würde.

Glimepirid

Ein Vergleich der Pharmakokinetik von Glimepirid bei Patienten mit Typ-2-Diabetes ≤ 65 Jahre und Patienten> 65 Jahre wurde in einer Mehrfachdosisstudie unter Verwendung einer Tagesdosis von 6 mg bewertet. Es gab keine signifikanten Unterschiede in der Glimepirid-Pharmakokinetik zwischen den beiden Altersgruppen. Die mittlere AUC im Steady-State für die älteren Patienten war ungefähr 13% niedriger als die für die jüngeren Patienten; Die mittlere gewichtsbereinigte Clearance für die älteren Patienten war ungefähr 11% höher als für die jüngeren Patienten.

Pädiatrische Patienten

Bei pädiatrischen Patienten wurden keine pharmakokinetischen Studien zu Sonias HD durchgeführt.

Pioglitazon

Sicherheit und Wirksamkeit von Pioglitazon bei pädiatrischen Patienten wurden nicht nachgewiesen. Sonias HD wird für die Anwendung bei pädiatrischen Patienten nicht empfohlen.

Geschlecht

Pioglitazon

Die mittleren Cmax- und AUC-Werte von Pioglitazon waren bei Frauen im Vergleich zu Männern um 20% bis 60% erhöht. In kontrollierten klinischen Studien waren die HbA1c-Abnahmen gegenüber dem Ausgangswert bei Frauen im Allgemeinen größer als bei Männern (durchschnittlicher mittlerer Unterschied in HbA1c 0,5%). Da die Therapie für jeden Patienten individualisiert werden sollte, um eine Blutzuckerkontrolle zu erreichen, wird keine Dosisanpassung allein aufgrund des Geschlechts empfohlen.

Glimepirid

Es gab keine Unterschiede zwischen Männern und Frauen in der Pharmakokinetik von Glimepirid, wenn Unterschiede im Körpergewicht angepasst wurden.

Ethnizität

Pioglitazon

Pharmakokinetische Daten zwischen verschiedenen ethnischen Gruppen sind nicht verfügbar.

Glimepirid

Es wurden keine Studien durchgeführt, um die Auswirkungen der Rasse auf die Pharmakokinetik von Glimepirid zu bewerten. In placebokontrollierten Studien mit Glimepirid bei Patienten mit Typ-2-Diabetes war die Reduktion von HbA1c bei Kaukasiern (n = 536) und Schwarzen (n = 63) vergleichbar. und Hispanics (n = 63).

Übergewichtige Patienten

Die Pharmakokinetik von Glimepirid und seinen Metaboliten wurde in einer Einzeldosisstudie an 28 Patienten mit Typ-2-Diabetes gemessen, die entweder ein normales Körpergewicht hatten oder krankhaft fettleibig waren. Während Tmax, CL / F und Vd / F von Glimepirid bei krankhaft fettleibigen Patienten denen in der normalen Gewichtsgruppe ähnlich waren, hatten die krankhaft fettleibigen Patienten eine niedrigere Cmax und AUC als diejenigen mit normalem Körpergewicht. Die mittleren Cmax-, AUC0-24-, AUC0-∞-Werte von Glimepirid im Normalzustand vs. krankhaft fettleibige Patienten waren 547 ± 218 ng / ml vs. 410 ± 124 ng / ml, 3210 ± 1030 Stunden · ng / ml vs. 2820 ± 1110 Stunden · ng / ml und 4000 ± 1320 Stunden · ng / ml gegenüber 3280 ± 1360 Stunden · ng / ml.