Zoliget

Zoliget é indicado como um complemento à dieta e exercício para melhorar o controle glicêmico em adultos com diabetes mellitus tipo 2 que já são tratados com tiazolidinediona e sulfonilureia ou que têm controle glicêmico inadequado apenas em uma tiazolidinediona ou em uma sulfonilureia.

Limitações importantes de uso

A pioglitazona exerce seu efeito anti-hiperglicêmico apenas na presença de insulina endógena. Zoliget não deve ser utilizado para tratar diabetes tipo 1 ou cetoacidose diabética, pois não seria eficaz nessas configurações.

Tenha cuidado em pacientes com doença hepática.

Recommendations For All Patients

Zoliget should be taken once daily with the first main meal.

Zoliget tablets are available as a 30 mg pioglitazone plus 2 mg glimepiride or a 30 mg pioglitazone plus 4 mg glimepiride tablet. If therapy with a combination tablet containing pioglitazone and glimepiride is considered appropriate the recommended starting dose is:

• 30 mg/2 mg or 30 mg/4 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,
• for patients inadequately controlled on glimepiride monotherapy: 30 mg/2 mg or 30 mg/4 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,
• for patients inadequately controlled on pioglitazone monotherapy: 30 mg/2 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,
• for patients who are changing from combination therapy of pioglitazone plus glimepiride as separate tablets: Zoliget should be taken at doses that are as close as possible to the dose of pioglitazone and glimepiride already being taken,
• for patients currently on a different sulfonylurea monotherapy or switching from combination therapy of pioglitazone plus a different sulfonylurea (e.g., glyburide, glipizide, chlorpropamide, tolbutamide, acetohexamide): 30 mg/2 mg once daily and adjusted after assessing adequacy of therapeutic response. Observe for hypoglycemia for one to two weeks due to the potential overlapping drug effect.
• for patients with systolic dysfunction, the lowest approved dose of Zoliget should be prescribed only after titration from 15 mg to 30 mg of pioglitazone has been safely tolerated.

After initiation of Zoliget or with dose increase, monitor patients carefully for hypoglycemia and adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure.

Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating Zoliget. Routine periodic monitoring of liver tests during treatment with Zoliget is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of Zoliget or who are found to have abnormal liver tests while taking Zoliget should be managed as described under Warnings and Precautions.

Concomitant Use With An Insulin Secretagogue Or Insulin

If hypoglycemia occurs in a patient coadministered Zoliget and an insulin secretagogue, the dose of the insulin secretagogue should be reduced.

If hypoglycemia occurs in a patient coadministered Zoliget and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.

Concomitant Use With Strong CYP2C8 Inhibitors

Coadministration of pioglitazone and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of pioglitazone is 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors. If gemfibrozil or other CYP2C8 inhibitors need to co-administered, patients should switch to individual components of Zoliget because the minimum dose of pioglitazone in Zoliget exceeds 15 mg see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

Concomitant Use With Colesevelam

When colesevelam is coadministered with glimepiride, maximum plasma concentration and total exposure to glimepiride is reduced. Therefore, Zoliget should be administered at least four hours prior to colesevelam see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

• Initiation in patients with established NYHA Class III or IV heart failure.
• Use in patients with known hypersensitivity to pioglitazone, glimepiride or any other component of Zoliget.
• Use in patients with known history of an allergic reaction to sulfonamide derivatives.

Reported hypersensitivity reactions with glimepiride include cutaneous eruptions with or without pruritus as well as more serious reactions (e.g., anaphylaxis, angioedema, Stevens-Johnson Syndrome, dyspnea)

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 Zoliget 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 Zoliget must be considered.

Hypoglycemia

Glimepiride

All sulfonylureas, including glimepiride, a component of Zoliget, 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 Zoliget 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 Zoliget, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, promptly discontinue Zoliget, 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 Zoliget therapy. In patients with abnormal liver tests, Zoliget 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), Zoliget treatment should be interrupted and investigation done to establish the probable cause. Zoliget 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 Zoliget. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with Zoliget 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, Zoliget should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with Zoliget 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.

Zoliget 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, Zoliget should be used with caution in patients at risk for congestive heart failure. Patients treated with Zoliget 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 Zoliget 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 Zoliget 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 Zoliget.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION).

• Inform patients that Zoliget 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 Zoliget 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 Zoliget 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 Zoliget 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 Zoliget 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 Zoliget should immediately report these symptoms to a physician.
• Tell patients to promptly stop taking Zoliget 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 Zoliget 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 Zoliget. 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 Zoliget 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, Zoliget 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 Zoliget. The following data are based on studies conducted with the individual components of Zoliget.

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 Zoliget and any potential adverse effects on the breastfed infant from Zoliget 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 Zoliget in pediatric patients have not been established.

Zoliget 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 Zoliget should be conservative. During initiation of Zoliget 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 Zoliget and increasing the dose of Zoliget in this patient population.

Renal Impairment

To minimize the risk of hypoglycemia, the initial dosing, dose increments and maintenance dosage of Zoliget should be conservative. During initiation of Zoliget 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.

As seguintes reações adversas graves são discutidas em outras partes da rotulagem :

• Insuficiência Cardíaca Congestiva
• Hipoglicemia
• Edema
• Fraturas
• Anemia hemolítica

Experiência em ensaios clínicos

Como os ensaios clínicos são conduzidos em condições muito variadas, as taxas de reação adversa observadas nos ensaios clínicos de um medicamento não podem ser diretamente comparadas às taxas nos ensaios clínicos de outro medicamento e podem não refletir as taxas observadas na prática.

Os eventos adversos relataram em pelo menos 5% dos pacientes nos estudos clínicos controlados de 16 semanas entre o placebo mais uma sulfonilureia e pioglitazona (15 mg e 30 mg combinados) além disso, os braços de tratamento com sulfonilureia eram infecção do trato respiratório superior (15,5% e 16,6%) lesão acidental (8,6% e 3,5%) e edema combinado / edema periférico (2,1% e 7,2%) respectivamente.

A incidência e o tipo de eventos adversos relatados em pelo menos 5% dos pacientes em qualquer grupo de tratamento combinado do estudo de 24 semanas comparando pioglitazona 30 mg mais uma sulfonilureia e pioglitazona 45 mg mais uma sulfonilureia são mostrados na Tabela 1; a taxa de eventos adversos que resultou na descontinuação do estudo entre os dois grupos de tratamento foi de 6% e 9,7%, respectivamente.

Quadro 1. Eventos adversos que ocorreram em ≥5% dos pacientes em qualquer grupo de tratamento durante o estudo de 24 semanas

Em estudos duplo-cegos dos EUA, foi relatada anemia em ≤2% dos pacientes tratados com pioglitazona mais uma sulfonilureia.

Pioglitazona

Mais de 8500 pacientes com diabetes tipo 2 foram tratados com pioglitazona em ensaios clínicos randomizados, duplo-cegos e controlados, incluindo 2605 pacientes com diabetes tipo 2 e doença macrovascular tratados com pioglitazona no ensaio clínico PROactive. Nestes ensaios, mais de 6000 pacientes foram tratados com pioglitazona por seis meses ou mais, mais de 4500 pacientes foram tratados com pioglitazona por um ano ou mais e mais de 3000 pacientes foram tratados com pioglitazona por pelo menos dois anos.

Em seis ensaios combinados de monoterapia controlada por placebo de 16 a 26 semanas e terapia combinada de 16 a 24 semanas, a incidência de retiradas devido a eventos adversos foi de 4,5% para pacientes tratados com pioglitazona e 5,8% para pacientes tratados com comparador. pacientes. Os eventos adversos mais comuns que levaram à retirada foram relacionados ao controle glicêmico inadequado, embora a incidência desses eventos tenha sido menor (1,5%) com pioglitazona do que com placebo (3,0%).

No estudo PROactive, a incidência de retiradas devido a eventos adversos foi de 9,0% para pacientes tratados com pioglitazona e 7,7% para pacientes tratados com placebo. A insuficiência cardíaca congestiva foi o evento adverso grave mais comum que levou à retirada em 1,3% dos pacientes tratados com pioglitazona e 0,6% dos pacientes tratados com placebo.

Eventos adversos comuns: ensaios de monoterapia de 16 a 26 semanas

Um resumo da incidência e do tipo de eventos adversos comuns relatados em três ensaios combinados de monoterapia com 16 a 26 semanas, controlados por placebo, de pioglitazona é fornecido na Tabela 2. Os termos relatados representam aqueles que ocorreram com uma incidência> 5% e mais comumente em pacientes tratados com pioglitazona do que em pacientes que receberam placebo. Nenhum desses eventos adversos foi relacionado à dose de pioglitazona.

Quadro 2. Três ensaios clínicos combinados de 16 a 26 semanas, controlados por placebo, em monoterapia com pioglitazona: eventos adversos relatados em uma incidência> 5% e mais comumente em pacientes tratados com pioglitazona do que em pacientes tratados com placebo

Um resumo da incidência geral e dos tipos de eventos adversos comuns relatados no estudo PROactive é fornecido na Tabela 3. Os termos relatados representam aqueles que ocorreram com uma incidência> 5% e mais comumente em pacientes tratados com pioglitazona do que em pacientes que receberam placebo.

Quadro 3. Ensaio PROativo: Incidência e Tipos de Eventos Adversos Relatados em> 5% dos Pacientes Tratados com Pioglitazona e Mais Comumente que o Placebo

Insuficiência Cardíaca Congestiva

Um resumo da incidência de eventos adversos relacionados à insuficiência cardíaca congestiva é fornecido na Tabela 4 para o complemento de 16 a 24 semanas para ensaios com sulfonilureia, para o complemento de 16 a 24 semanas para ensaios com insulina e para o complemento de 16 a 24 semanas para ensaios de metformina. Nenhum dos eventos foi fatal.

Quadro 4. Eventos adversos emergentes do tratamento da insuficiência cardíaca congestiva (ICC)

Pacientes com diabetes tipo 2 e insuficiência cardíaca congestiva classe II ou classe III precoce foram randomizados para receber 24 semanas de tratamento duplo-cego com pioglitazona em doses diárias de 30 mg a 45 mg (n = 262) ou gliburida em doses diárias de 10 mg a 15 mg (n = 256). Um resumo da incidência de eventos adversos relacionados à insuficiência cardíaca congestiva relatados neste estudo é fornecido na Tabela 5.

Quadro 5. Eventos adversos emergentes do tratamento de insuficiência cardíaca congestiva (ICC) em pacientes com insuficiência cardíaca de classe II ou IIIC da NYHA tratados com pioglitazona ou gliburida

Eventos congestivos de insuficiência cardíaca que levaram à hospitalização que ocorreram durante o estudo PROactive estão resumidos na Tabela 6.

Quadro 6. Eventos adversos emergentes do tratamento da insuficiência cardíaca congestiva (ICC) no PROactiveTrial

Segurança Cardiovascular

No estudo PROactive, 5238 pacientes com diabetes tipo 2 e histórico de doença macrovascular foram randomizados para pioglitazona (N = 2605), com força titulada até 45 mg por dia ou placebo (N = 2633), além do padrão de atendimento. Quase todos os pacientes (95%) estavam recebendo medicamentos cardiovasculares (bloqueadores beta, inibidores da ECA, bloqueadores dos receptores da angiotensina II, bloqueadores dos canais de cálcio, nitratos, diuréticos, aspirina, estatinas e fibratos). No início, os pacientes tinham idade média de 62 anos, duração média do diabetes de 9,5 anos e HbA1c média de 8,1%. A duração média do acompanhamento foi de 34,5 meses.

O objetivo principal deste estudo foi examinar o efeito da pioglitazona na mortalidade e morbidade macrovascular em pacientes com diabetes mellitus tipo 2 que apresentavam alto risco de eventos macrovasculares. A variável de eficácia primária foi o tempo para a primeira ocorrência de qualquer evento em um endpoint composto cardiovascular que incluiu mortalidade por todas as causas, infarto do miocárdio não fatal (MI) incluindo MI silencioso, derrame, síndrome coronariana aguda, intervenção cardíaca, incluindo enxerto de revascularização do miocárdio ou intervenção percutânea, amputação da perna principal acima do tornozelo, e ignorar cirurgia ou revascularização na perna. Um total de 514 (19,7%) pacientes tratados com pioglitazona e 572 (21,7%) pacientes tratados com placebo experimentaram pelo menos um evento do endpoint composto primário (taxa de risco 0,90; intervalo de confiança de 95%: 0,80, 1,02; p = 0,10).

Embora não tenha havido diferença estatisticamente significativa entre pioglitazona e placebo na incidência de três anos de um primeiro evento dentro desse composto, não houve aumento na mortalidade ou no total de eventos macrovasculares com pioglitazona. O número de primeiras ocorrências e eventos individuais totais que contribuem para o endpoint composto primário é mostrado na Tabela 7.

Quadro 7. PROativo: Número de eventos primeiro e total para cada componente no endpoint composto cardiovascular

Ganho de peso

O ganho de peso relacionado à dose ocorre quando a pioglitazona é usada isoladamente ou em combinação com outros medicamentos antidiabéticos. O mecanismo de ganho de peso não é claro, mas provavelmente envolve uma combinação de retenção de líquidos e acúmulo de gordura.

As Tabelas 8 e 9 resumem as alterações no peso corporal com pioglitazona e placebo nos ensaios de terapia combinada randomizada de 16 a 26 semanas, em monoterapia com dupla ocultação e em 16 a 24 semanas e no estudo PROactive.

Quadro 8. Alterações de peso (kg) da linha de base durante ensaios clínicos randomizados e duplo-cegos

Quadro 9. Alteração mediana do peso corporal em pacientes tratados com pioglitazona vsPacients tratados com placebo durante o período de tratamento duplo-cego no estudo PROactive

Edema

O edema induzido a tomar pioglitazona é reversível quando a pioglitazona é descontinuada. O edema geralmente não requer hospitalização, a menos que haja insuficiência cardíaca congestiva coexistente. Um resumo da frequência e tipos de eventos adversos ao edema que ocorrem em investigações clínicas de pioglitazona é fornecido na Tabela 10.

Quadro 10. Eventos adversos do edema em pacientes tratados com pioglitazona

Quadro 11. Eventos adversos do edema em pacientes no estudo PROactive

Efeitos hepáticos

Não houve evidência de hepatotoxicidade induzida por pioglitazona no banco de dados de ensaios clínicos controlados por pioglitazona até o momento. Um randomizado, duplo-cego, O estudo de três anos comparando pioglitazona com gliburida como complemento da metformina e terapia com insulina foi projetado especificamente para avaliar a incidência de elevação sérica da ALT para mais de três vezes o limite superior da faixa de referência, medido a cada oito semanas nas primeiras 48 semanas do julgamento e depois a cada 12 semanas. Um total de 3/1051 (0,3%) pacientes tratados com pioglitazona e 9/1046 (0,9%) pacientes tratados com gliburida desenvolveram valores de ALT superiores a três vezes o limite superior da faixa de referência. Até o momento, nenhum dos pacientes tratados com pioglitazona no banco de dados de ensaios clínicos controlados por pioglitazona teve um ALT sérico superior a três vezes o limite superior do intervalo de referência e uma bilirrubina total correspondente superior a duas vezes o limite superior do intervalo de referência, uma combinação preditiva do potencial de lesão hepática grave induzida por drogas.

Hipoglicemia

Nos ensaios clínicos com pioglitazona, foram relatados eventos adversos de hipoglicemia com base no julgamento clínico dos pesquisadores e não exigiram confirmação com o teste de glicose com a etiqueta.

No período adicional de 16 semanas ao estudo com sulfonilureia, a incidência de hipoglicemia relatada foi de 3,7% com pioglitazona 30 mg e 0,5% com placebo. No período de 16 semanas para o estudo com insulina, a incidência de hipoglicemia relatada foi de 7,9% com pioglitazona 15 mg, 15,4% com pioglitazona 30 mg e 4,8% com placebo.

A incidência de hipoglicemia relatada foi maior com pioglitazona 45 mg em comparação com pioglitazona 30 mg no estudo de 24 semanas com adição ao estudo com sulfonilureia (15,7% versus 13,4%) e no estudo de 24 semanas com adição ao estudo de insulina (47,8% versus 43,5%).

Três pacientes nesses quatro ensaios foram hospitalizados devido à hipoglicemia. Todos os três pacientes estavam recebendo pioglitazona 30 mg (0,9%) no estudo de 24 semanas com adição de insulina. Outros 14 pacientes relataram hipoglicemia grave (definida como causando considerável interferência nas atividades usuais do paciente) que não exigiram hospitalização. Esses pacientes estavam recebendo pioglitazona 45 mg em combinação com sulfonilureia (N = 2) ou pioglitazona 30 mg ou 45 mg em combinação com insulina (N = 12).

Tumores da bexiga urinária

Tumores foram observados na bexiga urinária de ratos machos no estudo de carcinogenicidade de dois anos. Durante os três anos de ensaio clínico PROactive, 14 pacientes em 2605 (0,54%) randomizados para pioglitazona e 5 em 2633 (0,19%) randomizados para placebo foram diagnosticados com câncer de bexiga. Depois de excluir pacientes nos quais a exposição ao medicamento em estudo foi inferior a um ano no momento do diagnóstico de câncer de bexiga, houve 6 (0,23%) casos de pioglitazona e dois (0,08%) casos de placebo. Após a conclusão do estudo, um grande subconjunto de pacientes foi observado por até 10 anos adicionais, com pouca exposição adicional à pioglitazona. Durante os 13 anos de acompanhamento PROativo e observacional, a ocorrência de câncer de bexiga não diferiu entre os pacientes randomizados para pioglitazona ou placebo (HR = 1,00; IC 95%: 0,59-1,72).

Glimepirida

Os eventos adversos que ocorreram em ensaios clínicos controlados com placebo e monoterapia com glimepirida, exceto hipoglicemia, incluíram: dor de cabeça (7,8% e 8,2%), lesão acidental (3,4% e 5,8%), síndrome da gripe (4,4% e 5,4%), náusea (3,4% e 5,0%) e tontura (2.

Hipoglicemia

Em um estudo randomizado, duplo-cego e em monoterapia controlado por placebo, com duração de 14 semanas, os pacientes que já estavam em terapia com sulfonilureia passaram por um período de lavagem de 3 semanas e foram randomizados para glimepirida 1 mg, 4 mg, 8 mg ou placebo. Pacientes randomizados para glimepirida 4 mg ou 8 mg foram submetidos a titulação forçada de uma dose inicial de 1 mg a essas doses finais, conforme tolerado. A incidência geral de possível hipoglicemia (definido pela presença de pelo menos um sintoma que o investigador acreditava estar relacionado à hipoglicemia; não foi necessária uma medição simultânea da glicose) foi de 4% para glimepirida 1 mg, 17% para glimepirida 4 mg, 16% para glimepirida 8 mg e 0% para placebo. Todos esses eventos foram tratados por si mesmos.

Em um estudo randomizado, duplo-cego e em monoterapia controlado por placebo, com duração de 22 semanas, os pacientes receberam uma dose inicial de 1 mg de glimepirida ou placebo diariamente. A dose de glimepirida foi titulada para uma glicose plasmática em jejum alvo de 90 a 150 mg / dL. As doses diárias finais de glimepirida foram de 1, 2, 3, 4, 6 ou 8 mg. A incidência geral de possível hipoglicemia (conforme definida acima para o estudo de 14 semanas) de glimepirida versus placebo foi de 19,7% vs. 3,2%. Todos esses eventos foram tratados por si mesmos.

Ganho de peso

A glimepirida, como todas as sulfonilureias, pode causar ganho de peso.

Reações alérgicas

Em ensaios clínicos, reações alérgicas, como prurido, eritema, urticária e erupções morbiliformes ou maculopapulares, ocorreram em menos de 1% dos pacientes tratados com glimepirida. Estes podem resolver apesar do tratamento continuado com glimepirida. Existem relatos pós-comercialização de reações alérgicas mais graves (por exemplo,.dispnéia, hipotensão, choque).

Testes de laboratório

Soro elevado Alanina Aminotransferase (ALT)

Em 11 ensaios combinados de glimepirida controlados por placebo, 1,9% dos pacientes tratados com glimepirida e 0,8% dos pacientes tratados com placebo desenvolveram ALT sérica superior a duas vezes o limite superior da faixa de referência.

Anormalidades laboratoriais

Pioglitazona

Efeitos hematológicos

A pioglitazona pode causar reduções na hemoglobina e no hematócrito. Nos ensaios de monoterapia controlados por placebo, os valores médios de hemoglobina diminuíram 2% a 4% nos pacientes tratados com pioglitazona em comparação com uma alteração média na hemoglobina de -1% a + 1% nos pacientes tratados com placebo. Essas alterações ocorreram principalmente nas primeiras 4 a 12 semanas de terapia e permaneceram relativamente constantes posteriormente. Essas alterações podem estar relacionadas ao aumento do volume plasmático associado à terapia com pioglitazona e provavelmente não estão associadas a efeitos hematológicos clinicamente significativos.

Creatina fosfoquinase

Durante a medição especificada pelo protocolo da creatina fosfoquinase sérica (CPK) em ensaios clínicos com pioglitazona, foi observada uma elevação isolada na CPK para mais de 10 vezes o limite superior da faixa de referência em nove (0,2%) pacientes tratados com pioglitazona (valores de 2150 a 11400 UI / L) e em pacientes tratados com comparador. Seis desses nove pacientes continuaram recebendo pioglitazona, dois pacientes apresentaram elevação da CPK no último dia da administração e um paciente interrompeu a pioglitazona devido à elevação. Essas elevações foram resolvidas sem sequelas clínicas aparentes. A relação desses eventos com a terapia com pioglitazona é desconhecida.

Experiência pós-comercialização

As seguintes reações adversas foram identificadas durante o uso pós-aprovação de pioglitazona e glimepirida. Como essas reações são relatadas voluntariamente a partir de uma população de tamanho incerto, geralmente não é possível estimar com segurança sua frequência ou estabelecer uma relação causal com a exposição a medicamentos.

Pioglitazona

• Novo início ou agravamento do edema macular diabético com diminuição da acuidade visual.
• Insuficiência hepática fatal e não fatal.

Relatos pós-comercialização de insuficiência cardíaca congestiva foram relatados em pacientes tratados com pioglitazona, com e sem doença cardíaca conhecida anteriormente e com e sem administração concomitante de insulina.

Na experiência pós-comercialização, houve relatos de aumentos de peso incomumente rápidos e aumentos superiores aos geralmente observados em ensaios clínicos. Os pacientes que experimentam esses aumentos devem ser avaliados quanto ao acúmulo de líquidos e eventos relacionados ao volume, como edema excessivo e insuficiência cardíaca congestiva.

Glimepirida

• Reações graves de hipersensibilidade, incluindo anafilaxia, angioedema e síndrome de Stevens-Johnson
• Anemia hemolítica em pacientes com e sem deficiência de G6PD
• Compromisso da função hepática (por exemplo,. com colestase e icterícia), bem como hepatite, que pode progredir para insuficiência hepática.
• Porphyria cutanea tarda, reações de fotosensibilidade e vasculite alérgica
• Leucopenia, agranulocitose, anemia aplástica e pancitopenia
• Trombocitopenia (incluindo casos graves com contagem de plaquetas menor que 10.000 / mcL) e púrpura trombocitopênica
• Reações de porfiria hepática e reações do tipo dissulfiram
• Hiponatremia e síndrome da secreção inadequada de hormônio antidiurético (SIADH), na maioria das vezes em pacientes que tomam outros medicamentos ou que têm condições médicas conhecidas por causar hiponatremia ou aumentar a liberação do hormônio antidiurético