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治療オプション:
Militian Inessa Mesropovna 、薬局による医学的評価、 最終更新日:26.03.2022
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同じ成分を持つトップ20の薬:
同じ治療法の上位20の薬:
タンデマクトは、すでにチアゾリジンジオンとスルホニル尿素で治療されている、またはチアゾリジンジオン単独またはスルホニル尿素単独では不十分な血糖コントロールを有する2型糖尿病の成人の血糖コントロールを改善するための食事と運動の補助として示されています。.
使用の重要な制限。
ピオグリタゾンは、内因性インスリンの存在下でのみ抗高血糖効果を発揮します。. タンデマクトは、1型糖尿病や糖尿病性ケトアシドーシスの治療には使用しないでください。これらの設定では効果がないためです。.
肝疾患のある患者には注意してください。.
すべての患者への推奨事項。
タンデマクトは最初のメインミールで1日1回服用する必要があります。.
タンデマクト錠は、30 mgのピオグリタゾンと2 mgのグリメピリド、または30 mgのピオグリタゾンと4 mgのグリメピリド錠として入手できます。. ピオグリタゾンとグリメピリドを含む併用錠剤による治療が適切であると考えられる場合、推奨される開始用量は次のとおりです。
- 30 mg / 2 mgまたは30 mg / 4 mgを1日1回、必要に応じて、治療反応と忍容性の妥当性を評価した後、徐々に滴定します。
- グリメピリド単剤療法の管理が不十分な患者の場合:30 mg / 2 mgまたは30 mg / 4 mgを1日1回、必要に応じて、治療反応と忍容性の妥当性を評価した後、徐々に滴定します。
- ピオグリタゾン単剤療法の管理が不十分な患者の場合:治療反応と忍容性の妥当性を評価した後、必要に応じて、30 mg / 2 mgを1日1回、徐々に滴定します。
- 別の錠剤としてピオグリタゾンとグリメピリドの併用療法から変化している患者の場合:タンデマクトは、すでに服用されているピオグリタゾンとグリメピリドの用量に可能な限り近い用量で服用する必要があります。
- 現在、異なるスルホニル尿素単剤療法を受けている患者、またはピオグリタゾンと異なるスルホニル尿素の併用療法からの切り替え(例:.、グリブリド、グリピジド、クロルプロパミド、トルブタミド、アセトヘキサミド):30 mg / 2 mgを1日1回、治療反応の妥当性を評価した後に調整。. 薬物効果が重複する可能性があるため、低血糖を1〜2週間観察します。.
- 収縮機能障害のある患者の場合、タンデマクトの最低承認用量は、15 mgから30 mgのピオグリタゾンへの滴定が安全に許容された後にのみ処方されるべきです。.
タンデマクトの開始後または用量を増やした後、低血糖症と、体重増加、浮腫、うっ血性心不全の兆候や症状などの体液貯留に関連する副作用について患者を注意深く監視します。.
タンデマクトを開始する前に、肝臓検査(アラニン血清およびアスパラギン酸アミノトランスフェラーゼ、アルカリホスファターゼ、および総ビリルビン)を取得する必要があります。. タンデマクトによる治療中の肝臓検査の定期的なモニタリングは、肝疾患のない患者には推奨されません。. タンデマクトの開始前に肝臓検査の異常がある患者、またはタンデマクトの服用中に異常な肝臓検査を受けていることが判明した患者は、警告と注意事項に記載されているように管理する必要があります。.
インスリン分 ⁇ 器またはインスリンとの併用。
タンデマクトとインスリン分 ⁇ 器を併用した患者で低血糖症が発生した場合、インスリン分 ⁇ 器の用量を減らす必要があります。.
タンデマクトとインスリンを併用した患者で低血糖症が発生した場合、インスリンの用量を10%から25%減らす必要があります。. インスリン投与量のさらなる調整は、血糖反応に基づいて個別化されるべきです。.
強力なCYP2C8阻害剤との併用。
ピオグリタゾンと強力なCYP2C8阻害剤であるゲムフィブロジルの同時投与により、ピオグリタゾンへの曝露が約3倍に増加します。. したがって、ゲムフィブロジルまたは他の強力なCYP2C8阻害剤と組み合わせて使用 すると、ピオグリタゾンの最大推奨用量は1日15 mgになります。. ゲムフィブロジルまたは他のCYP2C8阻害剤を同時投与する必要がある場合、タンデマクト中のピオグリタゾンの最小用量が15 mgを超えるため、患者はタンデマクトの個々のコンポーネントに切り替える必要があります。 薬物相互作用。 と。 臨床薬理学。].
コールセベラムとの併用。
コレセベラムをグリメピリドと同時投与すると、最大血漿濃度とグリメピリドへの総曝露量が減少します。. したがって、タンデマクトは、コールセベラムの少なくとも4時間前に投与する必要があります。 薬物相互作用。 と。 臨床薬理学。].
- 確立されたNYHAクラスIIIまたはIV心不全の患者の開始。.
- ピオグリタゾン、グリメピリド、またはタンデマクトの他の成分に対する過敏症が知られている患者に使用します。.
- スルホンアミド誘導体に対するアレルギー反応の既知の歴史を持つ患者での使用。.
グリメピリドによる報告された過敏反応には、そう ⁇ の有無にかかわらず皮膚の発疹や、より深刻な反応(例:.、アナフィラキシー、血管性浮腫、スティーブンス・ジョンソン症候群、呼吸困難)。
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 Tandemact 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 Tandemact must be considered.
Hypoglycemia
Glimepiride
All sulfonylureas, including glimepiride, a component of Tandemact, 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 Tandemact 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 Tandemact, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, promptly discontinue Tandemact, 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 Tandemact therapy. In patients with abnormal liver tests, Tandemact 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), Tandemact treatment should be interrupted and investigation done to establish the probable cause. Tandemact 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 Tandemact. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with Tandemact 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, Tandemact should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with Tandemact 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.
Tandemact 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, Tandemact should be used with caution in patients at risk for congestive heart failure. Patients treated with Tandemact 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 Tandemact 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 Tandemact 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 Tandemact.
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION).
- Inform patients that Tandemact 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 Tandemact 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 Tandemact 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 Tandemact 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 Tandemact 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 Tandemact should immediately report these symptoms to a physician.
- Tell patients to promptly stop taking Tandemact 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 Tandemact 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 Tandemact. 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 Tandemact 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, Tandemact 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 Tandemact. The following data are based on studies conducted with the individual components of Tandemact.
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 Tandemact and any potential adverse effects on the breastfed infant from Tandemact 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 Tandemact in pediatric patients have not been established.
Tandemact 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 t1/2 (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 t1/2 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 Tandemact should be conservative. During initiation of Tandemact 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 Tandemact and increasing the dose of Tandemact in this patient population.
Renal Impairment
To minimize the risk of hypoglycemia, the initial dosing, dose increments and maintenance dosage of Tandemact should be conservative. During initiation of Tandemact 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.
吸収とバイオアベイラビリティ:。
タンデマクト。
生物学的同等性研究は、健康な被験者の空腹時条件下で、タンデマクト30 mg / 2 mgおよび30 mg / 4 mg錠剤の単回投与とピオグリタゾン(30 mg)およびグリメピリド(2 mgまたは4 mg)の併用投与後に実施されました。.
ピオグリタゾンとグリメピリドの両方の曲線下面積(AUC)と最大濃度(Cmax)に基づいて、タンデマクト30 mg / 2 mgと30 mg / 4 mgは、グリメピリドと併用して投与されたピオグリタゾン30 mgと生物学的に同等でした(2 mgまたは4 mg 、それぞれ)。.
タンデマクトの投与後、食品はグリメピリドまたはピオグリタゾンの全身曝露を変化させませんでした。. 食物の存在は、グリメピリドまたはピオグリタゾンのピーク血清濃度(Tmax)とピオグリタゾンのCmaxまでの時間を有意に変化させませんでした。. ただし、グリメピリドの場合、タンデマクトを食物とともに投与すると、Cmaxが22%増加しました。.
ピオグリタゾン。
ピオグリタゾンの1日1回投与後、ピオグリタゾンとその主要な活性代謝物であるM-III(ピオグリタゾンのケト誘導体)とM-IV(ピオグリタゾンのヒドロキシル誘導体)の両方の定常状態の血清濃度が7日以内に達成されます。. 定常状態では、M-IIIおよびM-IVはピオグリタゾンの血清濃度以上の血清濃度に達します。. 定常状態では、健康なボランティアと2型糖尿病患者の両方で、ピオグリタゾンはピークの総ピオグリタゾン血清濃度(ピオグリタゾンと活性代謝物)の約30%から50%、総AUCの20%から25%を占めます。
ピオグリタゾンとM-IIIおよびM-IVのCmax、AUC、およびトラフ血清濃度(Cmin)は、1日あたり15 mgおよび30 mgの投与量に比例して増加しました。.
ピオグリタゾンの経口投与後、ピオグリタゾンのTmaxは2時間以内でした。. 食品はTmaxを3〜4時間に遅らせますが、吸収の程度(AUC)は変わりません。.
グリメピリド。
健康な被験者にグリメピリドを単回経口投与し、2型糖尿病患者に複数回経口投与した研究では、投与後2〜3時間でピーク薬物濃度(Cmax)が示されました。. グリメピリドが食事とともに投与された場合、平均CmaxとAUCはそれぞれ8%と9%減少しました。.
グリメピリドは複数回投与しても血清中に蓄積しません。. グリメピリドの薬物動態は、健康な被験者と2型糖尿病患者の間で違いはありません。. 経口投与後のグリメピリドのクリアランス(CL / F)は、1 mgから8 mgの用量範囲で変化せず、線形薬物動態を示します。.
健康な被験者では、グリメピリドの薬物動態パラメータの個人内および個人間の変動は、それぞれ15%〜23%および24%〜29%でした。.
分布。
ピオグリタゾン。
単回投与後のピオグリタゾンの平均見かけの分布体積(Vd / F)は、0.63±0.41(平均±SD)L / kg体重です。. ピオグリタゾンは、主に血清アルブミンに、ヒト血清中のタンパク質結合が広範囲に(> 99%)されています。. ピオグリタゾンは他の血清タンパク質にも結合しますが、親和性は低くなります。. M-IIIおよびM-IVも血清アルブミンに広範囲に結合しています(> 98%)。.
グリメピリド。
健康な被験者に静脈内(IV)投与した後、Vd / Fは8.8 L(113 mL / kg)、全身クリアランス(CL)は47.8 mL / minでした。. タンパク質結合は99.5%を超えていました。.
代謝。
ピオグリタゾン。
ピオグリタゾンは、ヒドロキシル化と酸化によって広範囲に代謝されます。代謝物はまた、部分的にグルクロニドまたは硫酸塩抱合体に変換されます。. 代謝物M-IIIおよびM-IVは、ヒトの主要な循環活性代謝物です。.
In vitro。 データは、CYP2C8を含むピオグリタゾンの代謝に複数のCYPアイソフォームが関与しており、CYP3A4は、主に肝外CYP1A1を含む他のさまざまなアイソフォームから追加の寄与があることを示しています。. 生体内で。 強力なCYP2C8阻害剤であるゲムフィブロジルと組み合わせたピオグリタゾンの研究では、ピオグリタゾンがCYP2C8基質であることが示されました。. ピオグリタゾンで治療された患者で測定された尿中6β-ヒドロキシコルチゾール/コルチゾール比は、ピオグリタゾンが強力なCYP3A4酵素誘導剤ではないことを示しました。.
グリメピリド。
グリメピリドは、IVまたは経口投与後の酸化的生体内変化によって完全に代謝されます。. 主要な代謝産物は、シクロヘキシルヒドロキシメチル誘導体(M1)とカルボキシル誘導体(M2)です。. CYP2C9は、グリメピリドのM1への生体内変化に関与しています。. M1はさらに1つまたは複数の細胞質酵素によってM2に代謝されます。. 動物では、M1はグリメピリドの薬理活性の約3分の1を持っていますが、M1がヒトの血糖値に臨床的に意味のある影響を与えるかどうかは不明です。. M2は非アクティブです。.
排 ⁇ と排 ⁇ 。
ピオグリタゾン。
経口投与後、ピオグリタゾン投与量の約15%から30%が尿中に回収されます。. ピオグリタゾンの腎排 ⁇ は無視でき、薬物は主に代謝物とその抱合体として排 ⁇ されます。. 経口投与量のほとんどは、変化しないか代謝物として胆 ⁇ に排 ⁇ され、 ⁇ 便から排出されると推定されます。.
平均血清半減期(t。1/2。)ピオグリタゾンとその代謝産物(M-IIIおよびM-IV)の範囲は、それぞれ3〜7時間および16〜24時間です。. ピオグリタゾンには、5〜7 L / hrと計算された見かけのクリアランスCL / Fがあります。.
グリメピリド。
いつ。 14C-グリメピリドは3人の健康な男性被験者に経口投与され、総放射能の約60%が7日間で尿中に回収されました。. M1とM2は、尿中に回収された放射能の80%から90%を占めました。. 尿中のM1とM2の比率は、2人の被験者で約3:2、1人の被験者で4:1でした。. 全放射能の約40%が ⁇ 便から回収されました。. M1とM2は、 ⁇ 便で回収された放射能の約70%(M1からM2の比率は1:3)を占めました。. 親薬物は尿や ⁇ から回収されませんでした。. 患者にIV投与した後、グリメピリドまたはそのM1代謝産物の有意な胆 ⁇ 排 ⁇ は観察されなかった。.
腎障害。
ピオグリタゾン。
ピオグリタゾン、M-III、およびM-IVの血清排 ⁇ 半減期は、中等度[クレアチニンクリアランス(CLcr)30〜50 mL / min]および重度(CLcr <30 mL / min)の腎機能障害のある患者では変化しません。腎機能が正常な被験者と比較します。. したがって、腎障害のある患者では用量調整は必要ありません。.
グリメピリド。
単回投与で。, 非盲検試験グリメピリド3 mgを軽度の患者に投与した。, CLcrによって推定される中等度および重度の腎障害:グループIは、軽度の腎障害のある5人の患者で構成されていました。 (CLcr> 50 mL / min。) グループIIは、中等度の腎機能障害のある3人の患者で構成されていました。 (CLcr = 20〜50 mL / min。) グループIIIは、重度の腎機能障害のある7人の患者で構成されていました。 (CLcr <20 mL / min。). グリメピリド血清濃度は腎機能の低下とともに減少しましたが、グループIIIの平均AUCは、グループIの対応する平均AUCと比較して、M1の平均AUCが2.3倍、M2の平均AUCが8.6倍高かったです。½ グリメピリドは変化しなかったが、t。½ M1とM2は腎機能が低下するにつれて増加しました。. 用量の割合としてのM1とM2の平均尿中排 ⁇ は、グループIの44.4%からグループIIの21.9%、グループIIIの9.3%に減少しました。
肝障害。
ピオグリタゾン。
健康な対照と比較して、肝機能障害のある被験者(Child-Turcotte-Pugh Grade B / C)は、ピオグリタゾンが約45%減少し、総ピオグリタゾン(ピオグリタゾン、M-III、およびM-IV)はCmaxを意味しますが、平均AUC値。. したがって、肝障害のある患者の用量調整は必要ありません。.
ピオグリタゾンによる肝不全の市販後報告があり、臨床試験では一般に、血清ALTが参照範囲の上限2.5倍を超える患者を除外しています。.
肝疾患の患者には注意してタンデマクトを使用してください。.
グリメピリド。
グリメピリドの薬物動態は肝障害のある患者では十分に評価されていないため、グリメピリドの薬物動態に肝障害の影響があるかどうかは不明です。.
老人患者。
ピオグリタゾン。
健康な高齢の被験者では、ピオグリタゾンのCmaxはそれほど大きな違いはありませんでしたが、AUC値は若い被験者で達成された値よりも約21%高くなりました。. 平均t。½ ピオグリタゾンのうち、若い被験者(約7時間)と比較して、高齢者(約10時間)でも長引いていました。. これらの変化は、臨床的に関連があると考えられる大きさではありませんでした。.
グリメピリド。
2型糖尿病≤65歳と65歳以上の患者のグリメピリド薬物動態の比較は、1日6 mgの用量を使用した複数回投与試験で評価されました。. 2つの年齢層の間でグリメピリドの薬物動態に有意差はありませんでした。. 高齢患者の定常状態での平均AUCは、若い患者の平均AUCよりも約13%低くなりました。高齢患者の平均体重調整クリアランスは、若い患者の平均体重調整クリアランスよりも約11%高くなりました。.
小児患者。
タンデマクトの薬物動態研究は小児患者で行われなかった。.
ピオグリタゾン。
小児患者におけるピオグリタゾンの安全性と有効性は確立されていません。. タンデマクトは小児患者での使用は推奨されません。.
性別。
ピオグリタゾン。
ピオグリタゾンの平均CmaxおよびAUC値は、男性と比較して女性で20%から60%増加しました。. 対照臨床試験では、ベースラインからのHbA1cの減少は一般に男性よりも女性の方が大きかった(HbA1cの平均差0.5%)。. グリセミックコントロールを達成するには、患者ごとに治療を個別化する必要があるため、性別のみに基づいて用量調整を推奨しません。.
グリメピリド。
体重の違いを調整した場合、グリメピリドの薬物動態に男性と女性の間に違いはありませんでした。.
民族性。
ピオグリタゾン。
さまざまな民族グループの薬物動態データはありません。.
グリメピリド。
グリメピリドの薬物動態に対する人種の影響を評価するための研究は行われていませんが、2型糖尿病患者を対象としたグリメピリドのプラセボ対照試験では、HbA1cの減少は白人(n = 536)、黒人(n = 63)で同等でした。ヒスパニック(n = 63)。.
肥満患者。
グリメピリドとその代謝産物の薬物動態は、正常な体重または病的に肥満であった2型糖尿病の28人の患者を対象とした単回投与試験で測定されました。. 病的肥満患者のグリメピリドのTmax、CL / F、およびVd / Fは正常体重群のそれと同様でしたが、病的肥満は正常体重のものよりもCmaxおよびAUCが低かったです。. 通常のグリメピリドの平均Cmax、AUC0-24、AUC0-∞値と. 病的に肥満の患者は547±218 ng / mL対. 410±124 ng / mL、3210±1030時間・ng / mL対. 2820±1110時間・ng / mLおよび4000±1320時間・ng / mL対それぞれ3280±1360時間・ng / mL。.