Componentes:
Método de ação:
Opção de tratamento:
Medicamente revisado por Kovalenko Svetlana Olegovna, Farmácia Última atualização em 19.03.2022
Atenção! As informações na página são apenas para profissionais de saúde! As informações são coletadas em fontes abertas e podem conter erros significativos! Tenha cuidado e verifique novamente todas as informações desta página!
20 principais medicamentos com os mesmos componentes:
20 principais medicamentos com os mesmos tratamentos:
Monotherapy And Combination Therapy
Liovel LD is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both alogliptin and pioglitazone is appropriate.
Important Limitations Of Use
Liovel LD is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.
Recomendações para todos os pacientes
Liovel LD deve ser tomado uma vez ao dia e pode ser tomado com ou sem alimentos. Os comprimidos não devem ser divididos antes de engolir.
A dose inicial recomendada para Liovel LD (alogliptina e pioglitazona) :
- para pacientes inadequadamente controlados com dieta e exercício é de 25 mg / 15 mg ou 25 mg / 30 mg,
- para pacientes inadequadamente controlados com metformina em monoterapia é de 25 mg / 15 mg ou 25 mg / 30 mg
- para pacientes em alogliptina que necessitam de controle glicêmico adicional é de 25 mg / 15 mg ou 25 mg / 30 mg
- para pacientes em pioglitazona que necessitam de controle glicêmico adicional é de 25 mg / 15 mg, 25 mg / 30 mg ou 25 mg / 45 mg, conforme apropriado, com base na terapia atual
- para pacientes que mudam de alogliptina co-administrada com pioglitazona, o Liovel LD pode ser iniciado na dose de alogliptina e pioglitazona com base na terapia atual
- para pacientes com insuficiência cardíaca congestiva (classe I ou II da NYHA) é de 25 mg / 15 mg.
A dose de Liovel LD pode ser titulada até um máximo de 25 mg / 45 mg uma vez ao dia, com base na resposta glicêmica, conforme determinado pela hemoglobina A1c (A1C).
Após o início do Liovel LD ou com o aumento da dose, monitore cuidadosamente os pacientes quanto a reações adversas relacionadas à retenção de líquidos, como foi observado com a pioglitazona (por exemplo,., ganho de peso, edema e sinais e sintomas de insuficiência cardíaca congestiva).
Pacientes com deficiência renal
Não é necessário ajuste da dose de Liovel LD em pacientes com insuficiência renal leve (depuração da creatinina [CrCl] ≥60 mL / min).
A dose de Liovel LD é de 12,5 mg / 15 mg, 12,5 mg / 30 mg ou 12,5 mg / 45 mg uma vez ao dia para pacientes com insuficiência renal moderada (CrCl ≥30 a <60 mL / min).
Liovel LD não é recomendado em pacientes com insuficiência renal grave ou DRT. A administração concomitante de pioglitazona e alogliptina 6,25 mg uma vez ao dia, com base em requisitos individuais, pode ser considerada nesses pacientes.
Como é necessário um ajuste da dose com base na função renal, recomenda-se a avaliação da função renal antes do início da terapia com Liovel LD e periodicamente a partir de então.
Co-administração com inibidores fortes do CYP2C8
A administração concomitante de pioglitazona e gemfibrozil, um forte inibidor do CYP2C8, aumenta a exposição à pioglitazona aproximadamente três vezes. Portanto, a dose máxima recomendada de Liovel LD é de 25 mg / 15 mg por dia quando usada em combinação com gemfibrozil ou outros inibidores fortes do CYP2C8.
História de uma reação de hipersensibilidade grave à alogliptina ou pioglitazona, componentes do Liovel LD, como anafilaxia, angioedema ou reações adversas cutâneas graves.
Não inicie em pacientes com insuficiência cardíaca classe III ou IV da NYHA.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Congestive Heart Failure
Consider the risks and benefits of Liovel LD prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of congestive heart failure. Patients should be advised of the characteristic symptoms of congestive heart failure and should be instructed to immediately report such symptoms. If congestive heart failure develops, it should be managed according to current standards of care and consider discontinuation of Liovel LD.
Alogliptin
In the EXAMINE trial which enrolled patients with type 2 diabetes and recent acute coronary syndrome, 106 (3.9%) of patients treated with alogliptin and 89 (3.3%) of patients treated with placebo were hospitalized for 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 pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure.
Pancreatitis
Acute pancreatitis has been reported in the postmarketing setting and in randomized clinical trials. In glycemic control trials in patients with type 2 diabetes, acute pancreatitis was reported in six (0.2%) patients treated with alogliptin 25 mg and two (<0.1%) patients treated with active comparators or placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes and high cardiovascular (CV) risk), acute pancreatitis was reported in ten (0.4%) patients treated with alogliptin and in seven (0.3%) patients treated with placebo.
It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using Liovel LD.
After initiation of Liovel LD, patients should be observed for signs and symptoms of pancreatitis. If pancreatitis is suspected, Liovel LD should promptly be discontinued and appropriate management should be initiated.
Hypersensitivity Reactions
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin. These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue Liovel LD, assess for other potential causes for the event and institute alternative treatment for diabetes. Use caution in patients with a history of angioedema with another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with Liovel LD.
Hepatic Effects
There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking pioglitazone or alogliptin, although some of the reports contain insufficient information necessary to establish the probable cause.
In glycemic control trials of alogliptin in patients with type 2 diabetes, serum alanine aminotransferase (ALT) elevations greater than three times the upper limit of normal (ULN) were reported in 1.3% of patients treated with alogliptin 25 mg and 1.7% of patients treated with active comparators or placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes and high cardiovascular (CV) risk), increases in serum alanine aminotransferase three times the upper limit of the reference range occurred in 2.4% of patients treated with alogliptin and in 1.8% of patients treated with placebo.
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 (ALT, aspartate aminotransferase [AST], alkaline phosphatase and total bilirubin) and assessing the patient is recommended before initiating Liovel LD therapy. In patients with abnormal liver tests, Liovel LD 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 three times the upper limit of the reference range), Liovel LD treatment should be interrupted and an investigation done to establish the probable cause. Liovel LD should not be restarted in these patients without another explanation for the liver test abnormalities.
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 of edema have been received.
Liovel LD 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, Liovel LD should be used with caution in patients at risk for congestive heart failure. Patients treated with Liovel LD 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 pioglitazone and attention should be given to assessing and maintaining bone health according to current standards of care.
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 prospective10 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, Liovel LD should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with Liovel LD should be considered in patients with a prior history of bladder cancer.
Use With Medications Known To Cause Hypoglycemia
Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with Liovel LD.
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 their 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.
Severe And Disabling Arthralgia
There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
Bullous Pemphigoid
Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving Liovel LD. If bullous pemphigoid is suspected, Liovel LD should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Liovel LD.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients of the potential risks and benefits of Liovel LD.
Patients should be informed of the signs and symptoms of heart failure. 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 Liovel LD should immediately report these symptoms to their physician. Before initiating Liovel LD, patients should be asked about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment.
Patients should be informed that acute pancreatitis has been reported during use of alogliptin. Patients should be informed that persistent, severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue Liovel LD and contact their physician if persistent severe abdominal pain occurs.
Patients should be informed that allergic reactions have been reported during use of alogliptin and pioglitazone. If symptoms of allergic reactions (including skin rash, hives and swelling of the face, lips, tongue and throat that may cause difficulty in breathing or swallowing) occur, patients should be instructed to discontinue Liovel LD and seek medical advice promptly.
Patients should be informed that postmarketing reports of liver injury, sometimes fatal, have been reported during use of alogliptin and pioglitazone. If signs or symptoms of liver injury occur (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia or dark urine), patients should be instructed to discontinue Liovel LD and seek medical advice promptly.
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.
Inform patients that hypoglycemia can occur, particularly when an insulin secretagogue or insulin is used in combination with Liovel LD. Explain the risks, symptoms and appropriate management of hypoglycemia.
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.
Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs.
Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur.
Instruct patients to take Liovel LD only as prescribed daily. Liovel LD can be taken with or without meals. If a dose is missed, advise patients not to double their next dose. Patients should be informed that the tablets must never be split.
Instruct patients to read the Medication Guide before starting Liovel LD therapy and to reread each time the prescription is refilled. Instruct patients to inform their healthcare provider if an unusual symptom develops or if a symptom persists or worsens.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Alogliptin And Pioglitazone
No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with Liovel LD. The following data are based on findings in studies performed with alogliptin or pioglitazone individually.
Alogliptin
Rats were administered oral doses of 75, 400 and 800 mg/kg alogliptin for two years. No drug-related tumors were observed up to 75 mg/kg or approximately 32 times the maximum recommended clinical dose of 25 mg, based on area under the plasma concentration curve (AUC) exposure. At higher doses (approximately 308 times the maximum recommended clinical dose of 25 mg), a combination of thyroid C-cell adenomas and carcinomas increased in male but not female rats. No drug-related tumors were observed in mice after administration of 50, 150 or 300 mg/kg alogliptin for two years, or up to approximately 51 times the maximum recommended clinical dose of 25 mg, based on AUC exposure.
Alogliptin was not mutagenic or clastogenic, with and without metabolic activation, in the Ames test with S. typhimurium and E. coli or the cytogenetic assay in mouse lymphoma cells. Alogliptin was negative in the in vivo mouse micronucleus study.
In a fertility study in rats, alogliptin had no adverse effects on early embryonic development, mating or fertility at doses up to 500 mg/kg, or approximately 172 times the clinical dose based on plasma drug exposure (AUC).
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 MRHD of 45 mg based on mg/m²). Drug-induced tumors were not observed in any organ except for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg and above (approximately equal to the MRHD based on mg/m²). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg (approximately 11 times the MRHD based on mg/m²). No drug-induced tumors were observed in any organ.
Pioglitazone 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 daily prior to and throughout mating and gestation (approximately nine times the MRHD based on mg/m²).
Use In Specific Populations
Pregnancy
Risk Summary
Limited data with Liovel LD in pregnant women are not sufficient to inform a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.
In animal reproduction studies, 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 body surface area. No adverse developmental effects were observed when alogliptin was administered to pregnant rats and rabbits during organogenesis at exposures 180 and 149 times the 25 mg clinical dose, respectively, based on plasma drug exposure (AUC).
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, preeclampsia, 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.
Data
Animal Data
Alogliptin And Pioglitazone
Co-administration of 100 mg/kg alogliptin and 40 mg/kg pioglitazone (39 and 10 times the 25 mg and 45 mg clinical doses, respectively, based on body surface area) to pregnant rats during organogenesis slightly augmented pioglitazone-related fetal effects of delayed development and reduced fetal weights but did not result in embryofetal mortality or teratogenicity.
Alogliptin
Alogliptin administered to pregnant rabbits and rats during the period of organogenesis did not cause adverse developmental effects at doses of up to 200 mg/kg and 500 mg/kg, or 149 times and 180 times, the 25 mg clinical dose, respectively, based on plasma drug exposure (AUC). Placental transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats.
No adverse developmental outcomes were observed in offspring when alogliptin was administered to pregnant rats during gestation and lactation at doses up to 250 mg/kg (~95 times the 25 mg clinical dose, based on AUC).
Pioglitazone
Lactation
Risk Summary
There is no information regarding the presence of pioglitazone or alogliptin in human milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone and alogliptin 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 Liovel LD and any potential adverse effects on the breastfed infant from Liovel LD or from the underlying maternal condition.
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 Liovel LD in pediatric patients have not been established.
Liovel LD 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.
Geriatric Use
Alogliptin And Pioglitazone
Of the total number of patients (N=1533) in clinical safety and efficacy studies treated with alogliptin and pioglitazone, 248 (16.2%) patients were 65 years and older and 15 (1%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. While this and other reported clinical experiences have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be excluded.
Alogliptin
Of the total number of patients (N=9052) in clinical safety and efficacy studies treated with alogliptin, 2257 (24.9%) patients were ≥65 years old and 386 (4.3%) patients were ≥75 years old. No overall differences in safety or effectiveness were observed between patients ≥65 years old and younger patients.
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 16 to 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%) 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. These clinical experiences have not identified differences in effectiveness and safety between the elderly (≥65 years) and younger patients although small sample sizes for patients ≥75 years old limit conclusions.
Renal Impairment
Alogliptin
A total of 602 patients with moderate renal impairment (eGFR ≥30 and <60 mL/min/1.73 m²) and four patients with severe renal impairment/end-stage renal disease (eGFR <30 mL/min/1.73 m² or <15 mL/min/1.73 m², respectively) at baseline were treated with alogliptin in clinical trials in patients with type 2 diabetes. Reductions in HbA1c were generally similar in this subgroup of patients. The overall incidence of adverse reactions was generally balanced between alogliptin and placebo treatments in this subgroup of patients.
In the EXAMINE trial of high CV risk type 2 diabetes patients, 694 patients had moderate renal impairment and 78 patients had severe renal impairment or end-stage renal disease at baseline. The overall incidences of adverse reactions, serious adverse reactions and adverse reactions leading to study drug discontinuation were generally similar between the treatment groups.
Hepatic Impairment
Alogliptin
No dose adjustments are required in patients with mild to moderate hepatic impairment (Child-Pugh Grade A and B) based on insignificant change in systemic exposures (e.g., AUC) compared to subjects with normal hepatic function in a pharmacokinetic study. Alogliptin has not been studied in patients with severe hepatic impairment (Child-Pugh Grade C). Use caution when administering alogliptin to patients with liver disease.
Pioglitazone
No dose adjustments are required in patients with hepatic impairment (Child-Pugh Grade B and C) based on insignificant change in systemic exposures (e.g., AUC) compared to subjects with normal hepatic function in a pharmacokinetic study. However, use with caution in patients with liver disease.
The following serious adverse reactions are described below or elsewhere in the prescribing information:
- Congestive Heart Failure
- Pancreatitis
- Hypersensitivity Reactions
- Hepatic Effects
- Severe and Disabling Arthralgia
- Bullous Pemphigoid
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.
Alogliptin And Pioglitazone
Over 1500 patients with type 2 diabetes have received alogliptin coadministered with pioglitazone in four large, randomized, double-blind, controlled clinical trials. The mean exposure to Liovel LD was 29 weeks with more than 100 subjects treated for more than one year. The studies consisted of two placebo-controlled studies of 16 to 26 weeks in duration and two active-controlled studies of 26 weeks and 52 weeks in duration. In the Liovel LD arm, the mean duration of diabetes was approximately six years, the mean body mass index (BMI) was 31 kg/m² (54% of patients had a BMI ≥30 kg/m²), and the mean age was 54 years (16% of patients ≥65 years of age).
In a pooled analysis of these four controlled clinical studies, the overall incidence of adverse reactions was 65% in patients treated with Liovel LD compared to 57% treated with placebo. Overall discontinuation of therapy due to adverse reactions was 2.5% with Liovel LD compared to 2.0% with placebo, 3.7% with pioglitazone or 1.3% with alogliptin.
Adverse reactions reported in ≥4% of patients treated with Liovel LD and more frequently than in patients who received alogliptin, pioglitazone or placebo are summarized in Table 1.
Table 1: Adverse Reactions Reported in ≥4% of Patients Treated with Liovel LD and More Frequently than in Patients Receiving Either Alogliptin, Pioglitazone or Placebo
Number of Patients (%) | ||||
Liovel LD* N=1533 | Alogliptin† N=446 | Pioglitazone‡ N=949 | Placebo N=153 | |
Nasopharyngitis | 75 (4.9) | 21 (4.7) | 37 (3.9) | 6 (3.9) |
Back Pain | 64 (4.2) | 9 (2.0) | 32 (3.4) | 5 (3.3) |
Upper Respiratory Tract Infection | 63 (4.1) | 19 (4.3) | 26 (2.7) | 5 (3.3) |
*Liovel LD – includes data pooled for patients receiving alogliptin 25 mg and 12.5 mg combined with pioglitazone 15 mg, 30 mg and 45 mg †Alogliptin – includes data pooled for patients receiving alogliptin 25 mg and 12.5 mg ‡Pioglitazone – includes data pooled for patients receiving pioglitazone 15 mg, 30 mg and 45 mg |
Alogliptin Add-On Therapy To A Thiazolidinedione
In addition, in a 26 week, placebo-controlled, double-blind study, patients inadequately controlled on a thiazolidinedione alone or in combination with metformin or a sulfonylurea were treated with add-on alogliptin therapy or placebo; the adverse reactions reported in ≥5% of patients and more frequently than in patients who received placebo was influenza (alogliptin, 5.5%; placebo, 4.1%).
Hypoglycemia
In a 26 week, placebo-controlled factorial study with alogliptin in combination with pioglitazone on background therapy with metformin, the incidence of subjects reporting hypoglycemia was 0.8%, 0% and 3.8% for alogliptin 25 mg with pioglitazone 15 mg, 30 mg or 45 mg, respectively; 2.3% for alogliptin 25 mg; 4.7%, 0.8% and 0.8% for pioglitazone 15 mg, 30 mg or 45 mg, respectively; and 0.8% for placebo.
In a 26 week, active-controlled, double-blind study with alogliptin alone, pioglitazone alone or alogliptin coadministered with pioglitazone in patients inadequately controlled on diet and exercise, the incidence of hypoglycemia was 3% on alogliptin 25 mg with pioglitazone 30 mg, 0.6% on alogliptin 25 mg and 1.8% on pioglitazone 30 mg.
In a 52 week, active-controlled, double-blind study of alogliptin as add-on therapy to the combination of pioglitazone 30 mg and metformin compared to the titration of pioglitazone 30 mg to 45 mg and metformin, the incidence of subjects reporting hypoglycemia was 4.5% in the alogliptin 25 mg with pioglitazone 30 mg and metformin group versus 1.5% in the pioglitazone 45 mg and metformin group.
Alogliptin
A total of 14,778 patients with type 2 diabetes participated in 14 randomized, double-blind, controlled clinical trials of whom 9052 subjects were treated with alogliptin, 3469 subjects were treated with placebo and 2257 were treated with an active comparator. The mean duration of diabetes was seven years, the mean body mass index (BMI) was 31 kg/m² (49% of patients had a BMI ≥30 kg/m²) and the mean age was 58 years (26% of patients ≥65 years of age).
The mean exposure to alogliptin was 49 weeks with 3348 subjects treated for more than one year.
In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse reactions was 73% in patients treated with alogliptin 25 mg compared to 75% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse reactions was 6.8% with alogliptin 25 mg compared to 8.4% with placebo or 6.2% with active comparator.
Adverse reactions reported in ≥4% of patients treated with alogliptin 25 mg and more frequently than in patients who received placebo are summarized in Table 2.
Table 2: Adverse Reactions Reported in ≥4% Patients Treated with Alogliptin 25 mg and More Frequently than in Patients Given Placebo in Pooled Studies
Number of Patients (%) | |||
Alogliptin 25 mg N=6447 | Placebo N=3469 | Active Comparator N=2257 | |
Nasopharyngitis | 309 (4.8) | 152 (4.4) | 113 (5.0) |
Upper Respiratory Tract Infection | 287 (4.5) | 121 (3.5) | 113 (5.0) |
Headache | 278 (4.3) | 101 (2.9) | 121 (5.4) |
Hypoglycemia
Hypoglycemic events were documented based upon a blood glucose value and/or clinical signs and symptoms of hypoglycemia.
In the monotherapy study, the incidence of hypoglycemia was 1.5% in patients treated with alogliptin compared to 1.6% with placebo. The use of alogliptin as add-on therapy to glyburide or insulin did not increase the incidence of hypoglycemia compared to placebo. In a monotherapy study comparing alogliptin to a sulfonylurea in elderly patients, the incidence of hypoglycemia was 5.4% with alogliptin compared to 26% with glipizide.
In the EXAMINE trial, the incidence of investigator reported hypoglycemia was 6.7% in patients receiving alogliptin and 6.5% in patients receiving placebo. Serious adverse reactions of hypoglycemia were reported in 0.8% of patients treated with alogliptin and in 0.6% of patients treated with placebo.
Renal Impairment
In glycemic control trials in patients with type 2 diabetes, 3.4% of patients treated with alogliptin and 1.3% of patients treated with placebo had renal function adverse reactions. The most commonly reported adverse reactions were renal impairment (0.5% for alogliptin and 0.1% for active comparators or placebo), decreased creatinine clearance (1.6% for alogliptin and 0.5% for active comparators or placebo) and increased blood creatinine (0.5% for alogliptin and 0.3% for active comparators or placebo).
In the EXAMINE trial of high CV risk type 2 diabetes patients, 23% of patients treated with alogliptin and 21% of patients treated with placebo had an investigator reported renal impairment adverse reaction. The most commonly reported adverse reactions were renal impairment (7.7% for alogliptin and 6.7% for placebo), decreased glomerular filtration rate (4.9% for alogliptin and 4.3% for placebo) and decreased renal clearance (2.2% for alogliptin and 1.8% for placebo). Laboratory measures of renal function were also assessed. Estimated glomerular filtration rate decreased by 25% or more in 21.1% of patients treated with alogliptin and 18.7% of patients treated with placebo. Worsening of chronic kidney disease stage was seen in 16.8% of patients treated with alogliptin and in 15.5% of patients treated with placebo.
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.
Common Adverse Reactions: 16 To 26 Week Monotherapy Trials
A summary of the incidence and type of common adverse reactions reported in three pooled 16 to 26 week placebo-controlled monotherapy trials of pioglitazone 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. None of these adverse reactions were related to pioglitazone dose.
Table 3: Three Pooled 16 to 26 Week Placebo-Controlled Clinical Trials of Pioglitazone Monotherapy: Adverse Reactions Reported at an Incidence >5% and More Commonly in Patients Treated with Pioglitazone than in Patients Treated with Placebo
% of Patients | ||
Placebo N=259 | Pioglitazone N=606 | |
Upper Respiratory Tract Infection | 8.5 | 13.2 |
Headache | 6.9 | 9.1 |
Sinusitis | 4.6 | 6.3 |
Myalgia | 2.7 | 5.4 |
Pharyngitis | 0.8 | 5.1 |
Congestive Heart Failure
A summary of the incidence of adverse reactions related to congestive heart failure 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 were (at least one congestive heart failure, 0.2% to 1.7%; hospitalized due to congestive heart failure, 0.2% to 0.9%). None of the reactions were fatal.
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 reactions related to congestive heart failure reported in this study is provided in Table 4.
Table 4: Treatment-Emergent Adverse Reactions of Congestive Heart Failure (CHF) in Patients with NYHA Class II or III Congestive Heart Failure Treated with Pioglitazone or Glyburide
Number (%) of Subjects | ||
Pioglitazone N=262 | Glyburide N=256 | |
Death due to cardiovascular causes (adjudicated) | 5 (1.9%) | 6 (2.3%) |
Overnight hospitalization for worsening CHF (adjudicated) | 26 (9.9%) | 12 (4.7%) |
Emergency room visit for CHF (adjudicated) | 4 (1.5%) | 3 (1.2%) |
Patients experiencing CHF progression during study | 35 (13.4%) | 21 (8.2%) |
Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 5.
Table 5: Treatment-Emergent Adverse Reactions of Congestive Heart Failure (CHF) in PROactive Trial
Number (%) of Patients | ||
Placebo N=2633 | Pioglitazone N=2605 | |
At least one hospitalized congestive heart failure event | 108 (4.1%) | 149 (5.7%) |
Fatal | 22 (0.8%) | 25 (1%) |
Hospitalized, nonfatal | 86 (3.3%) | 124 (4.7%) |
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 A1C 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 6.
Table 6: PROactive: Number of First and Total Events for Each Component Within the Cardiovascular Composite Endpoint
Cardiovascular Events | Placebo N=2633 | Pioglitazone N=2605 | ||
First Events n (%) | Total Events n | First Events n (%) | Total Events n | |
Any Event | 572 (21.7) | 900 | 514 (19.7) | 803 |
All-Cause Mortality | 122 (4.6) | 186 | 110 (4.2) | 177 |
Nonfatal Myocardial Infarction (MI) | 118 (4.5) | 157 | 105 (4) | 131 |
Stroke | 96 (3.6) | 119 | 76 (2.9) | 92 |
Acute Coronary Syndrome | 63 (2.4) | 78 | 42 (1.6) | 65 |
Cardiac Intervention (CABG/PCI) | 101 (3.8) | 240 | 101 (3.9) | 195 |
Major Leg Amputation | 15 (0.6) | 28 | 9 (0.3) | 28 |
Leg Revascularization | 57 (2.2) | 92 | 71 (2.7) | 115 |
CABG=coronary artery bypass grafting; PCI=percutaneous intervention |
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.
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.
Hepatic Effects
There has been no evidence of pioglitazone-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date. One randomized, double-blind, three-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 reactions of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with finger stick 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).
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 four 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
Alogliptin
The following adverse reactions have been identified during the postmarketing use of alogliptin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Acute pancreatitis, hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria and severe cutaneous adverse reactions, including Stevens-Johnson syndrome, hepatic enzyme elevations, fulminant hepatic failure, severe and disabling arthralgia and bullous pemphigoid , diarrhea, constipation, nausea and ileus.
Pioglitazone
The following adverse reactions have been identified during the postmarketing use of pioglitazone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
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.
Alogliptina
As doses mais altas de alogliptina administradas em ensaios clínicos foram doses únicas de 800 mg para indivíduos saudáveis e doses de 400 mg uma vez ao dia por 14 dias para pacientes com diabetes tipo 2 (equivalente a 32 vezes e 16 vezes a dose clínica máxima recomendada de 25 mg, respectivamente). Não foram observadas reações adversas graves nessas doses.
No caso de uma overdose, é razoável instituir o monitoramento clínico e a terapia de suporte necessários, conforme ditado pelo estado clínico do paciente. Por julgamento clínico, pode ser razoável iniciar a remoção de material não absorvido do trato gastrointestinal.
A alogliptina é minimamente dializável; durante uma sessão de hemodiálise de três horas, aproximadamente 7% da droga foi removida. Portanto, é improvável que a hemodiálise seja benéfica em uma situação de overdose. Não se sabe se a alogliptina é dializável por diálise peritoneal.
Pioglitazona
Durante os ensaios clínicos controlados, foi relatado um caso de sobredosagem com pioglitazona. Um paciente do sexo masculino tomou 120 mg por dia durante quatro dias e depois 180 mg por dia durante sete dias. O paciente negou qualquer sintoma clínico durante esse período.
No caso de superdosagem, o tratamento de suporte apropriado deve ser iniciado de acordo com os sinais e sintomas clínicos do paciente.
Alogliptina e pioglitazona
Em um estudo randomizado e controlado por ativos de 26 semanas, pacientes com diabetes tipo 2 receberam alogliptina 25 mg co-administrada com pioglitazona 30 mg, alogliptina 12,5 mg co-administrada com pioglitazona 30 mg, alogliptina 25 mg isoladamente ou pioglitazona 30 mg isoladamente. Pacientes que foram randomizados para alogliptina 25 mg com pioglitazona 30 mg alcançaram uma diminuição de 26,2% nos níveis de triglicerídeos em relação a uma linha de base média de 214,2 mg / dL em comparação com uma diminuição de 11,5% apenas para alogliptina e uma redução de 21,8% apenas para pioglitazona. Além disso, também foi observado um aumento de 14,4% nos níveis de colesterol HDL a partir de uma linha de base média de 43,2 mg / dL para a alogliptina 25 mg com pioglitazona 30 mg em comparação com um aumento de 1,9% apenas para a alogliptina e um aumento de 13,2% apenas para a pioglitazona. As alterações nas medidas de colesterol LDL e colesterol total foram semelhantes entre a alogliptina 25 mg com pioglitazona 30 mg versus alogliptina isolada e a pioglitazona isolada. Um padrão semelhante de efeitos lipídicos foi observado em um estudo fatorial controlado por placebo, de 26 semanas.
Alogliptina
A administração de dose única de alogliptina em indivíduos saudáveis resultou em um pico de inibição da DPP-4 dentro de duas a três horas após a administração. O pico de inibição do DPP-4 excedeu 93% em doses de 12,5 mg a 800 mg. A inibição do DPP-4 permaneceu acima de 80% em 24 horas para doses maiores ou iguais a 25 mg. O pico e a exposição total ao longo de 24 horas ao BPL-1 ativo foram três a quatro vezes maiores com a alogliptina (em doses de 25 a 200 mg) que o placebo. Em um estudo de 16 semanas, duplo-cego, controlado por placebo, a alogliptina 25 mg demonstrou reduções no glucagon pós-prandial, enquanto aumenta os níveis de GLP-1 ativo pós-prandial em comparação com o placebo durante um período de oito horas após uma refeição padronizada. Não está claro como esses achados se relacionam com alterações no controle glicêmico geral em pacientes com diabetes mellitus tipo 2. Neste estudo, a alogliptina 25 mg demonstrou reduções na glicose pós-prandial de duas horas em comparação ao placebo (-30 mg / dL versus 17 mg / dL, respectivamente).
A administração de doses múltiplas de alogliptina em pacientes com diabetes tipo 2 também resultou em um pico de inibição do DPP-4 em uma a duas horas e excedeu 93% em todas as doses (25 mg, 100 mg e 400 mg) após uma dose única e após 14 dias de dosagem uma vez ao dia. Nestas doses de alogliptina, a inibição da DPP-4 permaneceu acima de 81% às 24 horas após 14 dias de administração.
Pioglitazona
Estudos clínicos demonstram que a pioglitazona melhora a sensibilidade à insulina em pacientes resistentes à insulina. A pioglitazona aumenta a capacidade de resposta celular à insulina, aumenta o descarte de glicose dependente de insulina e melhora a sensibilidade hepática à insulina. Em pacientes com diabetes tipo 2, a diminuição da resistência à insulina produzida pela pioglitazona resulta em concentrações plasmáticas mais baixas de glicose, concentrações plasmáticas mais baixas de insulina e valores mais baixos de A1C. Em ensaios clínicos controlados, a pioglitazona teve um efeito aditivo no controle glicêmico quando usada em combinação com uma sulfonilureia, metformina ou insulina. Pacientes com anormalidades lipídicas foram incluídos em ensaios clínicos com pioglitazona. No geral, os pacientes tratados com pioglitazona apresentaram reduções médias nos triglicerídeos séricos, aumentos médios no colesterol HDL e nenhuma alteração média consistente no LDL e no colesterol total. Não há evidência conclusiva de benefício macrovascular com pioglitazona.
Em um estudo de monoterapia, controlado por placebo e com dose de 26 semanas, os triglicerídeos séricos médios diminuíram nos grupos de dose de pioglitazona 15 mg, 30 mg e 45 mg em comparação com um aumento médio no grupo placebo. O colesterol médio do HDL aumentou em maior extensão nos pacientes tratados com pioglitazona do que nos pacientes tratados com placebo. Não houve diferenças consistentes para LDL e colesterol total em pacientes tratados com pioglitazona em comparação com placebo (Tabela 7).
Tabela 7: Lipídios em um estudo de 26 semanas, controlado por placebo, monoterapia e variação de doses
Placebo | Pioglitazona 15 mg uma vez ao dia | Pioglitazona 30 mg uma vez ao dia | Pioglitazona 45 mg uma vez ao dia | |
Triglicerídeos (mg / dL) | N = 79 | N = 79 | N = 84 | N = 77 |
Linha de base (média) | 263 | 284 | 261 | 260 |
Variação percentual em relação à linha de base (média ajustada *) | 4,8% | -9% † | -9,6% † | -9,3% † |
Colesterol HDL (mg / dL) | N = 79 | N = 79 | N = 83 | N = 77 |
Linha de base (média) | 42 | 40 | 41 | 41 |
Variação percentual em relação à linha de base (média ajustada *) | 8,1% | 14,1% † | 12,2% | 19,1% † |
Colesterol LDL (mg / dL) | N = 65 | N = 63 | N = 74 | N = 62 |
Linha de base (média) | 139 | 132 | 136 | 127 |
Variação percentual em relação à linha de base (média ajustada *) | 4,8% | 7,2% | 5,2% | 6% |
Colesterol total (mg / dL) | N = 79 | N = 79 | N = 84 | N = 77 |
Linha de base (média) | 225 | 220 | 223 | 214 |
Variação percentual em relação à linha de base (média ajustada *) | 4,4% | 4,6% | 3,3% | 6,4% |
* Ajustado para a linha de base, centro combinado e centro combinado por interação com o tratamento † p <0,05 versus placebo |
Nos outros dois estudos em monoterapia (16 semanas e 24 semanas) e em estudos de terapia combinada com sulfonilureia (16 semanas e 24 semanas), metformina (16 semanas e 24 semanas) ou insulina (16 semanas e 24 semanas), os resultados lipídicos foram geralmente consistente com os dados acima.
Absorção e biodisponibilidade
Alogliptina e pioglitazona
Em estudos de bioequivalência de Liovel LD, a área sob a curva de concentração plasmática (AUC) e concentração máxima (Cmax) do componente alogliptina e pioglitazona após uma dose única do comprimido combinado (12,5 mg / 15 mg ou 25 mg / 45 mg) eram bioequivalentes à alogliptina (12,5 mg ou 25 mg) administrado concomitantemente com pioglitazona (15 mg ou 45 mg, respectivamente) comprimidos em jejum em indivíduos saudáveis.
A administração de Liovel LD 25 mg / 45 mg com alimentos não resultou em alterações significativas na exposição geral de alogliptina ou pioglitazona. Liovel LD pode, portanto, ser administrado com ou sem alimentos.
Alogliptina
A biodisponibilidade absoluta da alogliptina é de aproximadamente 100%. A administração de alogliptina com uma refeição rica em gordura não resulta em alterações significativas na exposição total e máxima à alogliptina. A alogliptina pode, portanto, ser administrada com ou sem alimentos.
Pioglitazona
Após administração oral de cloridrato de pioglitazona, foram observadas concentrações máximas de pioglitazona em duas horas. Os alimentos atrasam levemente o tempo para atingir o pico da concentração sérica (Tmax) para três a quatro horas, mas não alteram a extensão da absorção (AUC).
Distribuição
Alogliptina
Após uma infusão intravenosa única de 12,5 mg de alogliptina em indivíduos saudáveis, o volume de distribuição durante a fase terminal foi de 417 L, indicando que o medicamento está bem distribuído nos tecidos.
A alogliptina está 20% ligada às proteínas plasmáticas.
Pioglitazona
A média aparente de Vd / F da pioglitazona após administração de dose única é de 0,63 ± 0,41 (média ± DP) L / kg de peso corporal. A pioglitazona é extensivamente ligada às proteínas (> 99%) no soro humano, principalmente à albumina sérica. A pioglitazona também se liga a outras proteínas séricas, mas com menor afinidade. Os metabólitos M-III e M-IV também estão extensivamente ligados (> 98%) à albumina sérica.
Metabolismo
Alogliptina
A alogliptina não sofre metabolismo extenso e 60% a 71% da dose é excretada como medicamento inalterado na urina.
Dois metabolitos menores foram detectados após a administração de uma dose oral de [14C] alogliptina, N-desmetilada, M-I (menos de 1% do composto original) e N-alogliptina acetilada, M-II (menos de 6% do composto original). M-I é um metabolito ativo e é um inibidor de DPP-4 semelhante à molécula original; M-II não exibe nenhuma atividade inibitória em relação ao DPP-4 ou outras enzimas relacionadas ao DPP. Dados in vitro indicam que o CYP2D6 e o CYP3A4 contribuem para o metabolismo limitado da alogliptina.
A alogliptina existe predominantemente como enantiômero (R) (mais de 99%) e sofre pouca ou nenhuma conversão quiral in vivo ao enantiômero (S). O enantiómero (S) não é detectável na dose de 25 mg.
Pioglitazona
A pioglitazona é extensamente metabolizada por hidroxilação e oxidação; os metabólitos também se convertem parcialmente em conjugados de glucuronido ou sulfato. Os metabólitos M-III e M-IV são os principais metabólitos ativos em circulação em humanos. Após administração uma vez ao dia de pioglitazona, as concentrações séricas no estado estacionário de pioglitazona e seus principais metabólitos ativos, M-III (derivado do tipo de pioglitazona) e M-IV (derivado de hidroxila da pioglitazona), são alcançadas em sete dias. No estado estacionário, M-III e M-IV atingem concentrações séricas iguais ou superiores às da pioglitazona. No estado estacionário, tanto em voluntários saudáveis quanto em pacientes com diabetes tipo 2, a pioglitazona compreende aproximadamente 30% a 50% do pico das concentrações séricas totais de pioglitazona (pioglitazona mais metabólitos ativos) e 20% a 25% da AUC total
A concentração sérica máxima (Cmax), a AUC e as concentrações séricas mínimas (Cmin) de pioglitazona e M-III e M-IV aumentaram proporcionalmente com doses administradas de 15 mg e 30 mg por dia.
Dados in vitro demonstram que várias isoformas do CYP estão envolvidas no metabolismo da pioglitazona. As isoformas do citocromo P450 envolvidas são o CYP2C8 e, em menor grau, o CYP3A4, com contribuições adicionais de uma variedade de outras isoformas, incluindo o CYP1A1 principalmente extra-hepático. Estudos in vivo de pioglitazona em combinação com gemfibrozil, um forte inibidor do CYP2C8, mostraram que a pioglitazona é um substrato do CYP2C8. As razões urinárias de 6β-hidroxicortisol / cortisol medidas em pacientes tratados com pioglitazona mostraram que a pioglitazona não é um forte indutor enzimático do CYP3A4.
Excreção e Eliminação
Alogliptina
A principal via de eliminação de [14C] a radioatividade derivada da alogliptina ocorre por excreção renal (76%), com 13% recuperados nas fezes, alcançando uma recuperação total de 89% da dose radioativa administrada. A depuração renal da alogliptina (9,6 L / h) indica que alguma secreção tubular renal ativa e a depuração sistêmica foi de 14,0 L / h.
Pioglitazona
Após administração oral, aproximadamente 15% a 30% da dose de pioglitazona é recuperada na urina. A eliminação renal da pioglitazona é insignificante e o medicamento é excretado principalmente como metabólitos e seus conjugados. Presume-se que a maior parte da dose oral seja excretada na bílis, inalterada ou como metabolitos, e eliminada nas fezes.
A meia-vida sérica média da pioglitazona e seus metabólitos (M-III e M-IV) varia de três a sete horas e 16 a 24 horas, respectivamente. A pioglitazona tem uma depuração aparente, CL / F, calculada em 5 a 7 L / h.