Rosiglitazone

When ATH:
A10BG02

Characteristic.

Oral hypoglycemic agent class of thiazolidinediones.

Rosiglitazona maleate is white or almost white solid, readily soluble in ethyl alcohol and a buffered aqueous solution at pH 2,3; solubility decreases with increasing pH in the physiological range.

Pharmacological action.
Hypoglycemic.

Application.

According to Physicians Desk Reference (2005), rosiglitazone maleate is indicated for improving glycemic control in patients with diabetes mellitus type 2 as an adjunct to diet and exercise. It is used both as monotherapy, in combination with a sulfonamide, metformin or insulin, If diet, exercise and monotherapy is not sufficient for adequate glycemic control. In patients with poor control of blood glucose levels when using maximum doses of metformin or sulfonamide, rosiglitazone maleate can be added to the treatment, it should not be completely replaced by a sulfonamide or metformin to rosiglitazone maleate.

Contraindications.

Hypersensitivity.

Restrictions apply.

Diabetes mellitus type 1 or ketoacidosis (ineffective in the absence of insulin), congestive heart failure, swelling, abnormal liver function (cm. Precautions), Age to 18 years (safety and efficacy of rosiglitazone maleate in patients younger than 18 years to be determined).

Pregnancy and breast-feeding.

It should not be used during pregnancy, except, when the effect of therapy outweighs the potential risk to the fetus (adequate and well-controlled studies in pregnant women have not performed). Based on available data considered, that the change in blood glucose levels during pregnancy is associated with an increased incidence of congenital abnormalities and an increase in neonatal morbidity and mortality. In order to maintain glucose levels as close to normal, most experts recommend the use during pregnancy monotherapy with insulin.

Effect of rosiglitazone on the generic activities and childbirth is not installed.

Category actions result in FDA - C. (The study of reproduction in animals has revealed adverse effects on the fetus, and adequate and well-controlled studies in pregnant women have not held, However, the potential benefits, associated with drugs in pregnant, may justify its use, in spite of the possible risk.)

Lactation. Substances, Related rosiglitazone, were determined in rat milk. No data on the excretion of rosiglitazone maleate with breast milk in women. Because many drugs penetrate the breast milk, rosiglitazone maleate should not be administered to nursing women.

Side effects.

In clinical studies, approximately 4600 patients with diabetes mellitus type 2 treated with rosiglitazone maleate; 3300 patients treated 6 months or more, 2000 patients- 12 months or more.

According to double-blind clinical trial in patients, were on monotherapy rosiglitazone maleate (n=2526) vs placebo (n=601), the most frequently observed side effects following (in parentheses % occurrence placebo): upper respiratory tract infection 9,9% (8,7), trauma 7,6% (4,3), headache 5,9% (5,0), lower back pain 4,0% (3,8), giperglikemiâ 3,9% (5,7), fatiguability 3,6% (5,0), sinusitis 3,2% (4,5); diarrhea 2,3% (3,3), gipoglikemiâ 0,6% (0,2).

A small number of patients, poluchavshih rosiglitazone maleate, develop anemia and swelling. Generally, side effects were mild or moderate and usually did not lead to treatment withdrawal. According to the double-blind studies, anemia developed in 1,9% patients, poluchavshih rosiglitazone maleate, compared with 0,7% placebo, 0,6% treated with sulfonamide and 2,2% metformin. Swelling developed in 4,8% patients, poluchavshih rosiglitazone maleate, compared to 1,3% placebo, 1,0% treated with sulfonamide and 2,2% -metformin. All side effects, It reported the appointment of a combination of rosiglitazone maleate with metformin or a sulfonamide, were similar to those observed with monotherapy. The largest percentage (7,1%) messages anemia have a combination of rosiglitazone maleate and metformin monotherapy compared with rosiglitazone or its combination with a sulfonamide. Probably, high frequency of anemia reported in studies of combination with metformin helped low baseline hemoglobin / hematocrit in patients, included in this group (cm. Laboratory abnormalities. Gematologiya).

In the 26-week double-blind, fixed-dose studies with the combination of insulin and rosiglitazone maleate with great frequency reported edema (among those who received insulin- 5,4%, from receiving rosiglitazona maleate in combination with insulin — 14,7%). The emergence or exacerbation of congestive heart failure occurs in 1% receiving insulin only, in 2% (the dose of rosiglitazona maleate 4 mg / day) and 3% (the dose of rosiglitazona maleate 8 mg / day) treated with a combination of insulin with rosiglitazone maleate (cm. Precautions. Heart failure and other cardiac effects). In postmarketingovom experience rosiglitazona maleate side effects have been reported, potentially associated with increased fluid volume (congestive heart failure, pulmonary edema, pleural effusion).

Fixed dose combination studies of insulin with rosiglitazona maleatom the most frequent side effect was hypoglycemia. Some patients because of hypoglycemia were withdrawn from trials (4 from 408, treated with rosiglitazona maleate with insulin and 1 from 203, receiving insulin only). The frequency of hypoglycemia, confirmed by the analysis of capillary blood glucose levels ≤ 2.78 mmol/l, was 6% for receiving only insulin, 12 and 14% for receiving a combination of rosiglitazona maleate (4 and 8 mg respectively) with insulin.

Laboratory abnormalities

Gematologiya. Patients, poluchavshih rosiglitazone maleate, observed dose-dependent reduction in the average level of hemoglobin and hematocrit (in each case, the average reduction was 10,0 g/l for hemoglobin and 3,3% for hematocrit). Course duration and reduce the value of these indicators in patients, treated with rosiglitazona maleate in combination with other gipoglikemicakimi means and rosiglitazona maleate as monotherapy, were identical. Hemoglobin and hematocrit before treatment was lowered in patients in a study of combination with metformin, that could contribute to the high frequency of messages on anemia in this group. The number of white blood cells also declined slightly in patients, poluchavshih rosiglitazone maleate. Decrease in haematological parameters can be associated with the observed increase in plasma.

Lipids. During treatment rosiglitazona maleatom variations of plasma lipids (cm. "Pharmacology" and "precautions").

The level transaminaz plasma. In clinical studies in 4598 patients, poluchavshih rosiglitazone maleate, including approximately 3600 patients with an annual Exposition, There was no apparent drug hepatotoxicity or ALT level rise.

In controlled trials have 0,2% patients, poluchavshih rosiglitazone maleate, increased ALT level more than 3 times the upper limit of normal, compared with 0,2% to placebo and 0,5% for comparator. Giperbilirubinemia revealed at 0,3% patients, poluchavshih rosiglitazone maleate, compared with 0,9% to placebo and 1% for comparator. In the clinical program, included a long open kategorizirujushhee study, increase the transaminaz more than 3 times above the upper border of the norms of totaled 0,35% for patients, poluchavshih rosiglitazone maleate, 0,59% for receiving placebo and 0,78% for receiving an active combination.

Cooperation.

Medicines, metabolizirujushhiesja with cytochrome p 450. Studies in vitro shows, What is rosiglitazone in clinically relevant concentrations inhibits not none of the major cytochrome p 450 Isoenzymes. According to studies in vitro, Rosiglitazone is metabolized, primarily, with the participation of CYP2C8 and, at least, CYP2С9. CYP2C8 Inhibitor (gemfibrozil) may reduce the metabolism of rosiglitazona, inductor (rifampicin) — improve. Concerning, If the inhibitors or inducers of CYP2C8 appoint or cancel during therapy rosiglitazona maleatom, may require a dosage adjustment rosiglitazona maleate in accordance with clinical response.

Rosiglitazona maleate (4 mg 2 once a day) had no clinically significant effect on farmakokinetiku and nifedipine oral contraceptives (ethinyl estradiol and norethindrone), which are metabolized primarily by CYP3A4.

Gliʙurid. When taking rosiglitazona maleate (2 mg 2 once a day) in conjunction with gliburidom (3,75-10 Mg /) during 7 days average value equilibrium daily plasma concentration glucose in patients with diabetes mellitus, stabilized at therapy gliburidom, It did not change.

Metformin. The simultaneous appointment rosiglitazona maleate (2 mg 2 once a day) and metformin (500 mg 2 once a day) healthy volunteers during 4 days do not have influence on equilibrium farmakokinetiku nor rosiglitazona maleate, Neither metformin.

Akarʙoza. Joint application of acarbose (100 mg 3 once a day) during 7 days in healthy volunteers do not have clinically significant effects on farmakokinetiku single dose rosiglitazona maleate.

Digoxin. Reception of rosiglitazona maleate (8 mg 1 once a day) during 14 days did not change the equilibrium farmakokinetiku digoxin (0,375 mg 1 once a day) in healthy volunteers.

Warfarin. Iterative reception of rosiglitazona maleate had no clinically significant effects on equilibrium farmakokinetiku enantiomers of warfarin.

Ethanol. Single dose of moderate amounts of alcohol does not raise the risk of a sudden development of hypoglycemia in patients with diabetes mellitus type 2, receiving rosiglitazona maleate.

Ranitidine. Preview reception ranitidine (150 mg 2 twice a day for 4 days) did not change neither the single oral dose farmakokinetiku, neither a single on/in the introduction of rosiglitazona maleate in healthy volunteers. These results show, What is absorption rosiglitazona ingestion does not change in conditions, accompanied by increasing the pH in DIGESTIVE TRACT.

Gemfiʙrozil. Simultaneous application gemfibrosila (600 mg 2 once a day) and rosiglitazona maleate (4 mg 1 once a day) during 7 days resulted in increased AUC of rosiglitazona maleate in 2 compared to the rosiglitazona alone maleatom (4 mg 1 once a day); given the potential dose-dependent effects of rosiglitazona maleate, When adding gemfibrozilom therapy may need lower doses rosiglitazona.

Overdose.

Available data on overdose rosiglitazona maleate in humans is not enough. Rosiglitazona maleate is well tolerated by a single admission dose in volunteers 20 mg. In cases of overdose must be assigned appropriate supportive therapy, taking into account the condition of the patient.

Dosing and Administration.

Inside, regardless of the meal. Tactics of hypoglycemic therapy strictly individual.

Monotherapy: the usual initial dose is 4 mg / day 1 or in 2 admission. According to clinical studies, maximum reduction of fasting plasma glucose and HbA1c is observed at a dose of 4 mg twice a day.

In combination with sulfonamidom, metformin or insulin, the last dose is not changed at the beginning of treatment rosiglitazona maleatom.

In combination with the recommended dose of sulfonamidom rosiglitazona maleate is 4 mg / day 1 or 2 admission. When the development gipoglikemii dose sulfonamida dropping.

In combination with metformin initial dose of rosiglitazona maleate is 4 mg / day 1 or 2 admission. While the likelihood of a need for dose adjustment of metformin due to Hypoglycemia is low.

Insulin: Patient, stabilized on insulin, insulin dose was retained at the beginning of treatment rosiglitazona maleatom. Dose rosiglitazona maleate- 4 mg / day. Exceeding this dose in combination with insulin is not shown. It is recommended that you reduce the dose rosiglitazona maleate on 10-25%, If the patient answered hypoglycemia or decrease in fasting blood glucose concentrations less than 5,55 mmol / l. Subsequent dose adjustment must be individual and based on the response, reducing blood glucose.

The maximum recommended dose of rosiglitazona maleate, that do not exceed, is 8 mg/day in one or divided into two reception. This dose has proved safe and effective in large-scale trials as monotherapy and in combination with metformin. Dose rosiglitazona maleate, exceeding 4 mg / day, in combination with sulfonamidom not enough explored in controlled clinical trials. Dose rosiglitazona maleate over 4 mg/day in combination with insulin is not shown.

Precautions.

General. In accordance with the mechanism of action, rosiglitazona maleate is active only in the presence of endogenous insulin, Therefore, it should not be used in patients with diabetes mellitus type 1 or to treat the Ketoacidosis.

Heart failure and other cardiac effects. Application of rosiglitazona maleate, like other tiazolidindionov alone or in combination with various means of hypoglycemic, may be the cause of fluid retention, that, in turn, can cause or worsen heart failure. You must survey patients to identify the signs and symptoms of heart failure. In combination with insulin thiazolidinedione may also increase the risk of other side effects of cardiovascular system. Rosiglitazona maleate should be abolished in all cases, the deterioration of the cardio-vascular system.

Patients with chronic heart failure III and IV class (According to the NYHA functional classification) did not participate in clinical trials. Such patients rosiglitazona maleate is not recommended.

IN THE UNITED STATES, in the 26-week three studies of patients with diabetes mellitus type 2, 216 people receive 4 mg rosiglitazona maleate per day in combination with insulin, 322 the patient received 8 mg rosiglitazona maleate per day plus insulin and 338 only insulin. In these studies included patients with prolonged course of diabetes mellitus and with a high rate of comorbidity, including peripheral nejropatiju, retinopathy, CHD, vascular disease and congestive heart failure. In these clinical studies, an increase in the frequency of edema, congestive heart failure and other undesirable phenomena on the part of the cardiovascular system met more often in patients, treated with combination of rosiglitazona maleate with insulin compared with insulin and placebo. Patients, who had developed cardiovascular disorders, were on average older and were more lasting for diabetes. Cardiovascular disorders were observed in patients, Additionally treated with rosiglitazona maleate in dose 4 mg / day, or in a group, receiving 8 mg / day. However, in this population, it was not possible to allocate specific risk factors, that could be used to identify all patients with the threat of development of heart failure and other cardiovascular complications in combination therapy. Three of the 10 patients, who developed heart failure during the double-blind studies, previously did not know about the existence of signs of congestive heart failure or predisposing to cardiac pathology factors.

In a double-blind trial in patients with diabetes mellitus type 2 and chronic renal failure (112 people receive 4 or 8 mg, rosiglitazona maleate plus insulin and 108 received insulin control) differences in the frequency of side effects from the circulatory system between the Group, receiving a combination of rosiglitazona maleate with insulin, and group, receiving only insulin, not observed.

Patients, receiving a combination of rosiglitazona maleate and insulin, must be observed to identify possible side effects on the cardiovascular system. This combined therapy is contraindicated in patients, not responded apparent decrease HbA1c or insulin doses through 4-5 months of treatment, and patients with any developed significant side reactions (cm. Side effects).

Gipoglikemiâ. There is a risk of hypoglycemia in patients, receiving rosiglitazona maleate in combination with other hypoglycemic means. It may be necessary to decrease the doses used drugs.

Swelling. Rosiglitazona maleate should be used with caution in patients with fluid retention. In a clinical study in healthy volunteers, which was prepared 8 mg, rosiglitazona maleate 1 Once a day every day for 8 Sun, observed a statistically significant increase in the average volume of plasma compared to placebo.

According to controlled clinical trials, in patients with diabetes mellitus type 2, poluchavshih rosiglitazone maleate, It was reported on the development of minor or moderate edema, probably, dozozavisimyh. In patients with existing swelling great likelihood of side effects when using combination therapy and insulin maleatom rosiglitazonom (cm. Side effects).

Weight gain. When you use rosiglitazona maleate as monotherapy and in combination with other gipoglikemicakimi means there has been a sharp increase in body mass index. According to the 26-week trials with the use of rosiglitazona maleate in doses 4 and 8 mg/day as monotherapy the mean weight gain amounted to 1,0 and 3,1 kg respectively. In combination with sulfonamidom, metformin or insulin average increase of body weight dose rosiglitazona maleate 4 mg/day was 1,8; 0,8 and 4,1 kg respectively. Mechanism for increasing body weight is unclear, but, perhaps, due to water retention and fat accumulation.

In postmarketingovyh studies reported on rare occasions an unusually rapid increase in body mass index, greater than the observed in the conduct of clinical trials. Such patients should assess the accumulation of fluid and related side effects (pronounced swelling, congestive heart failure).

Lipids. We recommend that you determine the level of HDL and triglyceride levels before treatment and monitor their levels in the future.

Gematologiya. With the appointment of rosiglitazona maleate as monotherapy or in combination with other gipoglikemicakimi means all controlled clinical trials was observed lower hemoglobin and hematocrit (the average decline in individual studies ≤ 10.0 g/l and ≤ 3.3% respectively). Changes in these indicators took place, primarily, during the first 3 Months, following the beginning of the therapy rosiglitazonom maleatom or after increasing the dose. The number of cells is also slightly declined. These changes may be associated with increased plasma, observed in the treatment of rosiglitazonom and maleatom, perhaps, They are dose-dependent (cm. Side effects. Laboratory abnormalities).

Ovulation. Application of rosiglitazona maleate, like other tiazolidindionov, may cause ovulation in some women with anovulatorian cycle in premenopausal women. These women are at risk of pregnancy during treatment rosiglitazonom maleatom, women in premenopausal women recommended adequate contraception. This potential effect is not specifically studied in clinical studies and the frequency of its appearance is unknown.

Although changes in hormonal balance observed in preclinical studies (cm. "Pharmacology". Carcinogenicity, mutagenicity, the effect on fertility), clinical significance of their unknown. In the case of menstrual irregularities, should assess the potential risks and expected benefits from the continuation of therapy rosiglitazona maleatom.

Effect on liver. In preliminary clinical trials 4598 patients, poluchavshih rosiglitazone maleate, comprising approximately 3600 patients with an annual Exposition, There were no reports of drug hepatotoxicity or ALT level rise. In preliminary controlled trials have 0,2% patients, poluchavshih rosiglitazone maleate, celebrated the rise of ALT more than 3 times higher than the upper bound of the norm compared to 0,2% to placebo and 0,5% for comparator. Increased ALT in patients, poluchavshih rosiglitazone maleate, It was reversible and did not have a clear causation using the HP.

In postmarketingovom experience destination rosiglitazona maleate reports were received of the development of hepatitis and liver enzymes in 3 or more times higher than the upper bound of the norm. Not found a clear causal link between the rare cases of liver failure with favorable or lethal outcomes and use of rosiglitazona maleate. Pending the results of additional large-scale long-term controlled clinical studies and additional data on security postmarketingovoj, all patients are recommended to monitor the level of liver enzymes prior to the therapy rosiglitazonom maleatom. In case of revealing the source of raising the level of enzymes in more than 2,5 times higher than the upper bound of the norm of rosiglitazona maleate is not appointed. In patients with normal baseline levels of enzymes after the start of treatment it is recommended to monitor the level transaminaz every 2 months during the first 12 Months, and then periodically. Patients with a slight increase of liver enzymes (excess of normal values ≤ 2.5) at the beginning of or during treatment rosiglitazonom maleatom should be examined to identify the causes of the. Be careful to start or to continue therapy rosiglitazonom maleatom with a slight increase of liver enzymes; such patients require more frequent monitoring of their level to assess the dynamics of indicators. In all cases, the ALT rise more than 3 times greater than the upper bound of the norm in patients, receiving rosiglitazona maleate, There is an urgent need to repeat this analysis. If the ALT level really exceeds the upper bound of the norm in more than 3 times, the rosiglitazona maleate should be abolished.

If a patient develops symptoms, allowing suspect liver (unexplained nausea, vomiting, stomach ache, fatiguability, anorexia and/or dark urine), You must take the analysis on liver enzymes. The decision to continue rosiglitazona maleatom therapy in these patients should be based on clinical data and laboratory assessment changes. If there was jaundice, the rosiglitazona maleate should be abolished.

Laboratory findings. It is necessary to periodically measure fasting blood glucose level and Serum for evaluation of therapeutic effect of treatment. All patients prior to the therapy rosiglitazonom maleatom and periodically during treatment, it is necessary to check the level of liver enzymes (cm. Side effects. The level transaminaz plasma).

Patient Information

Patients should be informed of the following. Therapy of diabetes mellitus type 2 includes diet. Limiting caloric intake, reduce body weight and exercise are essential to successful treatment, because it helps increase tissue sensitivity to insulin. This is important not only in the treatment of diabetes mellitus, but in a subsequent to maintain the effectiveness of drug therapy. It is important to adhere to the recommended diet and regularly monitor blood glucose levels and glycosylated hemoglobin. Patients should be notified, that a noticeable reduction of blood glucose levels should be about 2 Sun, and for the full effect from 2 to 8 Months. Patients should be informed, that it is necessary to perform a blood test to assess liver function before starting treatment and every 2 months during the first 12 months of therapy and then periodically. Patients, who are experiencing unexplained nausea, vomiting, stomach ache, fatiguability, anorexia, dark urine, must immediately report these symptoms to the doctor. Patients, have observed abnormally rapid weight gain, swelling, shortness of breath or other symptoms of heart failure against the backdrop of the admission of rosiglitazona maleate, must also immediately inform your doctor.

Rosiglitazona maleate can be taken with or without food. When it is used in combination with other hypoglycemic means, the patient and his family members have to be informed about the risk of gipoglikemii, its symptoms and treatment, as well as the conditions, predisposing to the development.

Despite the fact that hormonal imbalance was identified in preclinical studies (cm. "Pharmacology". Carcinogenicity, mutagenicity, the effect on fertility), the clinical significance of this phenomenon is unknown. If you are experiencing sudden violation menstrual function, It is necessary to revise the expected benefits from the continuation of treatment rosiglitazona maleatom.

In patients at risk of developing congestive heart failure rosiglitazona maleate should be used with caution, because thiazolidinedione, including rosiglitazona maleate, can cause fluid retention and cause or exacerbate manifestations of congestive heart failure. Such patients should be examined prior to the start of therapy.

Cooperation