Befree

Pioglitazone is indicated as second or third line treatment of type 2 diabetes mellitus as described below:

as monotherapy

- in adult patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin is in appropriate because of contraindications or intolerance

as dual oral therapy in combination with

- metformin, in adult patients (particularly overweight patients) with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin

- a sulphonylurea, only in adult patients who show intolerance to metformin or for whom metformin is contraindicated, with insufficient glycaemic control despite maximal tolerated dose of monotherapy with a sulphonylurea.

as triple oral therapy in combination with

- metformin and a sulphonylurea, in adult patients (particularly overweight patients) with insufficient glycaemic control despite dual oral therapy.

Pioglitazone is also indicated for combination with insulin in type 2 diabetes mellitus adult patients with insufficient glycaemic control on insulin for whom metformin is inappropriate because of contraindications or intolerance.

After initiation of therapy with pioglitazone, patients should be reviewed after 3 to 6 months to assess adequacy of response to treatment (e.g. reduction in HbA_1c). In patients who fail to show an adequate response, pioglitazone should be discontinued. In light of potential risks with prolonged therapy, prescribers should confirm at subsequent routine reviews that the benefit of pioglitazone is maintained.

Befreeazone is indicated as second or third line treatment of type 2 diabetes mellitus as described below:

as monotherapy

- in adult patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin is inappropriate because of contraindications or intolerance.

- Befreeazone is also indicated for combination with insulin in type 2 diabetes mellitus adult patients with insufficient glycaemic control on insulin for whom metformin is inappropriate because of contraindications or intolerance.

After initiation of therapy with Befreeazone, patients should be reviewed after 3 to 6 months to assess adequacy of response to treatment (e.g. reduction in HbA1c). In patients who fail to show an adequate response, Befreeazone should be discontinued. In light of potential risks with prolonged therapy, prescribers should confirm at subsequent routine reviews that the benefit of Befreeazone is maintained.

Posology

Pioglitazone treatment may be initiated at 15 mg or 30 mg once daily. The dose may be increased in increments up to 45 mg once daily.

In combination with insulin, the current insulin dose can be continued upon initiation of pioglitazone therapy. If patients report hypoglycaemia, the dose of insulin should be decreased.

Special population

Elderly

No dose adjustment is necessary for elderly patients.).

Renal impairment

No dose adjustment is necessary in patients with impaired renal function (creatinine clearance > 4 ml/min). No information is available from dialysed patients therefore pioglitazone should not be used in such patients.

Hepatic impairment

Pioglitazone should not be used in patients with hepatic impairment.

Paediatric population

The safety and efficacy of Befree in children and adolescents under 18 years of age have not been established. No data are available.

Method of administration

Pioglitazone tablets are taken orally once daily with or without food. Tablets should be swallowed with a glass of water.

Posology

Befreeazone treatment may be initiated at 15 mg or 30 mg once daily. The dose may be increased in increments up to 45 mg once daily.

In combination with insulin, the current insulin dose can be continued upon initiation of Befreeazone therapy. If patients report hypoglycaemia, the dose of insulin should be decreased.

Special population

Elderly

No dose adjustment is necessary for elderly patients.).

Renal impairment

No dose adjustment is necessary in patients with impaired renal function (creatinine clearance > 4 ml/min). No information is available from dialysed patients, therefore Befreeazone should not be used in such patients.

Hepatic impairment

Befreeazone should not be used in patients with hepatic impairment.

Paediatric population

The safety and efficacy of Befreeazone in children and adolescents under 18 years of age have not been established. No data are available.

Method of administration

Befreeazone tablets are taken orally once daily with or without food. Tablets should be swallowed with a glass of water.

Pioglitazone is contraindicated in patients with:

- hypersensitivity to the active substance or to any of the excipients listed in 6.1

- cardiac failure or history of cardiac failure (NYHA stages I to IV)

- hepatic impairment

- diabetic ketoacidosis

- current bladder cancer or a history of bladder cancer

- uninvestigated macroscopic haematuria

Befreeazone is contraindicated in patients with:

- hypersensitivity to the active substance or to any of the excipients

- cardiac failure or history of cardiac failure (NYHA stages I to IV)

- hepatic impairment

- diabetic ketoacidosis

- current bladder cancer or a history of bladder cancer

- uninvestigated macroscopic haematuria.

Fluid retention and cardiac failure

Pioglitazone can cause fluid retention, which may exacerbate or precipitate heart failure. When treating patients who have at least one risk factor for development of congestive heart failure (e.g. prior myocardial infarction or symptomatic coronary artery disease or the elderly), physicians should start with the lowest available dose and increase the dose gradually. Patients should be observed for signs and symptoms of heart failure, weight gain or oedema; particularly those with reduced cardiac reserve. There have been post-marketing cases of cardiac failure reported when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure. Patients should be observed for signs and symptoms of heart failure, weight gain and oedema when pioglitazone is used in combination with insulin. Since insulin and pioglitazone are both associated with fluid retention, concomitant administration may increase the risk of oedema. Post marketing cases of peripheral oedema and cardiac failure have also been reported in patients with concomitant use of pioglitazone and nonsteroidal anti-inflammatory drugs, including selective COX-2 inhibitors. Pioglitazone should be discontinued if any deterioration in cardiac status occurs.

A cardiovascular outcome study of pioglitazone has been performed in patients under 75 years with type 2 diabetes mellitus and pre-existing major macrovascular disease. Pioglitazone or placebo was added to existing antidiabetic and cardiovascular therapy for up to 3.5 years. This study showed an increase in reports of heart failure, however this did not lead to an increase in mortality in this study.

Elderly

Combination use with insulin should be considered with caution in the elderly because of increased risk of serious heart failure.

In light of age- related risks (especially bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully both before and during treatment in the elderly.

Bladder cancer

Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials with pioglitazone (19 cases from 12506 patients, 0.15%) than in control groups (7 cases from 10212 patients, 0.07%) HR=2.64 (95% CI 1.11-6.31, P=0.029). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 7 cases (0.06%) on pioglitazone and 2 cases (0.02%) in control groups. Epidemiological studies have also suggested a small increased risk of bladder cancer in diabetic patients treated with pioglitazone, although not all studies identified a statistically significant increased risk.

Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment (risks include age, smoking history, exposure to some occupational or chemotherapy agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuria should be investigated before starting pioglitazone therapy.

Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment.

Monitoring of liver function

There have been rare reports of hepatocellular dysfunction during post-marketing experience. It is recommended, therefore, that patients treated with pioglitazone undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy with pioglitazone in all patients. Therapy with pioglitazone should not be initiated in patients with increased baseline liver enzyme levels (ALT > 2.5 X upper limit of normal) or with any other evidence of liver disease.

Following initiation of therapy with pioglitazone, it is recommended that liver enzymes be monitored periodically based on clinical judgement. If ALT levels are increased to 3 X upper limit of normal during pioglitazone therapy, liver enzyme levels should be reassessed as soon as possible. If ALT levels remain > 3 X the upper limit of normal, therapy should be discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with pioglitazone should be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, the medicinal product should be discontinued.

Weight gain

In clinical trials with pioglitazone there was evidence of dose related weight gain, which may be due to fat accumulation and in some cases associated with fluid retention. In some cases weight increase may be a symptom of cardiac failure, therefore weight should be closely monitored. Part of the treatment of diabetes is dietary control. Patients should be advised to adhere strictly to a calorie-controlled diet.

Haematology

There was a small reduction in mean haemoglobin (4% relative reduction) and haematocrit (4.1% relative reduction) during therapy with pioglitazone, consistent with haemodilution. Similar changes were seen in metformin (haemoglobin 3-4% and haematocrit 3.6-4.1% relative reductions) and to a lesser extent sulphonylurea and insulin (haemoglobin 1-2% and haematocrit 1-3.2% relative reductions) treated patients in comparative controlled trials with pioglitazone.

Hypoglycaemia

As a consequence of increased insulin sensitivity, patients receiving pioglitazone in dual or triple oral therapy with a sulphonylurea or in dual therapy with insulin may be at risk for dose-related hypoglycaemia, and a reduction in the dose of the sulphonylurea or insulin may be necessary.

Eye disorders

Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual acuity have been reported with thiazolidinediones, including pioglitazone. Many of these patients reported concurrent peripheral oedema. It is unclear whether or not there is a direct association between pioglitazone and macular oedema but prescribers should be alert to the possibility of macular oedema if patients report disturbances in visual acuity; an appropriate ophthalmological referral should be considered.

Others

An increased incidence in bone fractures in women was seen in a pooled analysis of adverse reactions of bone fracture from randomised, controlled, double blind clinical trials in over 8100 pioglitazone and 7400 comparator treated patients, on treatment for up to 3.5 years.

Fractures were observed in 2.6% of women taking pioglitazone compared to 1.7% of women treated with a comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).

The fracture incidence calculated was 1.9 fractures per 100 patient years in women treated with pioglitazone and 1.1 fractures per 100 patient years in women treated with a comparator. The observed excess risk of fractures for women in this dataset on pioglitazone is therefore 0.8 fractures per 100 patient years of use.

In the 3.5 year cardiovascular risk PROactive study, 44/870 (5.1%; 1.0 fractures per 100 patient years) of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures per 100 patient years) of female patients treated with comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%).

Some epidemiological studies have suggested a similarly increased risk of fracture in both men and women.

The risk of fractures should be considered in the long term care of patients treated with pioglitazone.

As a consequence of enhancing insulin action, pioglitazone treatment in patients with polycystic ovarian syndrome may result in resumption of ovulation. These patients may be at risk of pregnancy. Patients should be aware of the risk of pregnancy and if a patient wishes to become pregnant or if pregnancy occurs, the treatment should be discontinued.

Pioglitazone should be used with caution during concomitant administration of cytochrome P450 2C8 inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored closely. Pioglitazone dose adjustment within the recommended posology or changes in diabetic treatment should be considered.

Befree tablets contain lactose monohydrate and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

Fluid retention and cardiac failure

Befreeazone can cause fluid retention, which may exacerbate or precipitate heart failure. When treating patients who have at least one risk factor for development of congestive heart failure (e.g. prior myocardial infarction or symptomatic coronary artery disease or the elderly), physicians should start with the lowest available dose and increase the dose gradually. Patients should be observed for signs and symptoms of heart failure, weight gain or oedema; particularly those with reduced cardiac reserve. There have been post-marketing cases of cardiac failure reported when Befreeazone was used in combination with insulin or in patients with a history of cardiac failure. Patients should be observed for signs and symptoms of heart failure, weight gain and oedema when Befreeazone is used in combination with insulin. Since insulin and Befreeazone are both associated with fluid retention, concomitant administration may increase the risk of oedema. Befreeazone should be discontinued if any deterioration in cardiac status occurs.

A cardiovascular outcome study of Befreeazone has been performed in patients under 75 years with type 2 diabetes mellitus and pre-existing major macrovascular disease. Befreeazone or placebo was added to existing antidiabetic and cardiovascular therapy for up to 3.5 years. This study showed an increase in reports of heart failure, however this did not lead to an increase in mortality in this study.

Elderly

Combination use with insulin should be considered with caution in the elderly because of increased risk of serious heart failure.

In light of age-related risks (especially bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully both before and during treatment in the elderly.

Bladder Cancer

Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials with Befreeazone (19 cases from 12506 patients, 0.15%) than in control groups (7 cases from 10212 patients, 0.07%) HR=2.64 (95% CI 1.11-6.31, P=0.029). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 7 cases (0.06%) on Befreeazone and 2 cases (0.02%) in control groups. Available epidemiological data also suggest a small increased risk of bladder cancer in diabetic patients treated with Befreeazone in particular in patients treated for the longest durations and with the highest cumulative doses. A possible risk after short term treatment cannot be excluded.

Risk factors for bladder cancer should be assessed before initiating Befreeazone treatment (risks include age, smoking history, exposure to some occupational or chemotherapy agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuria should be investigated before starting Befreeazone therapy.

Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment.

Monitoring of liver function

There have been rare reports of hepatocellular dysfunction during post-marketing experience. It is recommended, therefore, that patients treated with Befreeazone undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy with Befreeazone in all patients. Therapy with Befreeazone should not be initiated in patients with increased baseline liver enzyme levels (ALT > 2.5 X upper limit of normal) or with any other evidence of liver disease.

Following initiation of therapy with Befreeazone, it is recommended that liver enzymes be monitored periodically based on clinical judgement. If ALT levels are increased to 3 X upper limit of normal during Befreeazone therapy, liver enzyme levels should be reassessed as soon as possible. If ALT levels remain > 3 X the upper limit of normal, therapy should be discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with Befreeazone should be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, the medicinal product should be discontinued.

Weight gain

In clinical trials with Befreeazone there was evidence of dose related weight gain, which may be due to fat accumulation and in some cases associated with fluid retention. In some cases weight increase may be a symptom of cardiac failure, therefore weight should be closely monitored. Part of the treatment of diabetes is dietary control. Patients should be advised to adhere strictly to a calorie-controlled diet.

Haematology

There was a small reduction in mean haemoglobin (4% relative reduction) and haematocrit (4.1% relative reduction) during therapy with Befreeazone, consistent with haemodilution. Similar changes were seen in metformin (haemoglobin 3-4% and haematocrit 3.6-4.1% relative reductions) and to a lesser extent sulphonylurea and insulin (haemoglobin 1-2% and haematocrit 1-3.2% relative reductions) treated patients in comparative controlled trials with Befreeazone.

Hypoglycaemia

As a consequence of increased insulin sensitivity, patients receiving Befreeazone in dual or triple oral therapy with a sulphonylurea or in dual therapy with insulin may be at risk for dose-related hypoglycaemia, and a reduction in the dose of the sulphonylurea or insulin may be necessary.

Eye disorders

Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual acuity have been reported with thiazolidinediones, including Befreeazone. Many of these patients reported concurrent peripheral oedema. It is unclear whether or not there is a direct association between Befreeazone and macular oedema but prescribers should be alert to the possibility of macular oedema if patients report disturbances in visual acuity; an appropriate ophthalmological referral should be considered.

Others

An increased incidence in bone fractures in women was seen in a pooled analysis of adverse reactions of bone fracture from randomised, controlled, double blind clinical trials in over 8100 Befreeazone and 7400 comparator treated patients, on treatment for up to 3.5 years.

Fractures were observed in 2.6% of women taking Befreeazone compared to 1.7% of women treated with a comparator. No increase in fracture rates was observed in men treated with Befreeazone (1.3%) versus comparator (1.5%).

The fracture incidence calculated was 1.9 fractures per 100 patient years in women treated with Befreeazone and 1.1 fractures per 100 patient years in women treated with a comparator. The observed excess risk of fractures for women in this dataset on Befreeazone is therefore 0.8 fractures per 100 patient years of use.

In the 3.5 year cardiovascular risk PROactive study, 44/870 (5.1%; 1.0 fractures per 100 patient years) of Befreeazone-treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures per 100 patient years) of female patients treated with comparator. No increase in fracture rates was observed in men treated with Befreeazone (1.7%) versus comparator (2.1%).

The risk of fractures should be considered in the long term care of women treated with Befreeazone.

As a consequence of enhancing insulin action, Befreeazone treatment in patients with polycystic ovarian syndrome may result in resumption of ovulation. These patients may be at risk of pregnancy. Patients should be aware of the risk of pregnancy and if a patient wishes to become pregnant or if pregnancy occurs, the treatment should be discontinued.

Befreeazone should be used with caution during concomitant administration of cytochrome P450 2C8 inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored closely. Befreeazone dose adjustment within the recommended posology or changes in diabetic treatment should be considered.

Befreeazone Actavis tablets contain lactose monohydrate and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

Befree has no or negligible influence on the ability to drive and use machines. However patients who experience visual disturbance should be cautious when driving or using machines.

Befreeazone Actavis has no or negligible effect on the ability to drive and use machines. However patients who experience visual disturbance should be cautious when driving or using machines.

Tabulated list of adverse reactions

Adverse reactions reported in excess (> 0.5%) of placebo and as more than an isolated case in patients receiving pioglitazone in double-blind studies are listed below as MedDRA preferred term by system organ class and absolute frequency. Frequencies are defined as: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to< 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each system organ class, adverse reactions are presented in order of decreasing incidence followed by decreasing seriousness.

Description of selected adverse reactions

¹ Postmarketing reports of hypersensitivity reactions in patients treated with pioglitazone have been reported. These reactions include anaphylaxis, angioedema, and urticaria.

² Visual disturbance has been reported mainly early in treatment and is related to changes in blood glucose due to temporary alteration in the turgidity and refractive index of the lens as seen with other hypoglycaemic treatments.

³ In controlled clinical trials the incidence of reports of heart failure with pioglitazone treatment was the same as in placebo, metformin and sulphonylurea treatment groups, but was increased when used in combination therapy with insulin. In an outcome study of patients with pre-existing major macrovascular disease, the incidence of serious heart failure was 1.6% higher with pioglitazone than with placebo, when added to therapy that included insulin. However, this did not lead to an increase in mortality in this study. In this study in patients receiving pioglitazone and insulin, a higher percentage of patients with heart failure was observed in patients aged >65 years compared with those less than 65 years (9.7% compared to 4.0%). In patients on insulin with no pioglitazone the incidence of heart failure was 8.2% in those >65 years compared to 4.0% in patients less than 65 years. Heart failure has been reported with marketing use of pioglitazone, and more frequently when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure.

⁴ A pooled analysis was conducted of adverse reactions of bone fractures from randomised, comparator controlled, double blind clinical trials in over 8100 patients in the pioglitazone-treated groups and 7400 in the comparator-treated groups of up to 3.5 years duration. A higher rate of fractures was observed in women taking pioglitazone (2.6%) versus comparator (1.7%). No increase in fracture rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).

In the 3.5 year PROactive study, 44/870 (5.1%) of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%) of female patients treated with comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%). Post-marketing, bone fractures have been reported in both male and female patients.

⁵ Oedema was reported in 6-9% of patients treated with pioglitazone over one year in controlled clinical trials. The oedema rates for comparator groups (sulphonylurea, metformin) were 2-5%. The reports of oedema were generally mild to moderate and usually did not require discontinuation of treatment.

⁶ In active comparator controlled trials mean weight increase with pioglitazone given as monotherapy was 2-3 kg over one year. This is similar to that seen in a sulphonylurea active comparator group. In combination trials pioglitazone added to metformin resulted in mean weight increase over one year of 1.5 kg and added to a sulphonylurea of 2.8 kg. In comparator groups addition of sulphonylurea to metformin resulted in a mean weight gain of 1.3 kg and addition of metformin to a sulphonylurea a mean weight loss of 1.0 kg.

⁷ In clinical trials with pioglitazone the incidence of elevations of ALT greater than three times the upper limit of normal was equal to placebo but less than that seen in metformin or sulphonylurea comparator groups. Mean levels of liver enzymes decreased with treatment with pioglitazone. Rare cases of elevated liver enzymes and hepatocellular dysfunction have occurred in post-marketing experience. Although in very rare cases fatal outcome has been reported, causal relationship has not been established.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

Adverse reactions reported in excess (> 0.5%) of placebo and as more than an isolated case in patients receiving Befreeazone in double-blind studies are listed below as MedDRA preferred term by system organ class and absolute frequency. Frequencies are defined as: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing incidence and seriousness.

¹ Visual disturbance has been reported mainly early in treatment and is related to changes in blood glucose due to temporary alteration in the turgidity and refractive index of the lens as seen with other hypoglycaemic treatments.

² Oedema was reported in 6-9% of patients treated with Befreeazone over one year in controlled clinical trials. The oedema rates for comparator groups (sulphonylurea, metformin) were 2-5%. The reports of oedema were generally mild to moderate and usually did not require discontinuation of treatment.

³ In controlled clinical trials the incidence of reports of heart failure with Befreeazone treatment was the same as in placebo, metformin and sulphonylurea treatment groups, but was increased when used in combination therapy with insulin. In an outcome study of patients with pre-existing major macrovascular disease, the incidence of serious heart failure was 1.6% higher with Befreeazone than with placebo, when added to therapy that included insulin. However, this did not lead to an increase in mortality in this study. Heart failure has been reported rarely with marketing use of Befreeazone, but more frequently when Befreeazone was used in combination with insulin or in patients with a history of cardiac failure.

⁴ A pooled analysis was conducted of adverse reactions of bone fractures from randomised, comparator controlled, double blind clinical trials in over 8100 patients in the Befreeazone-treated groups and 7400 in the comparator-treated groups of up to 3.5 years duration. A higher rate of fractures was observed in women taking Befreeazone (2.6%) versus comparator (1.7%). No increase in fracture rates was observed in men treated with Befreeazone (1.3%) versus comparator (1.5%).

In the 3.5 year PROactive study, 44/870 (5.1%) of Befreeazone-treated female patients experienced fractures compared to 23/905 (2.5%) of female patients treated with comparator. No increase in fracture rates was observed in men treated with Befreeazone (1.7%) versus comparator (2.1%).

⁵ In active comparator controlled trials mean weight increase with Befreeazone given as monotherapy was 2-3 kg over one year. This is similar to that seen in a sulphonylurea active comparator group. In combination trials Befreeazone added to metformin resulted in mean weight increase over one year of 1.5 kg and added to a sulphonylurea of 2.8 kg. In comparator groups, addition of sulphonylurea to metformin resulted in a mean weight gain of 1.3 kg and addition of metformin to a sulphonylurea a mean weight loss of 1.0 kg.

⁶ In clinical trials with Befreeazone the incidence of elevations of ALT greater than three times the upper limit of normal was equal to placebo but less than that seen in metformin or sulphonylurea comparator groups. Mean levels of liver enzymes decreased with treatment with Befreeazone. Rare cases of elevated liver enzymes and hepatocellular dysfunction have occurred in post-marketing experience. Although in very rare cases fatal outcome has been reported, causal relationship has not been established.

In clinical studies, patients have taken pioglitazone at higher than the recommended highest dose of 45 mg daily. The maximum reported dose of 120 mg/day for four days, then 180 mg/day for seven days was not associated with any symptoms.

Hypoglycaemia may occur in combination with sulphonylureas or insulin. Symptomatic and general supportive measures should be taken in case of overdose.

In clinical studies, patients have taken Befreeazone at higher than the recommended highest dose of 45 mg daily. The maximum reported dose of 120 mg/day for four days, then 180 mg/day for seven days was not associated with any symptoms.

Hypoglycaemia may occur in combination with sulphonylureas or insulin. Symptomatic and general supportive measures should be taken in case of overdose.

Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins; ATC code: A10BG03.

Pioglitazone effects may be mediated by a reduction of insulin resistance. Pioglitazone appears to act via activation of specific nuclear receptors (peroxisome proliferator activated receptor gamma) leading to increased insulin sensitivity of liver, fat and skeletal muscle cells in animals. Treatment with pioglitazone has been shown to reduce hepatic glucose output and to increase peripheral glucose disposal in the case of insulin resistance.

Fasting and postprandial glycaemic control is improved in patients with type 2 diabetes mellitus. The improved glycaemic control is associated with a reduction in both fasting and postprandial plasma insulin concentrations. A clinical trial of pioglitazone vs. gliclazide as monotherapy was extended to two years in order to assess time to treatment failure (defined as appearance of HbA_1c > 8.0% after the first six months of therapy). Kaplan-Meier analysis showed shorter time to treatment failure in patients treated with gliclazide, compared with pioglitazone. At two years, glycaemic control (defined as HbA_1c < 8.0%) was sustained in 69% of patients treated with pioglitazone, compared with 50% of patients on gliclazide. In a two-year study of combination therapy comparing pioglitazone with gliclazide when added to metformin, glycaemic control measured as mean change from baseline in HbA_1c was similar between treatment groups after one year. The rate of deterioration of HbA_1c during the second year was less with pioglitazone than with gliclazide.

In a placebo controlled trial, patients with inadequate glycaemic control despite a three month insulin optimisation period were randomised to pioglitazone or placebo for 12 months. Patients receiving pioglitazone had a mean reduction in HbA_1c of 0.45% compared with those continuing on insulin alone, and a reduction of insulin dose in the pioglitazone treated group.

HOMA analysis shows that pioglitazone improves beta cell function as well as increasing insulin sensitivity. Two-year clinical studies have shown maintenance of this effect.

In one year clinical trials, pioglitazone consistently gave a statistically significant reduction in the albumin/creatinine ratio compared to baseline.

The effect of pioglitazone (45 mg monotherapy vs. placebo) was studied in a small 18-week trial in type 2 diabetics. Pioglitazone was associated with significant weight gain. Visceral fat was significantly decreased, while there was an increase in extra-abdominal fat mass. Similar changes in body fat distribution on pioglitazone have been accompanied by an improvement in insulin sensitivity. In most clinical trials, reduced total plasma triglycerides and free fatty acids, and increased HDL-cholesterol levels were observed as compared to placebo, with small, but not clinically significant increases in LDL-cholesterol levels.

In clinical trials of up to two years duration, pioglitazone reduced total plasma triglycerides and free fatty acids, and increased HDL cholesterol levels, compared with placebo, metformin or gliclazide. Pioglitazone did not cause statistically significant increases in LDL cholesterol levels compared with placebo, whilst reductions were observed with metformin and gliclazide. In a 20-week study, as well as reducing fasting triglycerides, pioglitazone reduced post prandial hypertriglyceridaemia through an effect on both absorbed and hepatically synthesised triglycerides. These effects were independent of pioglitazone's effects on glycaemia and were statistically significantly different to glibenclamide.

In PROactive, a cardiovascular outcome study, 5238 patients with type 2 diabetes mellitus and pre-existing major macrovascular disease were randomised to pioglitazone or placebo in addition to existing antidiabetic and cardiovascular therapy, for up to 3.5 years. The study population had an average age of 62 years; the average duration of diabetes was 9.5 years. Approximately one third of patients were receiving insulin in combination with metformin and/or a sulphonylurea. To be eligible patients had to have had one or more of the following: myocardial infarction, stroke, percutaneous cardiac intervention or coronary artery bypass graft, acute coronary syndrome, coronary artery disease, or peripheral arterial obstructive disease. Almost half of the patients had a previous myocardial infarction and approximately 20% had had a stroke. Approximately half of the study population had at least two of the cardiovascular history entry criteria. Almost all subjects (95%) were receiving cardiovascular medicinal products (beta blockers, ACE inhibitors, angiotensin II antagonists, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates).

Although the study failed regarding its primary endpoint, which was a composite of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, major leg amputation, coronary revascularisation and leg revascularisation, the results suggest that there are no long-term cardiovascular concerns regarding use of pioglitazone. However, the incidences of oedema, weight gain and heart failure were increased. No increase in mortality from heart failure was observed.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Pioglitazone in all subsets of the paediatric population in Type 2 Diabetes Mellitus.

Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins; ATC code: A10BG03.

Befreeazone effects may be mediated by a reduction of insulin resistance. Befreeazone appears to act via activation of specific nuclear receptors (peroxisome proliferator activated receptor gamma) leading to increased insulin sensitivity of liver, fat and skeletal muscle cells in animals. Treatment with Befreeazone has been shown to reduce hepatic glucose output and to increase peripheral glucose disposal in the case of insulin resistance.

Fasting and postprandial glycaemic control is improved in patients with type 2 diabetes mellitus. The improved glycaemic control is associated with a reduction in both fasting and postprandial plasma insulin concentrations. A clinical trial of Befreeazone vs. gliclazide as monotherapy was extended to two years in order to assess time to treatment failure (defined as appearance of HbA_1c > 8.0% after the first six months of therapy). Kaplan-Meier analysis showed shorter time to treatment failure in patients treated with gliclazide, compared with Befreeazone. At two years, glycaemic control (defined as HbA_1c < 8.0%) was sustained in 69% of patients treated with Befreeazone, compared with 50% of patients on gliclazide. In a two-year study of combination therapy comparing Befreeazone with gliclazide when added to metformin, glycaemic control measured as mean change from baseline in HbA_1c was similar between treatment groups after one year. The rate of deterioration of HbA_1c during the second year was less with Befreeazone than with gliclazide.

In a placebo controlled trial, patients with inadequate glycaemic control despite a three month insulin optimisation period were randomised to Befreeazone or placebo for 12 months. Patients receiving Befreeazone had a mean reduction in HbA1c of 0.45% compared with those continuing on insulin alone, and a reduction of insulin dose in the Befreeazone treated group.

HOMA analysis shows that Befreeazone improves beta cell function as well as increasing insulin sensitivity. Two-year clinical studies have shown maintenance of this effect.

In one year clinical trials, Befreeazone consistently gave a statistically significant reduction in the albumin/creatinine ratio compared to baseline.

The effect of Befreeazone (45 mg monotherapy vs. placebo) was studied in a small 18-week trial in type 2 diabetics. Befreeazone was associated with significant weight gain. Visceral fat was significantly decreased, while there was an increase in extra-abdominal fat mass. Similar changes in body fat distribution on Befreeazone have been accompanied by an improvement in insulin sensitivity. In most clinical trials, reduced total plasma triglycerides and free fatty acids, and increased HDL-cholesterol levels were observed as compared to placebo, with small, but not clinically significant increases in LDL-cholesterol levels.

In clinical trials of up to two years duration, Befreeazone reduced total plasma triglycerides and free fatty acids, and increased HDL cholesterol levels, compared with placebo, metformin or gliclazide. Befreeazone did not cause statistically significant increases in LDL cholesterol levels compared with placebo, whilst reductions were observed with metformin and gliclazide. In a 20-week study, as well as reducing fasting triglycerides, Befreeazone reduced post prandial hypertriglyceridaemia through an effect on both absorbed and hepatically synthesised triglycerides. These effects were independent of Befreeazone's effects on glycaemia and were statistically significant different to glibenclamide.

In PROactive, a cardiovascular outcome study, 5238 patients with type 2 diabetes mellitus and pre-existing major macrovascular disease were randomised to Befreeazone or placebo in addition to existing antidiabetic and cardiovascular therapy, for up to 3.5 years. The study population had an average age of 62 years; the average duration of diabetes was 9.5 years. Approximately one third of patients were receiving insulin in combination with metformin and/or a sulphonylurea. To be eligible patients had to have had one or more of the following: myocardial infarction, stroke, percutaneous cardiac intervention or coronary artery bypass graft, acute coronary syndrome, coronary artery disease, or peripheral arterial obstructive disease. Almost half of the patients had a previous myocardial infarction and approximately 20% had had a stroke. Approximately half of the study population had at least two of the cardiovascular history entry criteria. Almost all subjects (95%) were receiving cardiovascular medicinal products (beta blockers, ACE inhibitors, angiotensin II antagonists, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates).

Although the study failed regarding its primary endpoint, which was a composite of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, major leg amputation, coronary revascularisation and leg revascularisation, the results suggest that there are no long-term cardiovascular concerns regarding use of Befreeazone. However, the incidences of oedema, weight gain and heart failure were increased. No increase in mortality from heart failure was observed.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Befreeazone in all subsets of the paediatric population in Type 2 Diabetes Mellitus.

Absorption

Following oral administration, pioglitazone is rapidly absorbed, and peak plasma concentrations of unchanged pioglitazone are usually achieved 2 hours after administration. Proportional increases of the plasma concentration were observed for doses from 2-60 mg. Steady state is achieved after 4-7 days of dosing. Repeated dosing does not result in accumulation of the compound or metabolites. Absorption is not influenced by food intake. Absolute bioavailability is greater than 80%.

Distribution

The estimated volume of distribution in humans is 0.25 l/kg.

Pioglitazone and all active metabolites are extensively bound to plasma protein (> 99%).

Biotransformation

Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic methylene groups. This is predominantly via cytochrome P450 2C8 although other isoforms may be involved to a lesser degree. Three of the six identified metabolites are active (M-II, M-III, and M-IV). When activity, concentrations and protein binding are taken into account, pioglitazone and metabolite M-III contribute equally to efficacy. On this basis M-IV contribution to efficacy is approximately three-fold that of pioglitazone, whilst the relative efficacy of M-II is minimal.

In vitro studies have shown no evidence that pioglitazone inhibits any subtype of cytochrome P450. There is no induction of the main inducible P450 isoenzymes 1A, 2C8/9, and 3A4 in man.

Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Concomitant administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) or with rifampicin (an inducer of cytochrome P450 2C8) is reported to increase or decrease, respectively, the plasma concentration of pioglitazone.

Elimination

Following oral administration of radiolabelled pioglitazone to man, recovered label was mainly in faeces (55%) and a lesser amount in urine (45%). In animals, only a small amount of unchanged pioglitazone can be detected in either urine or faeces. The mean plasma elimination half-life of unchanged pioglitazone in man is 5 to 6 hours and for its total active metabolites 16 to 23 hours.

Elderly

Steady state pharmacokinetics are similar in patients age 65 and over and young subjects.

Patients with renal impairment

In patients with renal impairment, plasma concentrations of pioglitazone and its metabolites are lower than those seen in subjects with normal renal function, but oral clearance of parent substance is similar. Thus free (unbound) pioglitazone concentration is unchanged.

Patients with hepatic impairment

Total plasma concentration of pioglitazone is unchanged, but with an increased volume of distribution. Intrinsic clearance is therefore reduced, coupled with a higher unbound fraction of pioglitazone.

Absorption

Following oral administration, Befreeazone is rapidly absorbed, and peak plasma concentrations of unchanged Befreeazone are usually achieved 2 hours after administration. Proportional increases of the plasma concentration were observed for doses from 2-60 mg. Steady state is achieved after 4-7 days of dosing. Repeated dosing does not result in accumulation of the compound or metabolites. Absorption is not influenced by food intake. Absolute bioavailability is greater than 80%.

Distribution

The estimated volume of distribution in humans is 0.25 l/kg.

Befreeazone and all active metabolites are extensively bound to plasma protein (> 99%).

Biotransformation

Befreeazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic methylene groups. This is predominantly via cytochrome P450 2C8 although other isoforms may be involved to a lesser degree. Three of the six identified metabolites are active (M-II, M-III, and M-IV). When activity, concentrations and protein binding are taken into account, Befreeazone and metabolite M-III contribute equally to efficacy. On this basis M-IV contribution to efficacy is approximately three-fold that of Befreeazone, whilst the relative efficacy of M-II is minimal.

In vitro studies have shown no evidence that Befreeazone inhibits any subtype of cytochrome P450. There is no induction of the main inducible P450 isoenzymes 1A, 2C8/9, and 3A4 in man.

Interaction studies have shown that Befreeazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Concomitant administration of Befreeazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) or with rifampicin (an inducer of cytochrome P450 2C8) is reported to increase or decrease, respectively, the plasma concentration of Befreeazone.

Elimination

Following oral administration of radiolabelled Befreeazone to man, recovered label was mainly in faeces (55%) and a lesser amount in urine (45%). In animals, only a small amount of unchanged Befreeazone can be detected in either urine or faeces. The mean plasma elimination half-life of unchanged Befreeazone in man is 5 to 6 hours and for its total active metabolites 16 to 23 hours.

Elderly

Steady state pharmacokinetics are similar in patients age 65 and over and young subjects.

Patients with renal impairment

In patients with renal impairment, plasma concentrations of Befreeazone and its metabolites are lower than those seen in subjects with normal renal function, but oral clearance of parent substance is similar. Thus free (unbound) Befreeazone concentration is unchanged.

Patients with hepatic impairment

Total plasma concentration of Befreeazone is unchanged, but with an increased volume of distribution. Intrinsic clearance is therefore reduced, coupled with a higher unbound fraction of Befreeazone.

In toxicology studies, plasma volume expansion with haemodilution, anaemia, and reversible eccentric cardiac hypertrophy was consistently apparent after repeated dosing of mice, rats, dogs, and monkeys. In addition, increased fatty deposition and infiltration were observed. These findings were observed across species at plasma concentrations ≤ 4 times the clinical exposure. Foetal growth restriction was apparent in animal studies with pioglitazone. This was attributable to the action of pioglitazone in diminishing the maternal hyperinsulinaemia and increased insulin resistance that occurs during pregnancy thereby reducing the availability of metabolic substrates for foetal growth.

Pioglitazone was devoid of genotoxic potential in a comprehensive battery of in vivo and in vitro genotoxicity assays. An increased incidence of hyperplasia (males and females) and tumours (males) of the urinary bladder epithelium was apparent in rats treated with pioglitazone for up to 2 years.

The formation and presence of urinary calculi with subsequent irritation and hyperplasia was postulated as the mechanistic basis for the observed tumourigenic response in the male rat. A 24-month mechanistic study in male rats demonstrated that administration of pioglitazone resulted in an increased incidence of hyperplastic changes in the bladder. Dietary acidification significantly decreased but did not abolish the incidence of tumours. The presence of microcrystals exacerbated the hyperplastic response but was not considered to be the primary cause of hyperplastic changes. The relevance to humans of the tumourigenic findings in the male rat cannot be excluded.

There was no tumorigenic response in mice of either sex. Hyperplasia of the urinary bladder was not seen in dogs or monkeys treated with pioglitazone for up to 12 months.

In an animal model of familial adenomatous polyposis (FAP), treatment with two other thiazolidinediones increased tumour multiplicity in the colon. The relevance of this finding is unknown.

Environmental Risk Assessment (ERA):

No environmental impact is anticipated from the clinical use of pioglitazone.

In toxicology studies, plasma volume expansion with haemodilution, anaemia, and reversible eccentric cardiac hypertrophy was consistently apparent after repeated dosing of mice, rats, dogs, and monkeys. In addition, increased fatty deposition and infiltration were observed. These findings were observed across species at plasma concentrations ≤4 times the clinical exposure. Foetal growth restriction was apparent in animal studies with Befreeazone. This was attributable to the action of Befreeazone in diminishing the maternal hyperinsulinaemia and increased insulin resistance that occurs during pregnancy thereby reducing the availability of metabolic substrates for foetal growth.

Befreeazone was devoid of genotoxic potential in a comprehensive battery of in vivo and in vitro genotoxicity assays. An increased incidence of hyperplasia (males and females) and tumours (males) of the urinary bladder epithelium was apparent in rats treated with Befreeazone for up to 2 years.

The formation and presence of urinary calculi with subsequent irritation and hyperplasia was postulated as the mechanistic basis for the observed tumourigenic response in the male rat. A 24-month mechanistic study in male rats demonstrated that administration of Befreeazone resulted in an increased incidence of hyperplastic changes in the bladder. Dietary acidification significantly decreased but did not abolish the incidence of tumours. The presence of microcrystals exacerbated the hyperplastic response but was not considered to be the primary cause of hyperplastic changes. The relevance to humans of the tumourigenic findings in the male rat cannot be excluded.

There was no tumorigenic response in mice of either sex. Hyperplasia of the urinary bladder was not seen in dogs or monkeys treated with Befreeazone for up to 12 months.

In an animal model of familial adenomatous polyposis (FAP), treatment with two other thiazolidinediones increased tumour multiplicity in the colon. The relevance of this finding is unknown.

Environmental Risk Assessment: no environmental impact is anticipated from the clinical use of Befreeazone.

Not applicable

Not applicable.

No special requirements for disposal.

No special requirements.