Pioglitazone is indicated in the treatment of type 2 diabetes mellitus:

 

As monotherapy

- in adult patients (particularly overweight patients) inadequately controlled by diet and

  exercise for whom metformin is inappropriate 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.

Glados should be taken once daily without regard to meals.

 

Pioglitazone 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.

 

The management of antidiabetic therapy should be individualized. Ideally, the response to

therapy should be evaluated using HbA1c which is a better indicator of long-term glycemic control that FBG alone. HbA_1c reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with Glados for a period of time adequate to evaluate change in HbA1c (three months) unless glycemic control deteriorates.

Monotherapy

Glados monotherapy in patients not adequately controlled with diet and exercise may be

initiated at 15 mg or 30 mg once daily. For patients who respond inadequately to the initial

dose of Glados, the dose can be increased in increments up to 45 mg once daily.

For patients not responding adequately to monotherapy, combination therapy should be

considered.

 

Combination Therapy:

Sulfonylureas:

Glados in combination with a sulfonylurea may be initiated at 15 mg or 30 mg once daily.

The current sulfonylurea dose can be continued upon initiation of Glados therapy. If

patients report hypoglycemia, the dose of the sulfonylurea should be decreased.

 

Metformin:

Glados in combination with metformin may be initiated at 15 mg or 30 mg once daily. The current metformin dose can be continued upon initiation of Glados therapy. It is unlikely that the dose of metformin will require adjustment due to hypoglycemia during combination therapy with Glados.

 

Insulin:

Glados in combination with insulin may be initiated at 15 mg or 30 mg once daily. The

current insulin dose can be continued upon initiation of Glados therapy. In patients

receiving Glados and insulin, the insulin dose can be decreased by 10% to 25% if the

patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100

mg/dl. Further adjustments should be individualized based on glucose-lowering response.

 

Maximum Recommended Dose:

The dose of Glados should not exceed 45 mg once daily in monotherapy or in combination with sulfonylurea, metformin, or insulin.

 

Special Populations:

- 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 Pioglitazone 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.

Pioglitazone 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. 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. Available epidemiological data also suggest a small increased risk of bladder cancer in diabetic patients treated with Pioglitazone 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 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 (see section 4.8). 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%).

The risk of fractures should be considered in the long term care of women 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 (see section 4.6).

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 (see section 4.5).

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

Interaction studies have shown that Pioglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin.

Co-administration of Pioglitazone with sulphonylureas does not appear to affect the pharmacokinetics of the sulphonylurea. Studies in man suggest no induction of the main inducible cytochrome P450, 1A, 2C8/9 and 3A4. In vitro studies have shown no inhibition of any subtype of cytochrome P450. Interactions with substances metabolised by these enzymes, e.g. oral contraceptives, cyclosporin, calcium channel blockers, and HMGCoA reductase inhibitors are not to be expected.

Co-administration of Pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) is reported to result in a 3-fold increase in AUC of Pioglitazone. Since there is a potential for an increase in dose-related adverse events, a decrease in the dose of Pioglitazone may be needed when gemfibrozil is concomitantly administered. Close monitoring of glycaemic control should be considered. Co-administration of Pioglitazone with rifampicin (an inducer of cytochrome P450 2C8) is reported to result in a 54% decrease in AUC of Pioglitazone. The Pioglitazone dose may need to be increased when rifampicin is concomitantly administered. Close monitoring of glycaemic control should be considered.

 

Pregnancy Category C: -There are no adequate and well-controlled studies in pregnant women. Pioglitazone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.   -Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m2, respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m2). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m2). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m2).   Lactation: It is not known whether Pioglitazone is secreted in human milk. Because many drugs are excreted in human milk, Pioglitazone should not be administered to a breast-feeding woman.

No effects on ability to drive and use machines have been observed.

The overall incidence and types of adverse events reported in placebo-controlled clinical trials of Pioglitazone monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in the following table:

 

Side Effects	(% 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
Tooth Disorder	2.3	5.3
Diabetes Mellitus Aggravated	8.1	5.1
Pharyngitis	0.8	5.1

 

The types of clinical adverse events reported when Pioglitazone was used in combination with sulfonylureas, metformin or insulin were generally similar to those reported during Pioglitazone monotherapy with the exception of an increase in the occurrence of edema in the insulin combination study.

Mild to moderate hypoglycemia was reported during combination therapy with sulfonylurea or insulin.

Pioglitazone may cause decreases in hemoglobin and hematocrit. These changes may be related to increased plasma volume associated with Pioglitazone therapy and have not been associated with any significant hematologic clinical effects.

Fewer than 0.12 % of Pioglitazone-treated patients were withdrawn from clinical trials due to abnormal liver function tests. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure.

Consult your Pharmacist or Physician if any side effect is observed

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.

 

Pharmacotherapeutic group: oral blood glucose lowering drugs; Thiazolidinediones;

 

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 HbA1c ≥ 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 HbA1c < 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 HbA1c was similar between treatment groups after one year. The rate of deterioration of HbA1c 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 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 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 medications (beta blockers, ACE inhibitors, angiotensin II antagonists, calcium channel blockers, nitrates, diuretics, aspirin, statins, and 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.

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.

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.

Lactose

Carboxymethylcellulose Calcium 

Hydroxypropyl cellulose LF

Magnesium Stearate   

Not applicable.

2 years.

This medicinal product does not require any special storage conditions.

30 tablets packed in HDPE bottle with PP silicated cap, in printed carton with folded leaflet.

No special requirements.