TANDEMACT 30 MG / 4 MG TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Tandemact 30 mg/4 mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 30 mg of pioglitazone (as hydrochloride) and 4 mg of glimepiride.

Excipient with known effect

Each tablet contains approximately 177 mg lactose monohydrate (see section 4.4).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

White to off-white, round, convex and debossed ‘4833 G’ on one face and ‘30/4’ on the other.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Tandemact is indicated as second line treatment of adult patients with type 2 diabetes mellitus who show intolerance to metformin or for whom metformin is contraindicated and who are already treated with a combination of pioglitazone and glimepiride.

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 HbA1c). 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 (see section 4.4).

4.2 Posology and method of administration

Posology

The recommended dose of Tandemact is one tablet taken once daily.

If patients report hypoglycaemia, the dose of Tandemact should be reduced or free combination therapy should be considered.

If patients are receiving pioglitazone in combination with a sulphonylurea other than glimepiride, patients should be stabilised with concomitant pioglitazone and glimepiride before switching to Tandemact.

Special populations

Elderly

Physicians should start treatment with the lowest available dose and increase the dose gradually, particularly when pioglitazone is used in combination with insulin (see section 4.4 Fluid retention and cardiac failure).

Renal impairment

Tandemact should not be used in patients with severe renal function disorders (creatinine clearance < 30 ml/min, see section 4.3).

Hepatic impairment

Tandemact should not be used in patients with hepatic impairment (see section 4.3 and 4.4).

Paediatric population

The safety and efficacy of Tandemact in children and adolescents under

18 years of age have not been established. No data are available.

Method of administration

The tablets are taken orally shortly before or with the first main meal. The tablets should be swallowed with a glass of water.

4.3 Contraindications

Tandemact is contraindicated in patients with:

– Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or other sulphonylureas or sulphonamides

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

– Current bladder cancer or a history of bladder cancer

– Uninvestigated macroscopic haematuria

– Hepatic impairment

– Type 1 diabetes mellitus

– Diabetic coma

– Diabetic ketoacidosis

– Severe renal function disorders (creatinine clearance < 30 ml/min)

– Pregnancy

– Breast-feeding (see section 4.6)

4.4 Special warnings and precautions for use

There is no clinical trial experience of other oral anti-hyperglycaemic medicinal products added to treatment with Tandemact or concomitantly administered glimepiride and pioglitazone.

Hypoglycaemia

When meals are taken at irregular hours or skipped altogether, treatment with Tandemact may lead to hypoglycaemia due to the sulphonylurea component. Symptoms can almost always be promptly controlled by immediate intake of carbohydrates (sugar). Artificial sweeteners have no effect.

It is known from other sulphonylureas that, despite initially successful countermeasures, hypoglycaemia may recur. Severe hypoglycaemia or prolonged hypoglycaemia, only temporarily controlled by the usual amounts of sugar, require immediate medical treatment and occasionally hospitalisation.

Treatment with Tandemact requires regular monitoring of glycaemic control.

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 of pioglitazone 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. 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. Tandemact should be discontinued if any deterioration in cardiac state 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 12,506 patients, 0.15%) than in control groups (7 cases from 10,212 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.

Liver function

There have been rare reports of elevated liver enzymes and hepatocellular dysfunction during post-marketing experience with pioglitazone and glimepiride (see section 4.8). Although in very rare cases fatal outcome has been reported, causal relationship has not been established.

It is recommended, therefore, that patients treated with Tandemact undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy with Tandemact in all patients. Therapy with Tandemact 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 Tandemact, 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 Tandemact 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 Tandemact 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 and sulphonylurea monotherapy or in combination 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

Rare changes in haematology have been observed with glimepiride treatment (see section 4.8). Treatment with Tandemact therefore requires regular haematological monitoring (especially leucocytes and platelets).

During therapy with pioglitazone there was a small reduction in mean haemoglobin (4% relative reduction) and haematocrit (4.1% relative reduction), 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.

Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since glimepiride belongs to the chemical class of sulfonylurea medicinal products, caution should be used in patients with G6PD-deficiency and a non-sulfonylurea alternative should be considered.

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.

Polycystic ovarian syndrome

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).

Others

An increased incidence in bone fractures in women was seen in a pooled analysis of adverse reactions reports of bone fracture from randomised, controlled, double blind clinical trials (see section 4.8).

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.

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 (see section 4.8).

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).

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

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

There have been no formal interaction studies for Tandemact, however, the concomitant use of the active substances in patients in clinical use has not resulted in any unexpected interactions. The following statements reflect the information available on the individual active substances (pioglitazone and glimepiride).

Pioglitazone

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. A decrease in the dose of pioglitazone may be needed when gemfibrozil is concomitantly administered. Close monitoring of glycaemic control should be considered (see section 4.4). 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 (see section 4.4).

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 pioglitazonewith 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.

Glimepiride

If glimepiride is taken simultaneously with certain other medicinal products, both undesired increases and decreases in the hypoglycaemic action of glimepiride can occur. For this reason, other medicinal products should only be taken with Tandemact with the knowledge (or at the prescription) of the doctor.

Based on the experience with glimepiride and with other sulphonylureas the following interactions have to be mentioned.

Potentiation of the blood-glucose-lowering effect and, thus, in some instances hypoglycaemia may occur when one of the following active substances is taken, for example:

phenylbutazone, azapropazone and oxyfenbutazone

insulin and oral antidiabetic products

metformin

salicylates and p-amino-salicylic acid

anabolic steroids and male sex hormones

chloramphenicol

clarithromycin

coumarin anticoagulants

disopyramide

fenfluramine

fibrates

angiotensin-converting enzyme (ACE) inhibitors

fluoxetine

allopurinol

sympatholytics

cyclo-, tro- and iphosphamides

sulphinpyrazone

certain long-acting sulphonamides

tetracyclines

MAO-inhibitors

quinolone antibiotics

probenecid

miconazole

pentoxyfylline (high dose parenteral)

tritoqualine

fluconazole

Weakening of the blood-glucose-lowering effect and, thus raised blood glucose levels may occur when one of the following active substances is taken, for example:

oestrogens and progestagens,

saluretics, thiazide diuretics,

thyroid stimulating agents, glucocorticoids,

phenothiazine derivatives, chlorpromazine,

adrenaline and sympathicomimetics,

nicotinic acid (high doses) and nicotinic acid derivatives,

laxatives (long-term use),

phenytoin, diazoxide, glucagon, barbiturates and rifampicin.

acetozolamide

H2 antagonists, betablockers, clonidine and reserpine may lead to either potentiation or weakening of the blood glucose lowering effect.

Under the influence of sympatholytic active substances such as betablockers, clonidine, guanethidine and reserpine, the signs of adrenergic counterregulation to hypoglycaemia may be reduced or absent.

Alcohol intake may potentiate or weaken the hypoglycaemic action of glimepiride in an unpredictable fashion.

Glimepiride may either potentiate or weaken the effects of coumarin derivatives.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in males and females

Tandemact is not recommended in women of childbearing potential not using contraception. If a patient wishes to become pregnant, treatment with Tandemact should be discontinued.

Pregnancy

Risk related to pioglitazone

There are no adequate data from the use of pioglitazone in pregnant women. Studies of pioglitazone in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Risk related to glimepiride

There are no adequate data from the use of glimepiride in pregnant women. Animal studies have shown reproductive toxicity which was most likely related to the pharmacological action (hypoglycaemia) of glimepiride.

Tandemact is contraindicated during pregnancy (see section 4.3). If a pregnancy occurs, treatment with Tandemact should be discontinued.

Breast-feeding

Sulphonylurea-derivatives like glimepiride pass into the breast milk.

Pioglitazone has been shown to be present in the milk of lactating rats. It is not known whether pioglitazone is secreted in human milk.

Tandemact is contra-indicated during breast-feeding (see section 4.3).

Fertility

In animal fertility studies with pioglitazone, there was no effect on copulation, impregnation or fertility index.

4.7 Effects on ability to drive and use machines

Tandemact has minor influence on the ability to drive and use machines. The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycaemia from glimepiride or, for example, as a result of visual impairment. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or using machines).

– Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This is particularly important in those who have reduced or absent awareness of the warnings of hypoglycaemia or have frequent episodes of hypoglycaemia. It should be considered whether it is advisable to drive or use machines in these circumstances.

Patients who experience visual disturbance should be cautious when driving or using machines.

4.8 Undesirable effects

Summary of the safety profile

Clinical trials have been conducted with co-administered pioglitazone and glimepiride (see section 5.1). Hypoglycaemic reactions mostly occur immediately due to the sulphonylurea component of Tandemact. Symptoms can almost always be promptly controlled by immediate intake of carbohydrates (sugar). This is a serious reaction which may occur uncommonly (> 1/1,000 to < 1/100) (see section 4.4). Moderate to severe thrombocytopenia, leucopenia, erythrocytopenia, granulocytopenia, agranulocytosis, haemolytic anaemia and pancytopenia may occur rarely (> 1/10,000 to < 1/1,000) (see section 4.4). Other reactions such as bone fracture, weight increase and oedema may occur commonly (> 1/100 to < 1/10) (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions reported in double-blind studies and post marketing experience 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 Moderate to severe thrombocytopenia, leucopenia, erythrocytopenia, granulocytopenia, agranulocytosis, haemolytic anaemia and pancyto-penia may occur. These are in general reversible upon discontinuation of treatment.

2 In very rare cases mild hypersensitivity reactions may develop into serious reactions with dyspnoea, fall in blood pressure and sometimes shock. Hypersensitivity reactions of the skin may occur as itching, rash, and urticaria. Cross allergenicity with sulphonylureas, sulphonamides or related substances is possible.

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

4 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 medicinal products.

5 Gastro-intestinal complaints are very rare and seldom lead to discontinuation of therapy.

6 Elevation of liver enzymes may occur. In very rare cases, impairment of liver function (e.g. with cholestasis and jaundice) may develop, as well as hepatitis which may progress to liver failure.

7

7 A pooled analysis was conducted of adverse event reports of bone fractures from randomised, comparator controlled, double blind clinical trials in over 8,100 patients in the pioglitazone-treated groups and 7,400 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%; 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. The observed excess risk of fractures for women on pioglitazone in this study is therefore 0.5 fractures per 100 patient years of use. 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 (see section 4.4).

8 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.

9 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 a sulphonylurea resulted in a mean weight increase over one year of 2.8 kg.

10 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.

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 in 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 (see section 4.4).

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 the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store..

4.9 Overdose

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.

After ingestion of an overdose of glimepiride, hypoglycaemia may occur, lasting from 12 to 72 hours, and may recur after initial recovery. Symptoms may not be present for up to 24 hours after ingestion. In general observation in hospital is recommended. Nausea, vomiting and epigastric pain may occur. The hypoglycaemia may in general be accompanied by neurological symptoms like restlessness, tremor, visual disturbances, coordination problems, sleepiness, coma and convulsions.

Treatment of overdose of Tandemact primarily consists of preventing absorption of glimepiride by inducing vomiting and then drinking water or lemonade with activated charcoal (adsorbent) and sodium-sulphate (laxative). If large quantities have been ingested, gastric lavage is indicated, followed by activated charcoal and sodium-sulphate. In case of (severe) overdose hospitalisation in an intensive care department is indicated. Start the administration of glucose as soon as possible, if necessary by a bolus intravenous injection of 50 ml of a 50% solution, followed by an infusion of a 10% solution with strict monitoring of blood glucose. Further treatment should be symptomatic.

In particular when treating hypoglycaemia due to accidental intake of Tandemact in infants and young children, the dose of glucose given must be carefully controlled to avoid the possibility of producing dangerous hyperglycaemia. Blood glucose should be closely monitored.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose lowering drugs; ATC code: A10BD06.

Tandemact combines two antihyperglycaemic active substances with complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes mellitus: pioglitazone, a member of the thiazolidinedione class and glimepiride, a member of the sulphonylurea clas­s.

Thiazolidinediones act primarily by reducing insulin resistance and sulphonylureas primarily by inducing insulin release from pancreatic beta cells.

Pioglitazone

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 HbA1c 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, 5,238 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, acetylsalicylic acid, 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 incidence of oedema, weight gain and heart failure were increased. No increase in mortality from heart failure was observed.

Glimepiride

Glimepiride acts mainly by stimulating insulin release from pancreatic beta cells.

As with other sulphonylureas this effect is based on an increase of responsiveness of the pancreatic beta cells to the physiological glucose stimulus. In addition, glimepiride seems to have pronounced extrapancreatic effects also postulated for other sulphonylureas.

Insulin release

Sulphonylureas regulate insulin secretion by closing the ATP-sensitive potassium channel in the beta cell membrane. Closing the potassium channel induces depolarisation of the beta cell and results – by opening of calcium channels – in an increased influx of calcium into the cell. This leads to insulin release through exocytosis. Glimepiride binds with a high exchange rate to a beta cell membrane protein which is associated with the ATP-sensitive potassium channel but which is different from the usual sulphonylurea binding site.

Extrapancreatic activity

The extrapancreatic effects are for example an improvement of the sensitivity of the peripheral tissue for insulin and a decrease of the insulin uptake by the liver.

The uptake of glucose from blood into peripheral muscle and fat tissues occurs via a special transport proteins, located in the cells membrane. The transport of glucose in these tissues is the rate limiting step in the use of glucose. Glimepiride increases very rapidly the number of active glucose transport molecules in the plasma membranes of muscle and fat cells, resulting in stimulated glucose uptake.

Glimepiride increases the activity of the glycosyl-phosphatidyli­nositol-specific phospholipase C which may be correlated with the induced lipogenesis and glycogenesis in isolated fat and muscle cells.

Glimepiride inhibits the glucose production in the liver by increasing the intracellular concentration of fructose-2,6-bisphosphate, which in turn inhibits the gluconeogenesis.

General

In healthy persons, the minimum effective oral dose is approximately 0.6 mg. The effect of glimepiride is dose-dependent and reproducible. The physiological response to acute physical exercise, reduction of insulin secretion, is still present under glimepiride.

There was no significant difference in effect regardless of whether glimepiride was given 30 minutes or immediately before a meal. In diabetic patients, good metabolic control over 24 hours can be achieved with a single daily dose.

Although the hydroxy metabolite of glimepiride caused a small but significant decrease in serum glucose in healthy persons, it accounts for only a minor part of the total effect.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Tandemact in all subsets of the paediatric population in type 2 diabetes mellitus. See section 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties

Tandemact

Studies in human volunteers have shown Tandemact to be bioequivalent to the administration of pioglitazone and glimepiride given as separate tablets.

The following statements reflect the pharmacokinetic properties of the individual active substances of Tandemact.

Pioglitazone

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 (see section 4.5).

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.

Linearity/non-linearity

Single dose studies demonstrate linearity of pharmacokinetics in the therapeutic dose range.

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.

Glimepiride

Absorption

The bioavailability of glimepiride after oral administration is complete. Food intake has no relevant influence on absorption, only absorption rate is slightly diminished. Maximum serum concentrations (Cmax) are reached approximately 2.5 hours after oral intake (mean 0.3 |ig/mL during multiple dosing of 4 mg daily).

Distribution

Glimepiride has a very low distribution volume (approximately 8.8 litres) which is roughly equal to the albumin distribution space, high protein binding (> 99%), and a low clearance (approximately 48 mL/min).

In animals, glimepiride is excreted in milk. Glimepiride is transferred to the placenta. Passage of the blood brain barrier is low.

Biotransformation and elimination

Mean dominant serum half-life, which is of relevance for the serum concentrations under multiple-dose conditions, is about 5 to 8 hours. After high doses, slightly longer half-lives were noted.

After a single dose of radiolabelled glimepiride, 58% of the radioactivity was recovered in the urine, and 35% in the faeces. No unchanged substance was detected in the urine. Two metabolites – most probably resulting from hepatic metabolism (major enzyme is CYP2C9) – were identified both in urine and faeces: the hydroxy derivative and the carboxy derivative. After oral administration of glimepiride, the terminal half-lives of those metabolites were 3 to 6 and 5 to 6 hours respectively.

Comparison of single and multiple once-daily dosing revealed no significant differences in pharmacokinetics, and the intra-individual variability was very low. There was no relevant accumulation.

Pharmacokinetics were similar in males and females, as well as in young and elderly (above 65 years) patients. In patients with low creatinine clearance, there was a tendency for glimepiride clearance to increase and for average serum concentrations to decrease, most probably resulting from a more rapid elimination because of lower protein binding. Renal elimination of the two metabolites was impaired.

Overall no additional risk of accumulation is to be assumed in such patients.

Pharmacokinetics in five non-diabetic patients after bile duct surgery were similar to those in healthy persons.

Linearity/non-linearity

There is a linear relationship between dose and both Cmax and AUC (area under the time/concentration curve).

5.3 Preclinical safety data

No animal studies have been conducted with the combined products of Tandemact. The following data are findings in studies performed with pioglitazone or glimepiride individually.

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 tumourigenic 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.

Glimepiride

Preclinical effects observed occurred at exposures sufficiently in excess of the maximum human exposure as to indicate little relevance to clinical use, or were due to the pharmacodynamic action (hypoglycaemia) of the compound. This finding is based on conventional safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, and reproduction toxicity studies. In the latter (covering embryotoxicity, teratogenicity and developmental toxicity), undesirable effects observed were considered to be secondary to the hypoglycaemic effects induced by the compound in dams and in offspring.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Cellulose microcrystalline Croscarmellose sodium

Hydroxypropyl­cellulose Lactose monohydrate Magnesium stearate Polysorbate 80

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Aluminium/aluminium blisters; packs of 14, 28, 30, 50, 90 or 98 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S

Delta Park 45

2665 Vallensbaek Strand Denmark