Tandemact

1.

NAME OF THE MEDICINAL PRODUCT

Tandemact 30 mg/2 mg tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 30 mg of pioglitazone (as hydrochloride) and 2 mg of glimepiride.

Excipient: Each tablet contains approximately 125 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Tablet

White to off-white, round, convex and embossed ‘4833 G’ on one face and ‘30/2’ on the other.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Tandemact is indicated for the treatment of 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.

4.2 Posology and method of administration

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.

Elderly:

No dosage adjustment is necessary for elderly patients (see section 5.2).

Patients with renal impairment:

Tandemact should not be used in patients with severe renal function disorders (creatinine clearance

<30 ml/min, see section 4.3).

Patients with hepatic impairment:

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

Children and adolescents:

Tandemact is not recommended for use in patients below age 18 due to insufficient data on safety and

efficacy.

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The tablets are taken orally once daily shortly before or with the first main meal. The tablets should

be swallowed whole with some liquid.

4.3 Contraindications

Tandemact is contraindicated in patients with:

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Hypersensitivity to the active substances, or to any of the excipients, or other sulphonylureas or

sulphonamides

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

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Type 1 diabetes mellitus

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Diabetic coma

-

Diabetic ketoacidosis

-

Severe renal function disorders

-

Pregnancy

-

Lactation

4.4 Special warnings and precautions for use

There is no clinical trial experience of other oral anti-hyperglycaemic agents 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), 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 cases of cardiac failure reported from the market when pioglitazone

was used in combination with insulin. or in patients with a history of cardiac failure. Since insulin and

pioglitazone are associated with fluid retention, concomitant administration may increase the risk of

oedema. 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.

Caution should be exercised in patients over 75 years because of the limited experience in this patient

group.

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Hepatic impairment

Liver function:

There have been rare reports of hepatocellular dysfunction during post-marketing experience with

pioglitazone and glimepiride (see section 4.8). 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, therapy with Tandemact 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.

Others:

An increased incidence in bone fractures in women was seen in a pooled analysis of adverse event

reports 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.

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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).

The 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.

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

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. 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).

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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 sulphonylurea 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, azapropazon and oxyfenbutazone

insulin and oral antidiabetic products

metformin

salicylates and p-amino-salicylic acid

anabolic steroids and male sex hormones

chloramphenicol

coumarin anticoagulants

fenfluramine

fibrates

ACE inhibitors

fluoxetine

allopurinol

sympatholytics

cyclo-, tro-and iphosphamides

sulphinpyrazone

certain long-acting sulphonamides

tetracyclines

MAO-inhibitors

quinolone antibiotics

probenecid

miconazol

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 dosages) and nicotinic acid derivatives,

laxatives (long-term use),

phenytoin, diazoxide,

glucagon, barbiturates and rifampicin.

acetozolamide

H 2 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.

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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 Pregnancy and lactation

There are no adequate data from the use of pioglitazone and glimepiride in pregnant women. Studies

of pioglitazone in animals have shown reproductive toxicity (see section 5.3). The potential risk for

humans is unknown. 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 must not be used during

pregnancy.

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. Therefore, Tandemact must not be administered to breast-feeding women.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. 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 operating 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 operate machines in these circumstances.

4.8 Undesirable effects

No therapeutic clinical trials have been conducted with Tandemact. However, bioequivalence of

Tandemact with coadministered pioglitazone and glimepiride has been demonstrated (see section 5.2).

Adverse reactions reported in excess (> 0.5 %) of placebo and as more than an isolated case in patients

receiving pioglitazone in double-blind studies in combination with a sulphonylurea, including

glimepiride, are listed below as MedDRA preferred term by system organ class and absolute

frequency. Frequencies are defined as: common > 1/100, < 1/10; uncommon > 1/1000, < 1/100;

rare > 1/10000, < 1/1000; very rare < 1/10000; isolated reports: not known (cannot be estimated from

the available data). Within each frequency grouping, undesirable effects are presented in order of

decreasing seriousness.

PIOGLITAZONE IN COMBINATION THERAPY WITH SULPHONYLUREA

Ear and labyrinth disorders

Uncommon: vertigo

Eye disorders

Uncommon: visual disturbance

Gastrointestinal disorders

Common:

flatulence

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General disorders and administration site conditions

Uncommon: fatigue

Investigations

Common:

weight increased

Uncommon: increased lactic dehydrogenase

Metabolism and nutritional disorders

Uncommon: hypoglycaemia, appetite increased

Nervous system disorders

Common:

dizziness

Uncommon: headache

Renal and urinary disorders

Uncommon: glycosuria, proteinuria

Skin and subcutaneous tissue disorders

Uncommon: sweating

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.

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.

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 agents.

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.

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. Heart failure has been reported rarely with marketing use of

pioglitazone, but more frequently when pioglitazone was used in combination with insulin or in

patients with a history of cardiac failure.

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Additional information on the individual active substances of the fixed dose combination

Pioglitazone

In double blind placebo controlled clinical trials with pioglitazone upper respiratory tract infection and

hypoaesthesia were common; sinusitis and insomnia were uncommon.

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. Heart failure has been reported

rarely with marketing use of pioglitazone.

POST MARKETING DATA

Eye disorders

Macular oedema:

not known

Glimepiride

Based on experience with glimepiride and with other sulphonylureas the following adverse reactions

have to be mentioned.

Immune system disorders

Very rare:

Allergic shock, allergic vasculitis

Blood and lymphatic system disorders

Rare:

Changes in haematology

Gastro-intestinal disorders

Very rare:

Vomiting, diarrhoea, nausea, abdominal pressure, feeling of fullness in the stomach,

abdominal pain

Hepato-biliary disorders

Very rare:

Hepatitis, impairment of liver function (with cholestasis and jaundice)

Skin and subcutaneous tissue disorders

Very rare:

Hypersensitivity to light

Investigations

Very rare:

Decrease in sodium serum concentrations

In very rare cases mild hypersensivity 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.

Moderate to severe thrombocytopenia, leucopenia, erythrocytopenia, granulocytopenia,

agranulocytosis, haemolytic anemia and pancyto-penia may occur. These are in general reversible

upon discontinuation of medication.

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

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.

A pooled analysis was conducted of adverse event reports 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%).

4.9 Overdose

No case of overdose has been reported.

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 overdosage 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 overdosage 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) overdosage hospitalization 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: Combinations of oral blood glucose lowering drugs; ATC code:

A10BD06.

Tandemact combines two antihyperglycaemic agents with complementary mechanisms of action to

improve glycaemic control in patients with type 2 diabetes: 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.

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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 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 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

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cardiovascular medications (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 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.

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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 %).

Metabolism:

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.

Elderly:

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

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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

(C max ) are reached approximately 2.5 hours after oral intake (mean 0.3 µg/ml during multiple dosing of

4 mg daily) and there is a linear relationship between dose and both C max and AUC (area under the

time/concentration curve).

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.

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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 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.

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

15

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 Global Research and Development Centre (Europe) Ltd

61 Aldwych

London

WC2B 4AE

United Kingdom

8.

MARKETING AUTHORISATION NUMBERS

EU/1/06/366/017-22

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 8 th January 2007

10. DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the website of the European Medicines Agency

(EMEA) http://www.emea.europa.eu/

16

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: Each tablet contains approximately 177 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Tablet

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

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Tandemact is indicated for the treatment of 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.

4.2 Posology and method of administration

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.

Elderly:

No dosage adjustment is necessary for elderly patients (see section 5.2).

Patients with renal impairment:

Tandemact should not be used in patients with severe renal function disorders (creatinine clearance

<30 ml/min, see section 4.3).

Patients with hepatic impairment:

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

Children and adolescents:

Tandemact is not recommended for use in patients below age 18 due to insufficient data on safety and

efficacy.

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