pioglitazone: prescribing information – dosing, contraindications, interactions, side effects

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

as monotherapy
- in adult patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin is 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 (see section 4.4).

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).

Posology

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

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

Special populations

Elderly
No dose adjustment is necessary for elderly patients (see section 5.2). 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
No dose adjustment is necessary in patients with impaired renal function (creatinine clearance > 4 mL/min) (see section 5.2). 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 (see sections 4.3 and 4.4).

Paediatric population
The safety and efficacy of Actos 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 listed in section 6.1
• cardiac failure or history of cardiac failure (NYHA stages I to IV)
• hepatic impairment
• diabetic ketoacidosis
• current bladder cancer or a history of bladder cancer
• uninvestigated macroscopic haematuria

Tabulated list of adverse reactions

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

Adverse reaction
Frequency of adverse reactions of pioglitazone by treatment regimen

Mono- therapy
Combination

with metformin

with sulpho- nylurea

with metformin and sulpho- nylurea

with insulin
Infections and infestations

upper respiratory tract infection common common common common common bronchitis

common sinusitis uncommon uncommon uncommon uncommon uncommon

Adverse reaction
Frequency of adverse reactions of pioglitazone by treatment regimen

Mono- therapy
Combination

with metformin

with sulpho- nylurea

with metformin and sulpho- nylurea

with insulin
Neoplasms benign, malignant and unspecified
(including cysts and polyps)

bladder cancer uncommon uncommon uncommon uncommon uncommon
Blood and lymphatic system disorders

anaemia

common

Immune System
Disorders

hypersensitivity and allergic reactions1 not known not known not known not known not known Metabolism and nutrition disorders

hypo-glycaemia

uncommon very common common appetite increased

uncommon

Nervous system disorders

hypo-aesthesia common common common common common headache

common uncommon

dizziness

common

insomnia uncommon uncommon uncommon uncommon uncommon
Eye disorders

visual disturbance2 common common uncommon

macular oedema not known not known not known not known not known
Ear and labyrinth disorders

vertigo

uncommon

Cardiac disorders

heart failure3

common
Respiratory, thoracic and mediastinal disorders

dyspnoea

common
Gastrointestinal disorders

flatulence

uncommon common

Skin and subcutaneous tissue disorders

sweating

uncommon

Adverse reaction
Frequency of adverse reactions of pioglitazone by treatment regimen

Mono- therapy
Combination

with metformin

with sulpho- nylurea

with metformin and sulpho- nylurea

with insulin
Musculoskeletal and connective tissue disorders

fracture bone4 common common common common common arthralgia

common

common common back pain

common
Renal and urinary disorders

haematuria

common

glycosuria

uncommon

proteinuria

uncommon

Reproductive system and breast disorders

erectile dysfunction

common

General disorders and administration site conditions

Oedema5

very common fatigue

uncommon

Investigations

weight increased6 common common common common common blood creatine phospho-kinase increased

common

increased lactic dehydro-genase

uncommon

alanine aminotransferase increased7 not known not known not known not known not known

Description of selected adverse reactions

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

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

3 In controlled clinical trials the incidence of reports of heart failure with pioglitazone treatment was the same as in placebo, metformin and sulphonylurea treatment groups, but was increased when used in combination therapy with insulin. In an outcome study of patients with pre-existing major macrovascular disease, the incidence of serious heart failure was 1.6% higher with pioglitazone than with placebo, when added to therapy that included insulin. However, this did not lead to an increase in mortality in this study. In this study in patients receiving pioglitazone and insulin, a higher percentage of patients with heart failure was observed in patients aged ≥ 65 years compared with those less than

65 years (9.7% compared to 4.0%). In patients on insulin with no pioglitazone the incidence of heart failure was 8.2% in those ≥ 65 years compared to 4.0% in patients less than 65 years. Heart failure has been reported with marketing use of pioglitazone, and more frequently when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure (see section 4.4).

4 A pooled analysis was conducted of adverse reactions 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%) of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%) of female patients treated with comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%).
Post-marketing, bone fractures have been reported in both male and female patients (see section 4.4)

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

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

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

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Fluid retention and cardiac failure

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

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

Elderly

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

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

Bladder cancer

Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials with pioglitazone (19 cases from 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.

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%).

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).

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).

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

Pregnancy

There are no adequate human data to determine the safety of pioglitazone during pregnancy. 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.
The relevance of such a mechanism in humans is unclear and pioglitazone should not be used in pregnancy.

Breast-feeding

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, pioglitazone should not be administered to breast-feeding women.

Fertility

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

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

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.

5.
PHARMACOLOGICAL PROPERTIES

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

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

Fasting and postprandial glycaemic control is improved in patients with type 2 diabetes mellitus. The improved glycaemic control is associated with a reduction in both fasting and postprandial plasma insulin concentrations. A clinical trial of pioglitazone vs. gliclazide as monotherapy was extended to two years in order to assess time to treatment failure (defined as appearance of 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.

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