Pioglitazone Mylan 15mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Pioglitazone Mylan 15 mg tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 15 mg of pioglitazone as hydrochloride. Excipient with known effect:
Each 15 mg tablet contains 49.17 mg of lactose monohydrate For the full list of excipients, see 6.1.
3 PHARMACEUTICAL FORM
Tablet.
White to off-white, round biconvex, uncoated tablet, debossed with “PG” over “15” on one side and “G”on the other side.
Dimensions: “6 mm ± 0.3 mm round”
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Pioglitazone is indicated as second or third line in the treatment of type 2 diabetes mellitus as described below:
- in adult patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin is inappropriate because of contraindications or intolerance
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).
4.2 Posology and method of administration
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.
Elderly patients
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).
Patients with 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.
Patients with hepatic impairment
Pioglitazone should not be used in patients with hepatic impairment (see section 4.3 and 4.4).
Paediatric population
The safety and efficacy of pioglitazone in children and adolescents under 18 years of age have not been established. No data are available.
Method of administration For oral use.
Pioglitazone tablets are taken orally once daily with or without food. Tablets should be swallowed with a glass of water.
4.3 Contraindications
- 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
4.4 Special warnings and precautions for use
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 non-steroidal 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 patients:
Combination use with insulin should be considered with caution in the elderly because of increased risk of serious heart failure.
In light of age-related risks (especially bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully both before and during treatment in the elderly.
Bladder Cancer:
Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials with pioglitazone (19 cases from 12506 patients, 0.15%) than in control groups (7 cases from 10212 patients, 0.07%) HR=2.64 (95% CI 1.11-6.31, P=0.029). After excluding patients in whom exposure to study medicinal product was less than one year at the time of diagnosis of bladder cancer, there were 7 cases (0.06%) on pioglitazone and 2 cases (0.02%) in control groups. Available epidemiological data also suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone in particular in patients treated for the longest durations and with the highest cumulative doses. A possible risk after short term treatment cannot be excluded.
Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment (risks include age, smoking history, exposure to some occupational or chemotherapy agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuria should be investigated before starting pioglitazone therapy.
Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment.
Monitoring of liver function
There have been rare reports of hepatocellular dysfunction during post-marketing experience (see section 4.8). It is recommended, therefore, that patients treated with pioglitazone undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy with pioglitazone in all patients. Therapy with pioglitazone should not be initiated in patients with increased baseline liver enzyme levels (ALT > 2.5 X upper limit of normal) or with any other evidence of liver disease.
Following initiation of therapy with pioglitazone, it is recommended that liver enzymes be monitored periodically based on clinical judgement. If ALT levels are increased to 3 X upper limit of normal during pioglitazone therapy, liver enzyme levels should be reassessed as soon as possible. If ALT levels remain > 3 X the upper limit of normal, therapy should be discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with pioglitazone should be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, the medicinal product should be discontinued.
Weight gain
In clinical trials with pioglitazone there was evidence of dose related weight gain, which may be due to fat accumulation and in some cases associated with fluid retention. In some cases weight increase may be a symptom of cardiac failure, therefore weight should be closely monitored. Part of the treatment of diabetes is dietary control. Patients should be advised to adhere strictly to a calorie-controlled diet.
Haematology
There was a small reduction in mean haemoglobin (4% relative reduction) and haematocrit (4.1% relative reduction) during therapy with pioglitazone, consistent with haemodilution. Similar changes were seen in metformin (haemoglobin 3 - 4% and haematocrit 3.6 - 4.1% relative reductions) and to a lesser extent sulfonylurea 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 sulfonylurea or in dual therapy with insulin may be at risk for dose-related hypoglycaemia, and a reduction in the dose of the sulfonylurea or insulin may be necessary.
Eye disorders
Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual acuity have been reported with thiazolidinediones, including pioglitazone. Many of these patients reported concurrent peripheral oedema. It is unclear whether or not there is a direct association between pioglitazone and macular oedema but prescribers should be alert to the possibility of macular oedema if patients report disturbances in visual acuity; an appropriate ophthalmological referral should be considered.
Others
An increased incidence in bone fractures in women was seen in a pooled analysis of adverse reactions of bone fracture from randomised, controlled, double blind clinical trials in over 8100 pioglitazone and 7400 comparator treated patients, on treatment for up to 3.5 years.
Fractures were observed in 2.6% of women taking pioglitazone compared to 1.7% of women treated with a comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).
The fracture incidence calculated was 1.9 fractures per 100 patient years in women treated with pioglitazone and 1.1 fractures per 100 patient years in women treated with a comparator. The observed excess risk of fractures for women in this dataset on pioglitazone is therefore 0.8 fractures per 100 patient years of use.
In the 3.5 year cardiovascular risk PROactive study, 44/870 (5.1%; 1.0 fractures per 100 patient years) of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures per 100 patient years) of female patients treated with comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%).
Some epidemiological studies have suggested a similarly increased risk of fracture in both men and women.
The risk of fractures should be considered in the long term care of patients treated with pioglitazone.
As a consequence of enhancing insulin action, pioglitazone treatment in patients with polycystic ovarian syndrome may result in resumption of ovulation. These patients may be at risk of pregnancy. Patients should be aware of the risk of pregnancy and if a patient wishes to become pregnant or if pregnancy occurs, the treatment should be discontinued (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).
Pioglitazone Mylan contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
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 sulfonylureas does not appear to affect the pharmacokinetics of the sulfonylurea. 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).
4.6 Pregnancy and lactation
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.
4.7 Effects on ability to drive and use machines
Pioglitazone Mylan 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.
4.8 Undesirable effects
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 frequency grouping, undesirable effects are presented in order of decreasing incidence and seriousness.
|
Adverse reaction |
Frequency of adverse reactions of pioglitazone by treatment regimen | ||||
|
Mono therapy |
Combination | ||||
|
with metformin |
with sulfonylurea |
with metformin and sulfonylurea |
with insulin | ||
|
Infections and infestations | |||||
|
upper respiratory tract infection |
common |
common |
common |
common |
common |
|
bronchitis |
common | ||||
|
sinusitis |
uncommon |
uncommon |
uncommon |
uncommon |
uncommon |
|
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 disturbance1 |
common |
common |
uncommon | ||
|
macular oedema2 |
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 sulfonylurea |
With metformin and sulfonylurea |
With insulin | ||
|
Musculoskeletal and connective tissue disorders | |||||
|
fracture bone5 |
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 | |||||
|
oedema |
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 increased4 |
not known |
not known |
not known |
not known |
not known |
Description of selected adverse reactions
1 Post-marketing reports of hypersensitivity reactions in patients treated with pioglitazone have been reported. These reactions include anaphylaxis, angioedema, and urticaria. 1 2 3
3 Oedema was reported in 6 - 9 % of patients treated with pioglitazone over one year in controlled clinical trials. The oedema rates for comparator groups (sulfonylurea, metformin) were 2 - 5 %. The reports of oedema were generally mild to moderate and usually did not require discontinuation of treatment.
4 In controlled clinical trials the incidence of reports of heart failure with pioglitazone treatment was the same as in placebo, metformin and sulfonylurea 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.
5 A pooled analysis was conducted of adverse reactions of bone fractures from randomised, comparator controlled, double blind clinical trials in over 8100 patients in the pioglitazone-treated groups and 7400 in the comparator-treated groups of up to 3.5 years duration. A higher rate of fractures was observed in women taking pioglitazone (2.6%) versus comparator (1.7%). No increase in fracture rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).
In the 3.5 year PROactive study, 44/870 (5.1%) of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%) of female patients treated with comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%).
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 sulfonylurea 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 sulfonylurea of 2.8 kg. In comparator groups addition of sulfonylurea to metformin resulted in a mean weight gain of 1.3 kg and addition of metformin to a sulfonylurea a mean weight loss of 1.0 kg. 4
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 sulfonylureas or insulin. Symptomatic and general supportive measures should be taken in case of overdose.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins; Thiazolidinediones; ATC code: A10BG03.
Mechanism of action
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.
Clinical efficacy and safety
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, 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 sulfonylurea. To be eligible patients had to have had one or more of the following: myocardial infarction, stroke, percutaneous cardiac intervention or coronary artery bypass graft, acute coronary syndrome, coronary artery disease, or peripheral arterial obstructive disease. Almost half of the patients had a previous myocardial infarction and approximately 20% had had a stroke. Approximately half of the study population had at least two of the cardiovascular history entry criteria. Almost all subjects (95%) were receiving cardiovascular medicinal products (beta blockers, ACE inhibitors, angiotensin II antagonists, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates).
Although the study failed regarding its primary endpoint, which was a composite of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, major leg amputation, coronary revascularisation and leg revascularisation, the results suggest that there are no long-term cardiovascular concerns regarding use of pioglitazone. However, the incidences of oedema, weight gain and heart failure were increased. No increase in mortality from heart failure was observed.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with the reference medicinal product containing pioglitazone 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
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.
Elderly patients
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.
5.3 Preclinical safety data
In toxicology studies, plasma volume expansion with haemodilution, anaemia, and reversible eccentric cardiac hypertrophy was consistently apparent after repeated dosing of mice, rats, dogs, and monkeys. In addition, increased fatty deposition and infiltration were observed. These findings were observed across species at plasma concentrations < 4 times the clinical exposure. Foetal growth restriction was apparent in animal studies with pioglitazone. This was attributable to the action of pioglitazone in diminishing the maternal hyperinsulinaemia and increased insulin resistance that occurs during pregnancy thereby reducing the availability of metabolic substrates for foetal growth.
Pioglitazone was devoid of genotoxic potential in a comprehensive battery of in vivo and in vitro genotoxicity assays. An increased incidence of hyperplasia (males and females) and tumours (males) of the urinary bladder epithelium was apparent in rats treated with pioglitazone for up to 2 years.
The formation and presence of urinary calculi with subsequent irritation and hyperplasia was postulated as the mechanistic basis for the observed tumourigenic response in the male rat. A 24-month mechanistic study in male rats demonstrated that administration of pioglitazone resulted in an increased incidence of hyperplastic changes in the bladder. Dietary acidification significantly decreased but did not abolish the incidence of tumours. The presence of microcrystals exacerbated the hyperplastic response but was not considered to be the primary cause of hyperplastic changes. The relevance to humans of the tumourigenic findings in the male rat cannot be excluded.
There was no tumorigenic response in mice of either sex. Hyperplasia of the urinary bladder was not seen in dogs or monkeys treated with pioglitazone for up to 12 months.
In an animal model of familial adenomatous polyposis (FAP), treatment with two other thiazolidinediones increased tumour multiplicity in the colon. The relevance of this finding is unknown.
Environmental Risk Assessment (ERA):
No environmental impact is anticipated from the clinical use of pioglitazone.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate Hypromellose (E464) Silica, colloidal anhydrous Croscarmellose sodium Polysorbate 80 (E433) Magnesium stearate
6.2 Incompatibilities
Not applicable
3 years
Bottles: Use within 90 days of opening.
6.4 Special precautions for storage
Blisters: This medicinal product does not require any special storage conditions. Bottles: Once open keep the bottle tightly closed in order to protect from moisture.
6.5 Nature and contents of container
Cold form blister packs comprising of cold form laminate (aluminium foil laminated to oriented polyamide on one side and to PVC on the other side i.e. OPA/Al/PVC) on one side and hard tempered aluminium foil coated with heat seal lacquer on the other side containing 10, 14, 28, 30, 56, 84, 90, 98 tablets.
HDPE bottle packs (marketable pack) comprising of white colored HDPE bottle with white opaque polypropylene closure with aluminium induction sealing liner and desiccant containing 500 tablets (hospital pack).
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Generics [UK] t/a Mylan
Station Close, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 04569/1245
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
01/03/2012
10 DATE OF REVISION OF THE TEXT
08/06/2015
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.
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 sulfonylurea 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 Yellow Card Scheme at www.mhra.gov .uk/yellowcard.