Piodiab®

Pioglitazone Hydrochloride
FORMS AND PRESENTATION triple oral therapy with a sulphonylurea or in dual therapy with insulin may be at risk for dose-related
Piodiab® 15: Tablets: Box of 30. hypoglycaemia, and a reduction in the dose of the sulphonylurea or insulin may be necessary.
Piodiab® 30: Tablets: Box of 30. Eye disorders: Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased
COMPOSITION: visual acuity have been reported with thiazolidinediones, including Pioglitazone. Many of these patients
Piodiab® 15: Each tablet contains: Pioglitazone Hydrochloride eq. to Pioglitazone 15 mg. reported concurrent peripheral oedema. It is unclear whether or not there is a direct association between
Piodiab® 30: Each tablet contains: Pioglitazone Hydrochloride eq. to Pioglitazone 30 mg. Pioglitazone and macular oedema but prescribers should be alert to the possibility of macular oedema if
Excipients: lactose, starch, croscarmellose sodium, povidone, magnesium stearate, colloidal silicone dioxide, patients report disturbances in visual acuity; an appropriate ophthalmological referral should be considered.
sodium starch glycolate. Others: An increased incidence in bone fractures in women was seen in a pooled analysis of adverse effects
PHARMACOLOGICAL PROPERTIES reports of bone fracture from randomised, controlled, double blind clinical trials in over 8100 Pioglitazone and
Pharmacodynamic Properties 7400 comparator treated patients, on treatment for up to 3.5 years.
Pioglitazone effects may be mediated by a reduction of insulin resistance. Pioglitazone appears to act via Fractures were observed in 2.6% of women taking Pioglitazone compared to 1.7% of women treated with a
activation of specific nuclear receptors (peroxisome proliferator activated receptor gamma) leading to comparator. No increase in fracture rates was observed in men treated with Pioglitazone (1.3%) versus
increased insulin sensitivity of liver, fat and skeletal muscle cells in animals. Treatment with Pioglitazone has comparator (1.5%).
been shown to reduce hepatic glucose output and to increase peripheral glucose disposal in the case of insulin The fracture incidence calculated was 1.9 fractures per 100 patient years in women treated with Pioglitazone
resistance. and 1.1 fractures per 100 patient years in women treated with a comparator. The observed excess risk of
Fasting and postprandial glycaemic control is improved in patients with type 2 diabetes mellitus. The improved fractures for women in this dataset on Pioglitazone is therefore 0.8 fractures per 100 patient years of use.
glycaemic control is associated with a reduction in both fasting and postprandial plasma insulin concentrations. In the 3.5 year cardiovascular risk PROactive study, 44/870 (5.1%; 1.0 fractures per 100 patient years) of
A clinical trial of Pioglitazone vs. gliclazide as monotherapy was extended to two years in order to assess time Pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures per 100
to treatment failure (defined as appearance of HbA1c ≥ 8.0% after the first six months of therapy). Kaplan-Mei- patient years) of female patients treated with comparator. No increase in fracture rates was observed in men
er analysis showed shorter time to treatment failure in patients treated with gliclazide, compared with treated with Pioglitazone (1.7%) versus comparator (2.1%).
Pioglitazone. At two years, glycaemic control (defined as HbA1c< 8.0%) was sustained in 69% of patients The risk of fractures should be considered in the long term care of women treated with Pioglitazone.
treated with Pioglitazone, compared with 50% of patients on gliclazide. In a two-year study of combination As a consequence of enhancing insulin action, Pioglitazone treatment in patients with polycystic ovarian
therapy comparing Pioglitazone with gliclazide when added to metformin, glycaemic control measured as syndrome may result in resumption of ovulation. These patients may be at risk of pregnancy. Patients should
mean change from baseline in HbA1c was similar between treatment groups after one year. The rate of be aware of the risk of pregnancy and if a patient wishes to become pregnant or if pregnancy occurs, the
deterioration of HbA1c during the second year was less with Pioglitazone than with gliclazide. treatment should be discontinued.
Pharmacokinetic Properties Pioglitazone should be used with caution during concomitant administration of cytochrome P450 2C8
Absorption: Following oral administration, Pioglitazone is rapidly absorbed, and peak plasma concentrations inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored closely.
of unchanged Pioglitazone are usually achieved 2 hrs after administration. Proportional increases of the plasma Pioglitazone dose adjustment within the recommended posology or changes in diabetic treatment should be
concentration were observed for doses from 2-60 mg. Steady state is achieved after 4-7 days of dosing. considered.
Repeated dosing does not result in accumulation of the compound or metabolites. Absorption is not influenced Piodiab tablets contain lactose monohydrate and therefore should not be administered to patients with rare
by food intake. Absolute bioavailability is greater than 80%. hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
Distribution: The estimated volume of distribution in humans is 0.25 l/kg. Ability to drive and use machines: No effects on ability to drive and use machines have been observed.
Pioglitazone and all active metabolites are extensively bound to plasma protein (> 99%). PREGNANCY AND LACTATION
Metabolism: Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic methylene There are no adequate human data to determine the safety of Pioglitazone during pregnancy. Foetal growth
groups. This is predominantly via cytochrome P450 2C8 although other isoforms may be involved to a lesser restriction was apparent in animal studies with Pioglitazone. This was attributable to the action of Pioglitazone
degree. Three of the six identified metabolites are active (M-II, M-III, and M-IV). When activity, in diminishing the maternal hyperinsulinaemia and increased insulin resistance that occurs during pregnancy
concentrations and protein binding are taken into account, Pioglitazone and metabolite M-III contribute thereby reducing the availability of metabolic substrates for foetal growth. The relevance of such a mechanism
equally to efficacy. On this basis M-IV contribution to efficacy is approximately three-fold that of Pioglitazone, in humans is unclear and Pioglitazone should not be used in pregnancy.
whilst the relative efficacy of M-II is minimal. Pioglitazone has been shown to be present in the milk of lactating rats. It is not known whether Pioglitazone is
In vitro studies have shown no evidence that Pioglitazone inhibits any subtype of cytochrome P450. There is secreted in human milk. Therefore, Pioglitazone should not be administered to breast-feeding women.
no induction of the main inducible P450 isoenzymes 1A, 2C8/9, and 3A4 in man. DRUG INTERACTIONS
Interaction studies have shown that Pioglitazone has no relevant effect on either the pharmacokinetics or 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 pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Co-administration of Pioglitazone
Pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) or with rifampicin (an inducer of with sulphonylureas does not appear to affect the pharmacokinetics of the sulphonylurea. Studies in man
cytochrome P450 2C8) is reported to increase or decrease, respectively, the plasma concentration of suggest no induction of the main inducible cytochrome P450, 1A, 2C8/9 and 3A4. In vitro studies have shown
Pioglitazone. no inhibition of any subtype of cytochrome P450. Interactions with substances metabolised by these enzymes,
Elimination: Following oral administration of radiolabelled Pioglitazone to man, recovered label was mainly e.g. oral contraceptives, cyclosporin, calcium channel blockers, and HMGCoA reductase inhibitors are not to
in faeces (55%) and a lesser amount in urine (45%). In animals, only a small amount of unchanged be expected.
Pioglitazone can be detected in either urine or faeces. The mean plasma elimination half-life of unchanged Co-administration of Pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) is reported to result
Pioglitazone in man is 5 to 6 hrs and for its total active metabolites 16 to 23 hrs. in a 3-fold increase in AUC of Pioglitazone. Since there is a potential for an increase in dose related adverse
Elderly: Steady state pharmacokinetics are similar in patients age 65 and over and young subjects. effects, a decrease in the dose of Pioglitazone may be needed when gemfibrozil is concomitantly administered.
Patients with renal impairment: In patients with renal impairment, plasma concentrations of Pioglitazone and Close monitoring of glycaemic control should be considered. Co-administration of Pioglitazone with
its metabolites are lower than those seen in subjects with normal renal function, but oral clearance of parent rifampicin (an inducer of cytochrome P450 2C8) is reported to result in a 54% decrease in AUC of
substance is similar. Thus free (unbound) Pioglitazone concentration is unchanged. Pioglitazone. The Pioglitazone dose may need to be increased when rifampicin is concomitantly administered.
Patients with hepatic impairment: Total plasma concentration of Pioglitazone is unchanged, but with an Close monitoring of glycaemic control should be considered.
increased volume of distribution. Intrinsic clearance is therefore reduced, coupled with a higher unbound ADVERSE EFFECTS
fraction of Pioglitazone. Adverse reactions reported in excess (> 0.5%) of placebo and as more than an isolated case in patients
INDICATIONS receiving Pioglitazone in double-blind studies are listed below as MedDRA preferred term by system organ
Piodiab® is indicated in the treatment of type 2 diabetes mellitus: class and absolute frequency. Frequencies are defined as: very common >1/10; common > 1/100, < 1/10;
As monotherapy: in patients (particularly overweight patients) inadequately controlled by diet and exercise for uncommon > 1/1000, < 1/100; rare > 1/10000, < 1/1000; very rare <1/10000; not known (cannot be estimated
whom metformin is inappropriate because of contraindications or intolerance. from the available data). Within each frequency grouping, undesirable effects are presented in order of
As dual oral therapy in combination with: decreasing seriousness.
- metformin, in patients (particularly overweight patients) with insufficient glycaemic control despite maximal Pioglitazone monotherapy:
tolerated dose of monotherapy with metformin. Eye disorders: Common: visual disturbance.
- a sulphonylurea, only in patients who show intolerance to metformin or for whom metformin is Infection and infestations: Common: upper respiratory tract infection; Uncommon: sinusitis.
contraindicated, with insufficient glycaemic control despite maximal tolerated dose of monotherapy with a Investigations: Common: weight increased.
sulphonylurea. Nervous system disorders: Common: hypoaesthesia; Uncommon: insomnia.
As triple oral therapy in combination with: metformin and a sulphonylurea, in patients (particularly overweight Pioglitazone in combination therapy with metformin:
patients) with insufficient glycaemic control despite dual oral therapy. Blood and lymphatic system disorders: Common: anaemia.
Piodiab® is also indicated for combination with insulin in type 2 diabetes mellitus patients with insufficient Eye disorders: Common: visual disturbance.
glycaemic control on insulin for whom metformin is inappropriate because of contraindications or intolerance. Gastrointestinal disorders: Uncommon: flatulence.
CONTRAINDICATIONS Investigations: Common: weight increased.
Pioglitazone is contraindicated in patients with: hypersensitivity to the active substance or to any of the Musculoskeletal system and connective tissue disorders: Common: arthralgia.
excipients, cardiac failure or history of cardiac failure (NYHA stages I to IV), hepatic impairment, diabetic Nervous system disorders: Common: headache.
ketoacidosis. Renal and urinary disorders: Common: haematuria.
PRECAUTIONS Reproductive system and breast disorders: Common: erectile dysfunction.
Elderly: Combination use with insulin should be considered with caution in the elderly because of increased Pioglitazone in combination therapy with sulphonylurea:
risk of serious heart failure. Ear and labyrinth disorders: Uncommon: vertigo.
In light of age- related risks (especially bladder cancer, fractures and heart failure), the balance of benefits and Eye disorders: Uncommon: visual disturbance.
risks should be considered carefully both before and during treatment in the elderly. Gastrointestinal disorders: Common: flatulence.
Bladder Cancer: Risk factors for bladder cancer should be assessed before initiating Pioglitazone treatment General disorders and administration site conditions: Uncommon: fatigue.
(risks include age, smoking history, exposure to some occupational or chemotherapy agents e.g. cyclophospha- Investigations: Common: weight increased; Uncommon: increased lactic dehydrogenase.
mide or prior radiation treatment in the pelvic region). Any macroscopic hematuria should be investigated Metabolism and nutritional disorders: Uncommon: appetite increased, hypoglycaemia.
before starting Pioglitazone therapy. Nervous system disorders: Common: dizziness; Uncommon: headache.
Patients should be advised to promptly seek the attention of their physician if macroscopic hematuria or other Renal and urinary disorders: Uncommon: glycosuria, proteinuria.
symptoms such as dysuria or urinary urgency develop during treatment. Skin and subcutaneous tissue disorders: Uncommon: sweating.
Fluid retention and cardiac failure: Pioglitazone can cause fluid retention, which may exacerbate or precipitate Pioglitazone in triple oral combination therapy with metformin and sulphonylurea:
heart failure. When treating patients who have at least one risk factor for development of congestive heart Investigations: Common: weight increased, blood creatine phosphokinase increased.
failure (e.g. prior myocardial infarction or symptomatic coronary artery disease), physicians should start with Metabolism and nutrition disorders: Very common: hypoglycaemia.
the lowest available dose and increase the dose gradually. Patients should be observed for signs and symptoms Musculoskeletal and connective tissue disorders: Common: arthralgia.
of heart failure, weight gain or oedema particularly those with reduced cardiac reserve. There have been cases Pioglitazone in combination therapy with insulin:
of cardiac failure reported from the market when Pioglitazone was used in combination with insulin or in Metabolism and nutrition disorders: Common: hypoglycaemia.
patients with a history of cardiac failure; patients should be observed for signs and symptoms of heart failure, General disorders and administration site conditions: Very common: oedema.
weight gain and oedema when Pioglitazone is used in combination with insulin. Since insulin and Pioglitazone Infections and infestations: Common: bronchitis.
are associated with fluid retention, concomitant administration may increase the risk of oedema. Pioglitazone Investigations: Common: weight increase.
should be discontinued if any deterioration in cardiac status occurs. Musculoskeletal system and connective tissue disorders: Common: back pain, arthralgia.
A cardiovascular outcome study of Pioglitazone has been performed in patients under 75 years with type 2 Respiratory, thoracic and mediastinal disorders: Common: dyspnoea.
diabetes mellitus and pre-existing major macrovascular disease. Pioglitazone or placebo was added to existing Cardiac disorders: Common: heart failure.
antidiabetic and cardiovascular therapy for up to 3.5 years. This study showed an increase in reports of heart DOSAGE AND ADMINISTRATION
failure, however this did not lead to an increase in mortality in this study. Caution should be exercised in Piodiab® tablets are taken orally once daily with or without food.
patients over 75 years because of the limited experience in this patient group. Piodiab® may be initiated at 15 mg or 30 mg once daily. The dose may be increased in increments up to 45 mg
Monitoring of liver function: There have been rare reports of hepatocellular dysfunction during post-marketing once daily. In combination with insulin, the current insulin dose can be continued upon initiation of Piodiab®
experience. It is recommended, therefore, that patients treated with Pioglitazone undergo periodic monitoring therapy. If patients report hypoglycaemia, the dose of insulin should be decreased.
of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy with Pioglitazone in all Elderly: No dosage adjustment is necessary for elderly patients.
patients. Therapy with Pioglitazone should not be initiated in patients with increased baseline liver enzyme Patients with renal impairment: No dosage adjustment is necessary in patients with impaired renal function
levels (ALT > 2.5 X upper limit of normal) or with any other evidence of liver disease. (Clcr > 4 ml/min). No information is available from dialysed patients therefore Piodiab® should not be used in
Following initiation of therapy with Pioglitazone, it is recommended that liver enzymes be monitored such patients.
periodically based on clinical judgement. If ALT levels are increased to 3 X upper limit of normal during Patients with hepatic impairment: Piodiab® should not be used in patients with hepatic impairment.
Pioglitazone therapy, liver enzyme levels should be reassessed as soon as possible. If ALT levels remain > 3 X Children and adolescents: There are no data available on the use of Piodiab® in patients under 18 years of age,
the upper limit of normal, therapy should be discontinued. If any patient develops symptoms suggesting and therefore its use is not recommended in this age group.
hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia OVERDOSAGE
and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy Patients have taken Pioglitazone at higher than the recommended highest dose of 45 mg daily. The maximum
with Pioglitazone should be guided by clinical judgement pending laboratory evaluations. If jaundice is reported dose of 120 mg/day for four days, then 180 mg/day for seven days was not associated with any
observed, drug therapy should be discontinued. symptoms. Hypoglycaemia may occur in combination with sulphonylureas or insulin. Symptomatic and
Weight gain: In clinical trials with Pioglitazone there was evidence of dose related weight gain, which may be general supportive measures should be taken in case of overdose.
due to fat accumulation and in some cases associated with fluid retention. In some cases weight increase may STORAGE CONDITIONS
be a symptom of cardiac failure, therefore weight should be closely monitored. Part of the treatment of diabetes Store below 30°C
is dietary control. Patients should be advised to adhere strictly to a calorie-controlled diet. Keep in original pack in intact conditions.
Haematology: There was a small reduction in mean haemoglobin (4% relative reduction) and haematocrit Date of revision: May 2015.
(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
PI039/4

patients in comparative controlled trials with Pioglitazone.