(BANM, US Adopted Name, rINNM)
Drug Nomenclature
International Nonproprietary Names (INNs) in main languages:
Adverse Effects and Precautions
As for Rosiglitazone Maleate. The effects of pioglitazone on serum lipid concentrations appear to differ from those of rosiglitazone, see below. Other adverse effects reported include upper respiratory-tract infections, haematuria, and visual disturbances. Liver function should be monitored periodically as there have been isolated reports of liver dysfunction, and the drug should be used with caution in patients with hepatic impairment (see below).
An increased incidence of bladder cancer has been seen in rats but not in mice treated with pioglitazone. Use is contra-indicated in patients with diabetic ketoacidosis. For precautions and contra-indications to the use of thiazolidinediones in heart failure see Effects on the Heart, under Rosiglitazone Maleate.
Effects on lipids. Thiazolidinediones are reported to affect serum concentrations of lipids. Compared with placebo, pioglitazone has been found to reduce triglycerides, increase high-density lipoprotein (HDL)-cholesterol, and have little or no effect on low-density lipoprotein (LDL)- and total cholesterol. In a studyof patients being transferred from troglitazone to either pioglitazone or rosiglitazone, there were decreases in concentrations of triglycerides, LDL- and total cholesterol, and an increase in HDL-cholesterol in those patients on pioglitazone, whereas the opposite occurred for rosiglitazone. Whether these effects of pioglitazone reduce cardiovascular risk in patients with type 2 diabetes is yet to be fully established, but the large prospective PROactive study did suggest that it could reduce the risk of mac-rovascular events in patients with evidence of macrovascular disease, although the risk of heart failure appears to be increased (see Diabetic Complications, below, and Effects on the Heart, under Rosiglitazone Maleate).
Effects on the liver. There have been isolated reports of hepatocellular injury in patients receiving pioglitazone.The UK and US licensed product information recommends that liver enzymes should be checked before starting therapy with pioglitazone patients with aminotransferase (ALT) concentrations more than 2.5 times the upper limit of normal should not be given pioglitazone. ALT concentrations should then be monitored periodically during treatment. If ALT concentrations rise to more than 3 times the upper limit of normal and remain so after retesting then treatment with pioglitazone should be stopped treatment should also be stopped if jaundice develops.
Interactions
When pioglitazone was given with gemfibrozil, an inhibitor of the cytochrome P450 isoenzyme CYP2C8, there was a threefold increase in the area under the concentration-time curve (AUC) of pioglitazone, and a decrease in pioglitazone dose may be needed if it is given with gemfibrozil or similar CYP2C8 inhibitors. Equally, rifampicin, a potent inducer of cytochrome P450, halves the AUC of pioglitazone when both are given, and pioglitazone dose may need to be increased.
Antibacterials. For a report of hypoglycaemia when gatifloxacin was given to a patient already receiving oral hypoglycaemics such as pioglitazone.
Pharmacokinetics
Pioglitazone is rapidly absorbed after oral doses. Peak plasma concentrations occur within 2 hours and bioavailability exceeds 80%. Pioglitazone is more than 99% bound to plasma proteins. It is extensively metabolised, primarily by the cytochrome P450 isoenzyme CYP2C8 to both active and inactive metabolites. It is excreted in urine and faeces and has a plasma half-life of up to 7 hours. The active metabolites have a half-life of up to 24 hours.
Uses and Administration
Pioglitazone is a thiazolidinedione oral antidiabetic similar to rosiglitazone. It is used in the management of type 2 diabetes mellitus. It is given as pioglitazone hydrochloride but doses are expressed in terms of the base pioglitazone hydrochloride 1.1 mg is equivalent to about 1 mg of pioglitazone. It is given orally as monotherapy, particularly in patients who are overweight and for whom metformin is contra-indicated or not tolerated. Pioglitazone may also be added to metformin or a sulfonylurea or both, or to insulin, when single-agent therapy is inadequate (but see Administration, below). The usual dose is 15 or 30 mg once daily. This may be increased to a maximum of 45 mg once daily if necessary. Pioglitazone may be taken with or without food.
Administration. Although pioglitazone is licensed for use with other antidiabetic drugs, the specifics of licensing and use may vary from country to country. In the UK, use of pioglitazone with insulin was originally considered to be contra-indicated, because of an increased risk of heart failure, although this was subsequently amended to permit dual therapy in patients who could not be given insulin plus metformin. Furthermore, although pioglitazone is licensed for use with metformin or a sulfonylurea (or both if necessary) in patients who do not respond to these drugs, NICE recommends this only in patients unsuited to combination therapy with metformin plus a sulfonylurea. However, in the USA, pioglitazone has always been licensed for use with insulin (with appropriate monitoring), metformin, or a sulfonylurea in any patient in whom single agent therapy is inadequate.
Diabetic complications. It has been suggested that, in addition to their hypoglycaemic effect, thiazolidinediones may have beneficial effects in the prevention of macrovascular diabetic complications. Studies in patients with type 2 diabetes mellitus have shown that pioglitazone may slow the progression of carotid intima-media thickness, an indicator for cardiovascular risk. A study of secondary prevention found that, compared with placebo (in addition to usual medications for glucose control), pioglitazone reduced death from any cause, myocardial infarction, and stroke. There was also a reduced need to add insulin for glucose control. However, there was no significant difference between the groups when the end-point was broader and also included acute coronary syndrome, leg amputation, and coronary or leg revascularisation. Subgroup analysis also found that pioglitazone reduced the risk of fatal and non-fatal myocardial infarction and acute coronary syndrome in patients with a history of myocardial infarction. A meta-analysis that included the results of this study with cardiovascular outcome data from studies of glycaemic control found that pioglitazone significantly reduced the risk of death, myocardial infarction, and stroke in a diverse population of patients with type 2 diabetes. However, the risk of serious heart failure was increased (see also Effects on the Heart).
It is unclear whether other thiazolidinediones might have similar effects and whether patients at lower risk might benefit. Rosiglitazone and pioglitazone are known to have different effects on lipids (above) and there is some evidence that rosiglitazone may have adverse cardiovascular effects.
Hepatitis. A small proof-of-concept study has suggested that pioglitazone 45 mg daily with a hypocaloric diet for 6 months produces greater metabolic and histological improvement in patients with nonalcoholic steatohepatitis than diet alone.
Malignant neoplasms. For references to the experimental use of pioglitazone with rofecoxib and trofosfamide as anti-ang-iogenic therapy for malignant neoplasms see Trofosfamide.
Psoriasis. It has been suggested that by binding to peroxisome proliferator-activated receptor gamma, pioglitazone may have an anti-rnflarnmatory effect in conditions such as chronic plaque psoriasis and psoriatic arthritis (see Spondyloarthropathies). In a small open-label study, oral doses of 30 mg daily were reported to improve moderate chronic plaque psoriasis in 4 of 5 patients, with definite improvement seen 1 to 3 months after starting therapy. Treatment was stopped in 1 other patient because of fluid retention. In a double-blind study, 70 patients with moderate to severe disease were treated for 10 weeks with daily doses of pioglitazone 15 mg, 30 mg, or placebo. Greater improvements were reported with pioglitazone than with placebo, and the dose of 30 mg appeared to be slightly more effective than 15 mg. There has also been a report of improvements in tender and swollen joints in a small group of patients with psoriatic arthritis who were given a high dose of pioglitazone (30 mg twice daily) for 12 weeks. Fluid retention was also reported.
Preparations
Proprietary Preparations
Argentina: Actos Cereluc Higlucem Pioglit Piotamax
Australia: Actos
Austria: Actos
Belgium: Actos
Brazil: Actos
Canada: Actos
Chile: Actosf Diabestat Tiazac
Czech Republic: Actos Glustin
Denmark: Actos
Finland: Actos
France: Actos
Germany: Actos
Greece: Actos
Hong Kong: Actos
India: Diaglit G-Tase Glita Glizone Opam P-Glitz Pepar Piomed Piosafe Piozulin
Indonesia: Actos Deculin
Italy: Actos
Japan: Actos
Malaysia: Actos
Mexico: Zactos
The Netherlands: Actos Glustin
Norway: Actos
New Zealand: Actos
Philippines: Actos Prialta Zypi
Portugal: Actos Glustin
Russia: Actos
South Africa: Actos
Spain: Actos
Sweden: Actos
Switzerland: Actos
Thailand: Actos
UK: Actos
USA: Actos
Multi-ingredient
Czech Republic: Competact Glubrava Tandemact
France: Competact Tandemact
India: Exermet P P-Glitz M Piomed M Piosafe M †
Portugal: Competact Tandemact
UK: Competact
USA: Actoplus Met Duetact