Full Prescribing Info
Pioglitazone HCl.
Oral hypoglycemic agent.
Pharmacology: Pharmacodynamics: Pioglitazone, a potent and highly selective peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is a thiazolidinedione oral antidiabetic agent that acts primarily by reducing insulin resistance. It improves glycemic control by increasing insulin sensitivity in target tissues, primarily skeletal muscle and adipose tissue, and by decreasing hepatic gluconeogenesis.
Activation of PPARγ nuclear receptors, which are found in key target tissues for insulin action (eg, adipose tissue, skeletal muscle, liver), modulates the transcription of insulin-responsive genes involved in the control of glucose and lipid metabolism.
Like other thiazolidinediones, pioglitazone minimizes the risk of hypoglycemia associated with the treatment of type 2 diabetes by decreasing insulin resistance without stimulating insulin release from pancreatic β-cells.
Pharmacokinetics: Pioglitazone is absorbed rapidly with peak plasma concentrations occurring within 2 hrs after oral administration (fasting state). Repeated dosing does not result in accumulation of pioglitazone or metabolites. Pioglitazone is >80% bioavailable. While food slightly delays pioglitazone's absorption, the extent of absorption is not altered.
Pioglitazone is >99% plasma protein-bound and its mean apparent volume of distribution after single-dose administration is about 0.63±0.41 L/kg bodyweight. Metabolites MIII and MIV are also extensively bound to serum albumin (>98%).
Pioglitazone is extensively metabolized by hydroxylation and oxidation through the cytochrome P-450 isoforms (mainly CYP2C8 and to a lesser degree CYP3A4, with additional contributions from other isoforms including the mainly extrahepatic CYP1A1); the metabolites are also partly converted to glucuronide or sulfate conjugates. M-II, M-III and M-IV are its pharmacologically active metabolites. Studies of pioglitazone in combination with P450 inhibitors and substrates have been performed and have shown that pioglitazone is not a strong CYP3A4 enzyme inducer.
Steady-state serum concentrations of both pioglitazone and total pioglitazone (pioglitazone plus active metabolites) are achieved within 7 days. At steady state, 2 of the pharmacologically active metabolites of pioglitazone, MIII and MIV, reach serum concentrations equal to or greater than pioglitazone. At steady state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30-50% of the peak total pioglitazone concentrations and 20-25% of the total area under the serum concentration-time-curve (AUC).
Peak plasma concentration (Cmax), AUC and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg/day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg/day.
Pioglitazone is primarily excreted through the bile as unchanged drug or as metabolites and eliminated in the feces. About 15-30% of an oral pioglitazone dose is recovered in the urine (as metabolites and its conjugates); its renal elimination is negligible. Pioglitazone’s plasma elimination t½ is up to 7 hrs while its active metabolites have a t½ of up to 24 hrs.
Special Populations: Renal Insufficiency: Compared with normal subjects, the serum elimination t½ of pioglitazone, M-III and M-IV remains unchanged in patients with moderate [creatinine clearance (CrCl) 30-60 mL/min] to severe (CrCl <30 mL/min) renal impairment.
Hepatic Insufficiency: Compared with normal subjects, patients with hepatic dysfunction (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak plasma concentrations and no change in the mean AUC values. Do not initiate the drug in patients who exhibit clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2.5 times the upper limit of normal.
Elderly: Peak serum concentrations of pioglitazone and total pioglitazone are not significantly different in healthy elderly subjects. However, the AUC values in these patients are slightly higher and the terminal t½ values slightly longer than for younger subjects. These changes are considered to be clinically irrelevant.
Treatment of type 2 diabetes mellitus as monotherapy in patients whose hyperglycemia cannot be controlled by diet and exercise alone, to decrease insulin-reisitance and blood glucose levels.
In combination with a sulfonylurea, metformin or insulin when adequate glycemic control is not achieved by diet, exercise and monotherapy.
Dosage/Direction for Use
Include nutritional counseling, weight reduction (as needed), and exercise in the management of type 2 diabetes.
Individualize antidiabetic therapy based on glycemic control and patient’s response to treatment.
Patients should be carefully monitored for adverse reactions related to fluid retention and signs of congestive heart failure after initiation of pioglitazone or with dose increase. (see Warnings and Precautions).
Liver enzymes should be checked prior to initiation of pioglitazone therapy (see Warnings and Precautions).
As adverse events eg, edema and weight gain appear to be dose-related, the smallest effective dose should be used.
During treatment initiation and dose titration, fasting plasma glucose should be used to determine the therapeutic response to pioglitazone HCl and identify the minimum effective dose. Thereafter, glycosylated hemoglobin (HbA1c) should be measured at intervals of approximately 3 months.
Monotherapy: Patients without Congestive Heart Failure: Starting Dose: 15 mg or 30 mg once daily, with or without meals.
Patients with NYHA Class I or II Heart Failure: Starting Dose: 15 mg once daily.
Dosage may be titrated in increments of 15 mg up to a maximum of 45 mg once daily based on glycemic response as determined by HbA1c.
Combination Therapy with Metformin: Pioglitazone in combination with metformin may be initiated at 15 mg or 30 mg once daily. Continue current metformin dose when starting pioglitazone therapy.
Combination Therapy with Sulfonylurea: Pioglitazone in combination with a sulfonylurea may be initiated at 15 mg or 30 mg once daily. Continue current sulfonylurea dose when starting pioglitazone therapy. Decrease the sulfonylurea dose if patients report hypoglycemia during combination therapy.
Combination with Insulin: Continue current insulin dose upon starting pioglitazone therapy. Decrease insulin dose by 10-25% if the patient reports hypoglycemia or if fasting plasma glucose (FPG) decreases to <100 mg/dL. Individualize further adjustments based on the glucose-lowering response.
Co-administration with Strong CYP2C8 Inhibitors (see Interactions): Maximum Recommended Dose: 15 mg once a day.
Missed Dose: When a dose is missed, pioglitazone should be taken as soon as the patient remembers. In cases where the time is too close to the next dose, the missed dose should be skipped and treatment should be resumed with the next scheduled dose.
There is limited data on pioglitazone overdosage in humans. Pioglitazone doses of up to 180 mg/day for 7 days have been taken without any clinical symptom. Hypoglycemia may occur in combination with sulfonylureas or insulin.
Initiate appropriate supportive treatment dictated by the patient's clinical signs and symptoms if overdose occurs.
Hypersensitivity to pioglitazone HCl or to any of the components of Piozone; patients with established New York Heart Association (NYHA) Class III or or IV heart failure; serious hepatic impairment; type 1 diabetes or diabetic ketoacidosis.
Use in pregnancy: Pregnancy Category C. Oral hypoglycemic agents (including pioglitazone) are not recommended during pregnancy. Although there are no adequate and well-controlled studies of pioglitazone in pregnant women, animal studies show increased rates of post-implantation loss, delayed development, reduced fetal weights, and delayed parturition at doses 10-40 times the maximum recommended human dose. Maintaining blood glucose levels as close to normal as possible is necessary during pregnancy since abnormal blood glucose levels are associated with a higher incidence of congenital abnormalities. Insulin is recommended during pregnancy.
Congestive Heart Failure: Thiazolidinediones, including pioglitazone, cause or exacerbate congestive heart failure in some patients (see Precautions). Monitor patients carefully for signs and symptoms of heart failure (eg, excessive, rapid weight gain, dyspnea, and/or edema) after initiation of pioglitazone and after dose increases. Manage heart failure according to current standards of care if these signs and symptoms develop. Consider discontinuation of pioglitazone or dose reduction.
Pioglitazone is not recommended in patients with symptomatic heart failure. Starting pioglitazone treatment in patients with established NYHA Class III or IV heart failure is contraindicated. (See Contraindications and Precautions.)
Special Precautions
Fluid Retention and Congestive Heart Failure: Like other thiazolidinediones, pioglitazone can cause fluid retention when used alone or in combination with other antidiabetic medicines and is most common when pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure.
Pioglitazone should be used with caution in patients with existing edema or heart failure. The incidence of heart failure increases in patients with a history of cardiac disease eg, coronary artery disease, previous coronary artery bypass graft procedures and myocardial infarction. Weight gain, usually dose-dependent and probably due to a combination of fluid retention and fat accumulation, has been reported with pioglitazone use. Patients who experience weight gain should be assessed for fluid accumulation and volume-related events eg, excessive edema and congestive heart failure.
Initiate pioglitazone therapy at the lowest approved dose when treating patients who have at least one risk factor for development of congestive heart failure. Monitor patients for signs and symptoms of heart failure and fluid retention. In particular, patients who are at risk for heart failure including those receiving concurrent therapy which increases insulin levels (ie, insulin, sulfonylureas) should be closely monitored (see Adverse Reactions).
Urinary Bladder Tumors: Do not use pioglitazone in patients with active bladder cancer. Use pioglitazone with caution in patients with prior history of bladder cancer. The benefits of blood sugar control with pioglitazone should be weighed against the unknown risk for cancer recurrence.
Results from a 5-year interim analysis of a 10-year observational cohort study showed a small increased risk of bladder cancer in diabetic patients treated with pioglitazone, in particular those who were treated for the longest durations and with the highest cumulative doses. The study suggest that the use of pioglitazone for >1 year increased the relative risk of developing bladder cancer in any given year by 40% (absolute risk of 3 cases in 10,000). Although there is insufficient evidence to determine whether pioglitazone promotes the development of urinary bladder tumors, pioglitazone should not be used in patients with active bladder cancer. In patients with a history of bladder cancer, the benefits of glycemic control versus unknown risks for cancer recurrence with pioglitazone should be considered.
Counsel patients to report any signs or symptoms of blood in the urine, urinary urgency, pain on urination, back or abdominal pain, as these may be due to bladder cancer.
Hepatic Effects: Therapy with pioglitazone should not be initiated in patients with increased baseline liver enzyme levels ie, ALT > 2.5 times the upper limit of normal (ULN), or active liver disease.
There have been post-marketing reports of fatal and nonfatal hepatic failure in patients taking pioglitazone. These reports, however, contain insufficient information necessary to establish the probable cause.
Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure (both of which may cause liver test abnormalities). These patients may also have other forms of liver disease many of which can be treated or managed. It is therefore recommended that prior to therapy with pioglitazone, a liver function test panel [ie, aspartate aminotransferase (AST), alanine aminotransfease (ALT), alkaline phosphatase, and total bilirubin] be obtained and patient be assessed for liver disease. Pioglitazone should be initiated with caution in patients with abnormal liver tests.
Measure liver tests promptly if manifestations suggestive of liver injury (eg, unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine or jaundice) develop in patients receiving pioglitazone. Discontinue pioglitazone therapy if ALT increases to >3 times the ULN during therapy and remains elevated, or if jaundice develops. Patients should be investigated and should not be restarted on pioglitazone without establishing the probable cause of the liver injury.
Do not restart pioglitazone in patients with serum ALT elevations >3 times the ULN and serum total bilirubin >2 times the reference range without alternative etiologies since they are at risk for severe drug-induced liver injury. Initiation of, or continuation of therapy with pioglitazone in patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, should proceed with caution.
Increased Risk of Fracture in Women: In clinical trials, there were more reports of fractures in female patients taking thiazolidinediones, including pioglitazone, than those taking a comparator (either placebo or active). The incidence of bone fracture in females was 5.1% for pioglitazone versus 2.5% for placebo. The difference was noted after the 1st year of treatment and remained during the course of the study. Majority of fractures observed in female patients were nonvertebral fractures including fractures in the distal upper limb (forearm, hand and wrist) or distal lower limb (foot, ankle, fibula, and tibia).
Consider the risk of fracture in the care of patients, especially female patients, being treated with pioglitazone or when starting pioglitazone treatment; attention should be given to assessing and monitoring bone health according to current standards of care.
Hypoglycemia: Use of pioglitazone in combination with insulin and antidiabetic medicines particularly insulin secretagogues eg, sulfonlyureas may increase the risk for hypoglycemia. Reduction in the dose of the concomitant antidiabetic medicine may be necessary.
Macular Edema: Macular edema, some with blurred vision or decreased visual acuity, has been reported in patients receiving pioglitazone or other thiazolidinediones. Most patients reported concurrent peripheral edema. In some patients, macular edema improved after discontinuation of thiazolidinedione treatment.
Although it is not known whether there is causal relationship between pioglitazone and macular edema, regular eye examination by an ophthalmologist is recommended for all diabetic patients. Promptly report and refer any visual symptom to an ophthalmologist.
Ovulation: Pioglitazone, like other thiazolidinediones, may cause ovulation in anovulatory premenoupausal women with insulin resistance. These women have an increased possibility of pregnancy unless contraceptive methods are initiated.
Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone or any other antidiabetic medicine. Pioglitazone should not be prescribed to lower the risk of cardiovascular diseases (ie, myocardial infarction and stroke) or to lower cardiovascular mortality.
Type 1 Diabetes Mellitus or Diabetic Ketoacidosis: Pioglitazone is active only in the presence of endogenous insulin and should therefore not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Hematologic: Pioglitazone may cause dose-related decreases in hemoglobin and hematocrit which usually become evident within the first 3 months of starting treatment. These hematologic effects may be related to plasma volume expansion.
Renal Impairment: There is no information available on the use of pioglitazone in dialysed patients. The use of pioglitazone is not recommended in these patients.
Use in lactation: It is not known whether pioglitazone is excreted in human milk although pioglitazone is secreted in the milk of lactating rats. Pioglitazone should not be administered to breastfeeding women.
Use in children: The safety and efficacy of pioglitazone in children have not been established. Use in patients <18 years old is not recommended.
Use in the elderly: There are no significant differences in the pharmacokinetics, efficacy and safety of pioglitazone between geriatric (≥65 years) and younger patients.
Use In Pregnancy & Lactation
Use in pregnancy: Pregnancy Category C. Oral hypoglycemic agents (including pioglitazone) are not recommended during pregnancy. Although there are no adequate and well-controlled studies of pioglitazone in pregnant women, animal studies show increased rates of post-implantation loss, delayed development, reduced fetal weights, and delayed parturition at doses 10-40 times the maximum recommended human dose. Maintaining blood glucose levels as close to normal as possible is necessary during pregnancy since abnormal blood glucose levels are associated with a higher incidence of congenital abnormalities. Insulin is recommended during pregnancy.
Use in lactation: It is not known whether pioglitazone is excreted in human milk although pioglitazone is secreted in the milk of lactating rats. Pioglitazone should not be administered to breastfeeding women.
Adverse Reactions
Respiratory Effects: Upper respiratory tract infection, dyspnea, sinusitis, bronchitis, pulmonary edema, and pharyngitis.
Endocrine Effects: Aggravated diabetes mellitus, erectile dysfunction.
Dose-related mild to moderate hypoglycemia has been reported when pioglitazone was used in combination with either a sulfonylurea or insulin.
Cardiovascular Effects: Congestive heart failure and edema/peripheral edema have been reported especially when pioglitazone is used in combination with insulin.
Cardiac failure, heart failure, chest pain, abnormal electrocardiogram (ECG), hypertension, ischemia, angina pectoris, myocardial infarction, myocardial ischemia and transient ischemic attacks. Heart rate and rhythm disorders have also been reported.
Central Nervous System Effects: Headache, hypoesthesia, vertigo, dizziness, and insomnia.
Musculoskeletal Effects: Arthralgia, myalgia, back pain, and cramps (legs). Increased risk of fractures in female patients taking pioglitazone has been reported (see Warnings and Precautions).
Hepatic Effects: Fatal and nonfatal hepatic failure and hepatitis have been reported. During all clinical trials in the US, 11 of 2561 (0.43%) patients treated with pioglitazone had ALT values ≥3 ULN. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with pioglitazone, mean values for bilirubin, AST, ALT, alkaline phosphatase, and gamma-glutamyl transferase (GGT) were decreased at the final visit compared with baseline. Sporadic, transient elevations in creatine phosphokinase (CPK) levels have also occurred.
Hematologic Effects: Anemia has been reported in patients taking pioglitazone in combination with sulfonylureas, metformin or insulin.
Dose-related decreases in hemoglobin and hematocrit have been associated with pioglitazone use.
Renal Effects: Urinary tract infection, hematuria, glycosuria, and proteinuria.
Gastrointestinal Effects: Flatulence, increased appetite and diarrhea.
Eye Disorders: New onset or worsening diabetic macular edema with decreased visual acuity has been reported.
Tumors: Urinary bladder tumors (rare).
Others: Tooth disorder, accidental injury, fatigue, sweating, pain in extremity, weight gain, increased lactic dehydrogenase levels.
Drug Interactions
Oral Contraceptives: Co-administration of pioglitazone (45 mg once daily) and an oral contraceptive (norethindrone 1 mg plus ethinyl estradiol 0.035 mg once daily) resulted in 11% and 11-14% decrease in ethinyl estradiol AUC and Cmax, respectively. Clinical significance of a high variability on ethinyl estradiol pharmacokinetics is unknown.
Insulin or Insulin Secretagogues: The dose of insulin and insulin secretagogues (eg, sulfonylurea) should be reduced since concomitant administration may result in hypoglycemia.
Midazolam: Administration of pioglitazone for 15 days followed by a 7.5 mg single dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC.
Strong CYP2C8 Inhibitors: Gemfibrozil (an inhibitor of CYP450 2C8) resulted in a 3-fold increase in the plasma concentration of parent pioglitazone and also inhibited the further metabolism of M-III and M-IV. Careful blood glucose monitoring and dosage adjustments are suggested during co-administration of pioglitazone and gemfibrozil. If used in combination with gemfibrozil or other strong CYP2C8 inhibitors, a maximum dose of pioglitazone 15 mg should be used.
CYP2C8 Inducers: Co-administration of pioglitazone with rifampicin (an inducer of CYP450 2C8) resulted in a 54% reduction in pioglitazone's AUC. The dose of pioglitazone may need to be increased when rifampicin is co-administered and glycemic control closely monitored.
If an inducer of CYP2C8 is started or stopped during treatment with pioglitazone, the maximum recommended dose of 45 mg should not be exceeded and changes in diabetes treatment may be needed based on the patient's clinical response.
Drugs Metabolized via Cytochrome P-450: The cytochrome P-450 isoform, CYP3A4, is partially responsible for the metabolism of pioglitazone. Potential pharmacokinetic interaction (reduction in Cmax and AUC) with CYP3A4 substrates (eg, atorvastatin, nifedipine). Clinical significance of this finding is unknown.
Peak plasma concentration and area under the AUC of pioglitazone may increase when taken concomitantly with CYP3A4 inhibitors eg, ketoconazole. However, pharmacokinetic interaction is unlikely with ranitidine which is a relatively weak CYP3A4 inhibitor.
In vitro studies have shown no inhibition of any subtype of cytochrome P-450. Interactions with substances metabolized by these enzymes are unlikely: Ciclosporin, calcium channel blockers, and HMGCoA reductase inhibitors.
Co-administration of pioglitazone with the following drugs did not show pharmacokinetic interactions: Metformin, glipizide, digoxin, phenprocoumon, fexofenadine, CYP2C9 substrates (eg, warfarin), CYP1A2 substrates (eg, theophylline).
Store at temperatures not exceeding 30°C.
MIMS Class
Antidiabetic Agents
ATC Classification
A10BG03 - pioglitazone ; Belongs to the class of thiazolidinediones. Used in the treatment of diabetes.
Tab 15 mg (white to off-white, 3/16" round, biconvex, plain on both sides) x 30's. 30 mg (white, 9/32" round, flat, bisected on one side and plain on the other) x 30's.
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