Pioglitazone Hcl Drug Information

Pioglitazone and metformin hydrochloride tablets, are a combination of pioglitazone, a thiazolidinedione agonist of peroxisome proliferator receptor gamma, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use: Not recommended for treatment of type 1 diabetes or diabetic ketoacidosis. Limitations of Use Pioglitazone and metformin hydrochloride tablets are not recommended to treat type 1 diabetes mellitus or diabetic ketoacidosis.

Important Dosage and Administration Information •

Obtain liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) prior to initiating pioglitazone and metformin hydrochloride tablets. • Pioglitazone and metformin hydrochloride tablets contains 15 mg of pioglitazone and 500 mg of metformin hydrochloride (HCl) and 15 mg of pioglitazone and 850 mg of metformin hydrochloride (HCl) in each tablet. • Take pioglitazone and metformin hydrochloride tablets with meals to reduce gastrointestinal adverse reactions with metformin. • If a dose is missed, do not double the next dose.

Recommended Dosage and Administration Recommended Starting Dosage Based on Current Regimen Individualize the starting dosage of pioglitazone and metformin hydrochloride tablets based on the patient's current regimen and the available strength of pioglitazone and metformin hydrochloride tablets (see Table 1). Table 1: Recommended Starting Dosage Based on the Patient’s *For dosage recommendations for patients with renal impairment and/or congestive heart failure, see Dosage and Administration Dosage Titration for Additional Glycemic Control Titrate the pioglitazone and metformin hydrochloride tablets dosage gradually, as needed, after assessing therapeutic response and tolerability. Pioglitazone and metformin hydrochloride tablets may be increased to a maximum recommended total daily dosage of three tablets per day (45 mg of pioglitazone and 2,550 mg of metformin HCl).

Total daily dosages of 2,550 mg of metformin HCl may be taken in divided doses three times a day to reduce gastrointestinal adverse reactions.

Recommendations for Use in Patients with Renal Impairment •

Assess renal function prior to initiation of pioglitazone and metformin hydrochloride tablets and periodically thereafter. • Pioglitazone and metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min. • Initiation of pioglitazone and metformin hydrochloride tablets in patients with an eGFR between 30 to 45 mL/min is not recommended. • In patients taking pioglitazone and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min, assess the benefit and risk of continuing therapy. • Discontinue pioglitazone and metformin hydrochloride tablets if the patient’s eGFR later falls below 30 mL/min.

Recommendations for Congestive Heart Failure Starting Dosage in Patients with NYHA Class I or II Congestive Heart Failure For patients with preexisting NYHA Class I or II congestive heart failure, the recommended starting dosage of pioglitazone and metformin hydrochloride tablets is 15 mg of pioglitazone and 850 mg of metformin. Monitoring for Fluid Retention and Dosage Modifications for Congestive Heart Failure After initiation of pioglitazone and metformin hydrochloride tablets or with dosage increase, monitor patients carefully for adverse reactions related to fluid retention as has been seen with pioglitazone (e.g., weight gain, edema and signs and symptoms of congestive heart failure). If congestive heart failure develops while taking pioglitazone and metformin hydrochloride tablets, consider discontinuation of pioglitazone and metformin hydrochloride tablets or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride tablets.

Coadministration with Strong CYP2C8 Inhibitors

The maximum recommended dosage of pioglitazone and metformin hydrochloride tablet is one tablet (15 mg of pioglitazone and 850 mg of metformin HCl) once daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors.

Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue pioglitazone and metformin hydrochloride tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart pioglitazone and metformin hydrochloride tablets if renal function is stable.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pioglitazone Over 8,500 patients with type 2 diabetes mellitus have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2,605 patients with type 2 diabetes mellitus and macrovascular disease treated with pioglitazone from the PROactive clinical trial. In these trials, over 6,000 patients have been treated with pioglitazone for six months or longer, over 4,500 patients have been treated with pioglitazone for one year or longer, and over 3,000 patients have been treated with pioglitazone for at least two years.

The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with pioglitazone than with placebo (3.0%). In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with pioglitazone and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with pioglitazone and 0.6% of patients treated with placebo.

Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo. None of these adverse events were related to the pioglitazone dose. Table 2: Three Pooled 16 to 26 Week Placebo-Controlled Clinical Trials of Pioglitazone Monotherapy: Adverse Events Reported at an Incidence >5% and More Commonly in Patients Treated with Common Adverse Events: 16 to 24 Week Add-on Combination Therapy Trials A summary of the overall incidence and types of common adverse events reported in trials of pioglitazone add-on to metformin is provided in Table 3.

Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of pioglitazone. Table 3: 16 to 24 Week Clinical Trials of Note: The preferred terms of edema peripheral, generalized edema, pitting edema, and fluid retention were combined to form the aggregate term of "edema." Common Adverse Events: 24 Week Pioglitazone and Metformin Hydrochloride Tablets Clinical Trial Table 4 summarizes the incidence and types of adverse reactions reported in a controlled, 24 week double-blind clinical trial of pioglitazone and metformin hydrochloride tablets dosed twice daily in patients with inadequate glycemic control on diet and exercise (N=600). Table 4: Adverse Events (≥5% for Pioglitazone and Metformin Hydrochloride Tablets) Reported by Patients with Inadequate Glycemic Control on Diet and Exercise in a 24 Week Double-Blind Clinical Trial of Pioglitazone and Metformin Hydrochloride Tablets Administered Twice Daily In this 24 week trial, abdominal pain was reported in 2.0% of patients in the pioglitazone and metformin hydrochloride group, 1.6% in the pioglitazone monotherapy group and 3.3% in the metformin monotherapy group.

Common Adverse Events: PROactive Trial A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 5. Table 5: PROactive Trial: Incidence and Types of Adverse Events Reported in >5 Mean duration of patient follow-up was 34.5 months. Congestive Heart Failure A summary of the incidence of adverse events related to congestive heart failure is provided in Table 6 for the 16 to 24 week add-on to metformin trials.

None of the events were fatal. Table 6: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) Table 7: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) Table 8: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in Patients with NYHA Class II or III Congestive Heart Failure Treated with Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 9. Table 9: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in PROactive Trial Cardiovascular Safety In the PROactive trial, 5,238 patients with type 2 diabetes mellitus and a history of macrovascular disease were randomized to pioglitazone (N=2,605), force-­titrated up to 45 mg daily or placebo (N=2,633) in addition to standard of care.

Almost all patients (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins, and fibrates). At baseline, patients had a mean age of 62 years, mean duration of diabetes of 9.5 years, and mean HbA1c of 8.1%. The primary objective of this trial was to examine the effect of pioglitazone on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events.

The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, nonfatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass surgery or revascularization in the leg. Although there was no statistically significant difference between pioglitazone and placebo for the three year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with pioglitazone. The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 10.

Table 10:PROactive Trial: Number of First and Total Events for Each Component Within the Cardiovascular Composite Endpoint CABG = coronary artery bypass grafting; PCI = percutaneous intervention. Weight Gain Dose-related weight gain occurs when pioglitazone is used alone or in combination with other antidiabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Table 11: Weight Changes (kg) from Baseline During Randomized, Double- Blind Clinical Trials N=338 Table 12: Median Change in Body Weight in Patients Treated with Pioglitazone vs Patients Treated with Placebo During the Double-Blind Treatment Period in the PROactive Trial +3.6 N=2,560 Note: Median exposure for both pioglitazone and placebo was 2.7 years. Table 13: Weight Changes (kg) from Baseline During Double-Blind Clinical Trial with Pioglitazone and Metformin Hydrochloride Tablets in Patients with Inadequate Glycemic Control on Diet and Exercise induced from taking pioglitazone is reversible when pioglitazone is discontinued. The edema usually does not require hospitalization unless there is co-existing congestive heart failure.

A summary of the frequency and types of edema adverse events occurring in clinical investigations of pioglitazone is provided in Table 14. Hepatic Effects There has been no evidence of pioglitazone-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date. One randomized, double-blind, three year trial comparing pioglitazone to glyburide as add-on to metformin and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than three times the upper limit of the reference range, measured every eight weeks for the first 48 weeks of the trial then every 12 weeks thereafter.

None of the patients treated with pioglitazone in the pioglitazone controlled clinical trial database to date have had a serum ALT greater than three times the upper limit of the reference range and a corresponding total bilirubin greater than two times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury. Hypoglycemia In the pioglitazone clinical trials, adverse events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick glucose testing. Three patients in these four trials were hospitalized due to hypoglycemia.

All three patients were receiving pioglitazone 30 mg (0.9%) in the 24 week add-on to insulin trial. An additional 14 patients reported severe hypoglycemia (defined as causing considerable interference with patients usual activities) that did not require hospitalization. These patients were receiving pioglitazone 45 mg in combination with sulfonylurea (n=2) or pioglitazone 30 mg or 45 mg in combination with insulin (n=12).

Urinary Bladder Tumors Tumors were observed in the urinary bladder of male rats in the two year carcinogenicity study. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and 2 (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone.

During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR = 1.00; ). Metformin HCl In a double-blind clinical study of metformin in patients with type 2 diabetes mellitus, a total of 141 patients received metformin therapy (up to 2,550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin patients, and that were more common in metformin than placebo-treated patients, are listed in Table 16.

In this trial, diarrhea led to discontinuation of study medication in 6% of patients treated with metformin. Laboratory Abnormalities Pioglitazone Hematologic Effects Pioglitazone may cause decreases in hemoglobin and hematocrit. These changes primarily occurred within the first four to 12 weeks of therapy and remained relatively constant thereafter.

These changes may be related to increased plasma volume associated with pioglitazone therapy and are not likely to be associated with any clinically significant hematologic effects. Creatine Phosphokinase During protocol-specified measurement of serum creatine phosphokinase (CPK) in pioglitazone clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in nine (0.2%) patients treated with pioglitazone (values of 2,150 to 11,400 IU/L) and in no comparator-treated patients. Six of these nine patients continued to receive pioglitazone, two patients were noted to have the CPK elevation on the last day of dosing, and one patient discontinued pioglitazone due to the elevation.

These elevations resolved without any apparent clinical sequelae. The relationship of these events to pioglitazone therapy is unknown. Metformin Vitamin B 12 Concentrations In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of pioglitazone and/or metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Pioglitazone Cardiac Disorders: Rapid increases in weight, edema, congestive heart failure with and without previously known heart disease or concomitant insulin administration Eye Disorders: New onset or worsening diabetic macular edema with decreased visual acuity Hepatobiliary Disorders: Fatal and nonfatal hepatic failure Metformin Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury.

Strong CYP2C8 Inhibitors

An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life (t1/2) of pioglitazone. Therefore, the maximum recommended dosage of pioglitazone and metformin hydrochloride tablets is 15 mg of pioglitazone and 850 mg of metformin HCl once daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors.

CYP2C8 Inducers

An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with pioglitazone and metformin hydrochloride tablets, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dosage of pioglitazone and metformin hydrochloride tablets (45 mg of pioglitazone and 2,550 mg of metformin HCl).

Carbonic Anhydrase Inhibitors Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with pioglitazone and metformin hydrochloride may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

Drugs That Reduce Metformin Clearance

Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 /multidrug and toxin extrusion inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use.

Alcohol Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving pioglitazone and metformin hydrochloride tablets.

Insulin Secretagogues or Insulin Coadministration of pioglitazone and metformin hydrochloride with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. If hypoglycemia occurs in a patient coadministered pioglitazone and metformin hydrochloride and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

Drugs Affecting Glycemic Control

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving pioglitazone and metformin hydrochloride tablets, the patient should be closely observed for loss of blood glucose control.

When such drugs are withdrawn from a patient receiving pioglitazone and metformin hydrochloride tablets, the patient should be observed closely for hypoglycemia.

Topiramate

A decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate. The clinical relevance of this decrease is unknown; however, when pioglitazone and metformin hydrochloride and topiramate are used concomitantly, monitor patients for adequate glycemic control.

Pregnancy Risk Summary Limited data with pioglitazone and metformin hydrochloride or pioglitazone in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

In animal reproduction studies, no adverse developmental effects were observed when pioglitazone was administered to pregnant rats and rabbits during organogenesis at exposures up to 5 and 35 times the 45 mg clinical dose, respectively, based on body surface area. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2 to 6 times, respectively, a 2,000 mg clinical dose, based on body surface area (see Data). The estimated background risk of miscarriage for the indicated population is unknown.

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

Data Human Data Published data from postmarketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Pioglitazone and Metformin HCl Animal reproduction studies were not conducted with the combined products in pioglitazone and metformin hydrochloride tablets.

The following data are based on studies conducted with the individual components of pioglitazone and metformin hydrochloride tablets. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in offspring at maternal doses of 10 mg/kg and above or ≥2 times the 45 mg clinical dose, by body surface area. Metformin HCl Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis.

Pediatric Use Safety and effectiveness of pioglitazone and metformin hydrochloride in pediatric patients have not been established. Pioglitazone and metformin hydrochloride is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors.

• In patients with established New York Heart Association (NYHA) Class III or IV heart failure at the time of pioglitazone and metformin hydrochloride tablets initiation.
• In patients with severe renal impairment: (eGFR below 30 mL/min).
• In patients with a history of serious hypersensitivity to pioglitazone, metformin HCl, or any of the excipients in pioglitazone and metformin hydrochloride tablets.
• In patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis. Pioglitazone and metformin hydrochloride tablets are contraindicated in patients with:
• Established NYHA Class III or IV heart failure at the time of pioglitazone and metformin hydrochloride tablets initiation.
• Severe renal impairment (eGFR below 30 mL/min).
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis.

Pioglitazone During controlled clinical trials, one case of overdose with pioglitazone was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.

Metformin HCl Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases.

Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated metformin from patients in whom metformin overdosage is suspected. In the event of overdosage, contact the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

Appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.