Pioglitazone 500: Each film coated tablet contains Pioglitazone 15 mg as Pioglitazone
Hydrochloride INN and Metformin Hydr ochloride BP 500 mg.
Pioglitazone 850: Each film coated tablet contains Pioglitazone 15 mg as Pioglitazone
Hydrochloride INN and Metformin Hydr ochloride BP 850 mg.
Pioglitazone (Pioglitazone Hydrochloride and Metformin Hydrochloride) combines two
antihyperglycemic agents with different mechanisms of action to improve glycemic control
in patients with type 2 diabetes: Pioglitazone hydrochloride, a member of the
thiazolidinedione class, and Metformin hydrochloride, a member of the biguanide class.
Pioglitazone depends on the presence of insulin for its mechanism of action. Pioglitazone
decreases insulin resistance in the peripher y and in the liver resulting in increased insulin-
dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is a potent
and highly selective agonist for peroxisome proliferator-activated receptor-gamma
(PPARg). Activation of PPARg nuclear receptors modulates the transcription of a number of
insulin responsive genes involved in the control of glucose and lipid metabolism.
Metformin hydr ochloride
Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes,
lowering both basal and postprandial plasma glucose. Metformin decreases hepatic
glucose production, decreases intestinal absorption of glucose and improves insulin
sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas,
metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal
subjects and does not cause hyperinsulinemia.
Indication and usage
Pioglitazone is indicated as an adjunct to diet and exercise to improve glycemic contr ol in
patients with type 2 diabetes who are already treated with a combination of Pioglitazone
and Metformin as separate tablets or whose diabetes is not adequately controlled with
Metformin alone, or for those patients who have initially responded to Pioglitazone alone
and require additional glycemic control.
Dosage and administration
General: The use of antihyperglycemic therapy in the management of type 2 diabetes
should be individualized on the basis of effectiveness and tolerability while not exceeding
the maximum r ecommended daily dose of Pioglitazone 45 mg and Metformin 2550 mg.
Dosage Recommendations: Selecting the starting dose of Pioglitazone should be based on the
patient’s current regimen of Pioglitazone and/or Metformin. Pioglitazone should be given in
divided daily doses with meals to reduce the gastrointestinal side effects associated with
Starting dose for patients inadequately controlled on Metformin monotherapy
Based on the usual starting dose of Pioglitazone (15-30 mg daily), Pioglitazone may be
initiated at either the 15 mg/500 mg or 15 mg/850 mg tablet strength once or twice daily,
and gradually titrated after assessing adequacy of therapeutic response.
Starting dose for patients who initially responded to Pioglitazone monotherapy and require
additional glycemic control
Based on the usual starting doses of Metformin ( 500 mg twice daily or 850 mg daily),
Pioglitazone may be initiated at either the 15 mg/500 mg twice daily or 15 mg/850 mg tablet
strength once daily, and gradually titrated after assessing adequacy of therapeutic
Starting dose for patients switching from combination ther apy of Pioglitazone plus
Metformin as separate tablets
Pioglitazone may be initiated with either the 15 mg/500 mg or 15 mg/850 mg tablet strengths
based on the dose of Pioglitazone and Metformin already being taken.
Maximum Recommended Dose: Pioglitazone tablets are available as a 15 mg Pioglitazone
plus 500 mg Metfor min or a 15 mg Pioglitazone plus 850 mg Metfor min formulation for oral
administration. The maximum recommended dose for Pioglitazone is 45 mg daily. The
maximum recommended daily dose for Metformin is 2550 mg in adults.
Special Patient Populations: The initial and maintenance dosing of combination of
Pioglitazone and Metformin should be conservative in patients with advanced age, due to
the potential for decreased renal function in this population. Generally, elderly, debilitated,
and malnourished patients should not be titrated to the maxi mum dose of combination of
Pioglitazone and Metformin. Monitoring of renal function is necessary to aid in prevention of
Metformin associated lactic acidosis, particularly in the elderly. Therapy with combination of
Pioglitazone and Metfor min should not be initiated if the patient exhibits clinical evidence of
active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the
upper limit of normal) at start of therapy. Liver enzyme monitoring is recommended in all
patients prior to initiation of therapy with combination of Pioglitazone and Metformin and
General: Pioglitazone hydrochloride: Pioglitazone exerts its antihyperglycemic effect only in
the presence of insulin. Therefore, combination of Pioglitazone and Metformin should not
be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Metformin hydrochloride: Metformin is known to be substantially excreted by the kidney and
the risk of Metformin accumulation and lactic acidosis increases with the degree of
impairment of renal function. Thus, patients with serum creatinine levels above the upper
limit of normal for their age should not receive combination of Pioglitazone and Metformin.
Hypoglycemia: Pioglitazone hydrochloride: Patients receiving Pioglitazone in combination
with insulin or oral hypoglycemic agents may be at risk for hypoglycemia, and a reduction in
the dose of the concomitant agent may be necessary. Metformin hydrochloride:
Hypoglycemia does not occur in patients receiving Metformin alone under usual
circumstances of use, but could occur when caloric intake is deficient, when strenuous
exercise is not compensated by caloric supplementation, or during concomitant use with
hypoglycemic agents (such as sulfonylureas or insulin) or ethanol. Cardiovascular: Therapy
with Pioglitazone, cases of congestive heart failur e has been reported in patients both with
and without previously known heart disease. Edema: Combination of Pioglitazone and
Metformin should be used with caution in patients with edema. Since thiazolidinediones,
including Pioglitazone can cause fluid retention, which can exacerbate or lead to congestive
heart failure, combination of Pioglitazone and Metformin should be used with caution in
patients at risk for hear t failure.
Hepatic Effects: Serum ALT (alanine aminotransferase) levels should be evaluated prior to
the initiation of therapy with combination of Pioglitazone and Metformin in all patients and
periodically thereafter per the clinical judgment of the health care professional.Liver function
tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction
occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. If jaundice is
observed, drug therapy should be discontinued. Loss of control of blood glucose: When a
patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma,
infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may
be necessary to withhold combination of Pioglitazone and Metformin and temporarily
administer insulin. Combination of Pioglitazone and Metfor min may be reinstituted after the
acute episode is resolved.
Combination of Pioglitazone and Metformin is contraindicated in patients with:
1. Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels >1.5
mg/dL [males], > 1.4 mg/dL [females], or abnormal creatinine clearance) which may
also result from conditions such as cardiovascular collapse (shock), acute
myocardial infarction, and septicemia
2. Known hypersensitivity to Pioglitazone, Metformin or any other component of
combination of Pioglitazone and Metformin.
3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without
coma. Diabetic ketoacidosis should be treated with insulin.
Combination of Pioglitazone and Metformin should be temporarily discontinued in patients
undergoing radiologic studies involving intravascular administration of iodinated contrast
materials, because use of such products may r esult in acute alteration of renal function.
The most common adverse events were upper respiratory tract infection, diarrhea,
combined edema/peripheral edema and headache, respectively. Most clinical adverse
events were similar between gr oups treated with Pioglitazone in combination with
metformin and those treated with pioglitazone monother apy.
Use in Pregnancy and lactation
Pregnancy category C. Combination of Pioglitazone and Metformin should not be used
during pregnancy unless the potential benefit justifies the potential risk to the fetus. There
are no adequate and well-controlled studies in pregnant women with combination of
Pioglitazone and Metformin or its individual components. It is not known whether
Pioglitazone and/or Metformin are secreted in human milk. Because many drugs are
excreted in human milk, combination of Pioglitazone and Metformin should not be
administered to a breastfeeding woman.
Use in Pediatric patients
Safety and effectiveness of combination of Pioglitazone and Metformin in pediatric patients
have not been established.
Use in Geriat ric pat ients
Pioglitazone: No significant differences in effectiveness and safety were observed between
these patients and younger patients. Metformin: Metformin is known to be substantially
excreted by the kidney and because the risk of serious adverse reactions to the drug is
greater in patients with impaired renal function. Because aging is associated with reduced
renal function, combination of Pioglitazone and Metformin should be used with caution as
age incr eases. Care should be taken in dose selection and should be based on careful and
regular monitoring of renal function.
Pioglitazone hydrochloride: In vivo drug-drug interaction studies have suggested that
Pioglitazone may be a weak inducer of CYP450 isoform 3A4 substrate.
Metformin hydrochloride: i) Furosemide: A single-dose, metformin-furosemide drug
interaction study in healthy subjects demonstrated that phar macokinetic parameters of both
compounds were affected by co-administration. Furosemide increased the metfor min