Pioglitazone “Pioglitazone and Metformin HCl”

Composition

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.

Pharmacology

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 hydrochloride

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

Metformin.

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

response.

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

periodically thereafter.

Precautions

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.

Contraindications

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.

Adverse effects

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.

Drug interaction

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

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