Pioglitazone and metformin

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Overview

What is Pioglitazone and metformin?

Pioglitazone and metformin hydrochloride tablets, USP are a thiazolidinediones and biguanide combination product that contains two oral antidiabetic medications: pioglitazone and metformin hydrochloride.

Pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl) ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert . No differences were found in the pharmacologic activity between the two enantiomers. The structural formula is as shown:

Pioglitazone hydrochloride is an odorless white to off white crystalline powder that has a molecular formula of CHNOS•HCl and a molecular weight of 392.91. It is soluble in -dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.

Metformin hydrochloride (-dimethylimidodicarbonimidic diamide hydrochloride) is a white to almost white crystalline powder with a molecular formula of CHN•HCl and a molecular weight of 165.62. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown:

Pioglitazone and metformin hydrochloride tablets, USP are available for oral administration containing 15 mg pioglitazone (as the base) with 500 mg metformin hydrochloride (15 mg/500 mg) or 15 mg pioglitazone (as the base) with 850 mg metformin hydrochloride (15 mg/850 mg) formulated with the following inactive ingredients: croscarmellose sodium, hydroxypropylcellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc, and titanium dioxide.

What does Pioglitazone and metformin look like?

What are the available doses of Pioglitazone and metformin?

Tablets: 15 mg pioglitazone/500 mg metformin hydrochloride and 15 mg pioglitazone/850 mg metformin hydrochloride ()

What should I talk to my health care provider before I take Pioglitazone and metformin?

How should I use Pioglitazone and metformin?

Pioglitazone and metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both pioglitazone and metformin is appropriate [see

Important Limitations of Use

Pioglitazone exerts its antihyperglycemic effect only in the presence of endogenous insulin. Pioglitazone and metformin hydrochloride tablets should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings.

Use caution in patients with liver disease [see

Pioglitazone and metformin hydrochloride tablets should be taken with meals to reduce the gastrointestinal side effects associated with metformin.

If therapy with a combination tablet containing pioglitazone and metformin is considered appropriate the recommended starting dose is:

Pioglitazone and metformin hydrochloride tablets may be titrated up to a maximum daily dose of 45 mg of pioglitazone and 2550 mg of metformin.

Metformin doses above 2000 mg may be better tolerated given 3 times a day.

After initiation of pioglitazone and metformin hydrochloride tablets or with dose increase, monitor patients carefully for adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure [see and . Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating pioglitazone and metformin hydrochloride tablets. Routine periodic monitoring of liver tests during treatment with pioglitazone and metformin hydrochloride tablets are not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of pioglitazone and metformin hydrochloride tablets or who are found to have abnormal liver tests while taking pioglitazone and metformin hydrochloride tablets should be managed as described under Warnings and Precautions [see and

What interacts with Pioglitazone and metformin?

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What are the warnings of Pioglitazone and metformin?

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What are the precautions of Pioglitazone and metformin?

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What are the side effects of Pioglitazone and metformin?

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What should I look out for while using Pioglitazone and metformin?

•Initiation in patients with established New York Heart Association (NYHA) Class III or IV heart failure [see ]. ()

•Renal impairment. ()

•Use in patients with known hypersensitivity to pioglitazone, metformin or any other component of pioglitazone and metformin hydrochloride. ()

•Metabolic acidosis, including diabetic ketoacidosis. (,)

Congestive Heart Failure

Lactic Acidosis

What might happen if I take too much Pioglitazone and metformin?

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.

In the event of overdosage, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.

Metformin hydrochloride

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

How should I store and handle Pioglitazone and metformin?

Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP.Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP.Pioglitazone and metformin hydrochloride tablets, USP are available in 15 mg pioglitazone (as the base)/500 mg metformin hydrochloride as follows: Pioglitazone and metformin hydrochloride 15 mg/500 mg tablets are white, oval, biconvex, film-coated tablets with “SZ441” on one side and are supplied as follows: NDC 70882-105-56, Package of 56 tablets (4 x 14 unit-of-dose blisters)StorageStore at 20° to 25° C (68° to 77°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity. Pioglitazone and metformin hydrochloride tablets, USP are available in 15 mg pioglitazone (as the base)/500 mg metformin hydrochloride as follows: Pioglitazone and metformin hydrochloride 15 mg/500 mg tablets are white, oval, biconvex, film-coated tablets with “SZ441” on one side and are supplied as follows: NDC 70882-105-56, Package of 56 tablets (4 x 14 unit-of-dose blisters)StorageStore at 20° to 25° C (68° to 77°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity. Pioglitazone and metformin hydrochloride tablets, USP are available in 15 mg pioglitazone (as the base)/500 mg metformin hydrochloride as follows: Pioglitazone and metformin hydrochloride 15 mg/500 mg tablets are white, oval, biconvex, film-coated tablets with “SZ441” on one side and are supplied as follows: NDC 70882-105-56, Package of 56 tablets (4 x 14 unit-of-dose blisters)StorageStore at 20° to 25° C (68° to 77°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity. Pioglitazone and metformin hydrochloride tablets, USP are available in 15 mg pioglitazone (as the base)/500 mg metformin hydrochloride as follows: Pioglitazone and metformin hydrochloride 15 mg/500 mg tablets are white, oval, biconvex, film-coated tablets with “SZ441” on one side and are supplied as follows: NDC 70882-105-56, Package of 56 tablets (4 x 14 unit-of-dose blisters)StorageStore at 20° to 25° C (68° to 77°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity. Pioglitazone and metformin hydrochloride tablets, USP are available in 15 mg pioglitazone (as the base)/500 mg metformin hydrochloride as follows: Pioglitazone and metformin hydrochloride 15 mg/500 mg tablets are white, oval, biconvex, film-coated tablets with “SZ441” on one side and are supplied as follows: NDC 70882-105-56, Package of 56 tablets (4 x 14 unit-of-dose blisters)StorageStore at 20° to 25° C (68° to 77°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity.

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Pioglitazone and metformin hydrochloride combines two antidiabetic medications with different mechanisms of action to improve glycemic control in adults with type 2 diabetes: pioglitazone, a thiazolidinedione, and metformin hydrochloride, a biguanide. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.

Pioglitazone

Pioglitazone is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.

Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

Metformin hydrochloride

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. Metformin does not produce hypoglycemia in either patients with type 2 diabetes or healthy subjects [except in specific circumstances, [see and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Non-Clinical Toxicology

•Initiation in patients with established New York Heart Association (NYHA) Class III or IV heart failure [see ]. ()

•Renal impairment. ()

•Use in patients with known hypersensitivity to pioglitazone, metformin or any other component of pioglitazone and metformin hydrochloride. ()

•Metabolic acidosis, including diabetic ketoacidosis. (,)

Congestive Heart Failure

Lactic Acidosis

Large doses of naloxone are required to antagonize buprenorphine since the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. The barbiturate methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts.

Pioglitazone

Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients treated with pioglitazone and metformin hydrochloride should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone and metformin hydrochloride must be considered [see and

The following serious adverse reactions are discussed elsewhere in the labeling:

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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