Prescription Drug Information: Pioglitazone Hydrochloride and Metformin Hydrochloride (Page 4 of 8)

8.6 Renal Impairment

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Pioglitazone and metformin hydrochloride is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m2 [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Pioglitazone and metformin hydrochloride is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.2)].

10 OVERDOSAGE


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 Warnings and Precautions (5.2)]. 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.

11 DESCRIPTION

Pioglitazone and metformin hydrochloride tablets, USP are a thiazolidinediones and biguanide combination product that contains two oral antidiabetic medications: pioglitazone hydrochloride 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 in vivo. No differences were found in the pharmacologic activity between the two enantiomers. The structural formula is as shown:

Piomet Structure1
(click image for full-size original)

Pioglitazone hydrochloride USP is an off-white to pale yellow color powder that has a molecular formula of C19 H20 N2 O3 S•HCl and a molecular weight of 392.90 daltons. It is soluble in N,N -dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.Metformin hydrochloride USP (N,N -dimethylimidodicarbonimidic diamide hydrochloride) is a white crystalline powder with a molecular formula of C4 H11 N5 •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:

Piomet Structure2
(click image for full-size original)

Pioglitazone and metformin hydrochloride is available as a tablet for oral administration containing 15 mg pioglitazone (as the base) with 500 mg metformin hydrochloride USP (15 mg/500 mg) or 15 mg pioglitazone (as the base) with 850 mg metformin hydrochloride USP (15 mg/850 mg) formulated with the following excipients: carboxymethylcellulose calcium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol 6000, talc, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action


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 Warnings and Precautions (5.4) ] 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.

12.2 Pharmacodynamics

Pioglitazone
Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal and improves hepatic sensitivity to insulin. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In controlled clinical trials, pioglitazone had an additive effect on glycemic control when used in combination with a sulfonylurea, metformin, or insulin [see Clinical Studies (14)].
Patients with lipid abnormalities were included in clinical trials with pioglitazone. Overall, patients treated with pioglitazone had mean decreases in serum triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. There is no conclusive evidence of macrovascular benefit with pioglitazone [see Warnings and Precautions (5.10) and Adverse Reactions (6.1)]. In a 26-week, placebo-controlled, dose-ranging monotherapy study, mean serum triglycerides decreased in the 15 mg, 30 mg, and 45 mg pioglitazone dose groups compared to a mean increase in the placebo group. Mean HDL cholesterol increased to a greater extent in patients treated with pioglitazone than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with pioglitazone compared to placebo (see Table 16).

Table 16. Lipids in a 26-Week Placebo-Controlled Monotherapy Dose-Ranging Study
Placebo Pioglitazone15 mgOnce Daily Pioglitazone30 mgOnce Daily Pioglitazone45 mgOnce Daily
* Adjusted for baseline, pooled center, and pooled center by treatment interaction † p < 0.05 versus placebo
Triglycerides (mg/dL) N=79 N=79 N=84 N=77
Baseline (mean) 263 284 261 260
Percent change from baseline (adjusted mean*) 4.8% -9% -9.6% -9.3%
HDL Cholesterol (mg/dL) N=79 N=79 N=83 N=77
Baseline (mean) 42 40 41 41
Percent change from baseline (adjusted mean*) 8.1% 14.1% 12.2% 19.1%
LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62
Baseline (mean) 139 132 136 127
Percent change from baseline (adjusted mean*) 4.8% 7.2% 5.2% 6%
Total Cholesterol (mg/dL) N=79 N=79 N=84 N=77
Baseline (mean) 225 220 223 214
Percent change from baseline (adjusted mean*) 4.4% 4.6% 3.3% 6.4%

In the two other monotherapy studies (16 weeks and 24 weeks) and in combination therapy studies with metformin (16 weeks and 24 weeks), the results were generally consistent with the data above.

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