Actoplus Met Xr Recall
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ACTOPLUS MET XR is 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 Clinical Studies (14)].
Important Limitations of Use
Pioglitazone exerts its antihyperglycemic effect only in the presence of endogenous insulin. ACTOPLUS MET XR 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 Warnings and Precautions (5.5)].
There is currently no drug history available for this drug.
ACTOPLUS MET XR tablets are a thiazolidinedione and biguanide combination product that contains two oral anti-diabetic medications: pioglitazone and metformin hydrochloride (extended-release).
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:
Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of C19H20N2O3S•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 (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a white crystalline powder with a molecular formula of C4H11N5•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:
ACTOPLUS MET XR is available as a tablet for oral administration containing 15 mg pioglitazone (as the base) and 1000 mg metformin hydrochloride (15 mg/1000 mg) or 30 mg pioglitazone (as the base) and 1000 mg metformin hydrochloride (30 mg/1000 mg) formulated with the following excipients: candelilla wax, cellulose acetate, povidone, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, hypromellose, polyethylene glycols (PEG 400, PEG 8000), sodium lauryl sulfate, titanium dioxide, and triacetin. Tablets are imprinted with ink containing shellac, iron oxide red (15 mg/1000 mg strength only), FD&C Blue No. 2 Lake (30 mg/1000 mg strength only), propylene glycol, and ammonium hydroxide.
SYSTEM COMPONENTS AND PERFORMANCE
ACTOPLUS MET XR consists of an extended-release metformin core coated tablet with an immediate-release pioglitazone layer. The tablet is similar in appearance to other film-coated orally administered tablets but it consists of an osmotically active core formulation that is surrounded by a semipermeable membrane and coated with a pioglitazone drug layer. Two laser drilled exit ports exist in the membrane, one on either side of the tablet. The core formulation is composed primarily of drug with small concentrations of excipients. The semipermeable membrane is permeable to water but not to higher molecular weight components of biological fluids. Upon ingestion, the pioglitazone layer is dissolved; water is then taken up through the membrane, which in turn dissolves the metformin and excipients in the core formulation. The dissolved metformin and excipients exit through the laser drilled ports in the membrane. The rate of drug delivery is constant and dependent upon the maintenance of a constant osmotic gradient across the membrane. This situation exists so long as there is undissolved metformin present in the core tablet. Following the dissolution of the core materials, the rate of drug delivery slowly decreases until the osmotic gradient across the membrane falls to zero at which time delivery ceases. The membrane coating remains intact during the transit of the dosage form through the gastrointestinal tract and is excreted in the feces.