`
`
`ACTOPLUS MET®
`
`(pioglitazone hydrochloride and metformin hydrochloride) tablets
`ACTOPLUS MET® XR
` (pioglitazone hydrochloride and metformin hydrochloride extended-release) tablets
`
`WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS
`Congestive Heart Failure
`• Thiazolidinediones, including pioglitazone, which is a component of ACTOPLUS MET
`
`and ACTOPLUS MET XR, cause or exacerbate congestive heart failure in some patients
`
` (see WARNINGS, Pioglitazone). After initiation of ACTOPLUS MET or ACTOPLUS
`MET XR, and after dose increases, observe patients carefully for signs and symptoms of
`heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these
`signs and symptoms develop, the heart failure should be managed according to the
`current standards of care. Furthermore, discontinuation or dose reduction of ACTOPLUS
`MET or ACTOPLUS MET XR must be considered.
`• ACTOPLUS MET and ACTOPLUS MET XR are not recommended in patients with
`
`symptomatic heart failure. Initiation of ACTOPLUS MET or ACTOPLUS MET XR in
`patients with established NYHA Class III or IV heart failure is contraindicated (see
`CONTRAINDICATIONS and WARNINGS, Pioglitazone).
`
`
`
`Lactic Acidosis
`• Lactic acidosis is a rare, but serious complication that can occur due to metformin
`
`accumulation. The risk increases with conditions such as sepsis, dehydration, excess
`alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart
`failure.
`• The onset is often subtle, accompanied only by nonspecific symptoms such as malaise,
`
`myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal
`distress.
`• Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate.
`
`• If acidosis is suspected, ACTOPLUS MET or ACTOPLUS MET XR should be
`
`discontinued and the patient hospitalized immediately (see WARNINGS, Metformin
`Hydrochloride).
`
`
`
`DESCRIPTION
`
`ACTOPLUS MET® tablets are formulated with pioglitazone hydrochloride and immediate-
`release metformin hydrochloride. ACTOPLUS MET® XR tablets are formulated with
`
`pioglitazone hydrochloride and extended-release metformin hydrochloride. Both
`ACTOPLUS MET® and ACTOPLUS MET® XR contain two oral antihyperglycemic drugs
`
`used in the management of type 2 diabetes: pioglitazone and metformin. ACTOPLUS MET®
`
`
`
`is available in 15 mg pioglitazone/500 mg metformin hydrochloride and 15 mg
`pioglitazone/850 mg metformin hydrochloride tablets. ACTOPLUS MET® XR is available in
`15 mg pioglitazone/1000 mg extended-release metformin hydrochloride and 30 mg
`pioglitazone/1000 mg extended-release metformin hydrochloride tablets.
`
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`Pioglitazone is an oral antihyperglycemic agent that acts primarily by decreasing insulin
`
`resistance. Pioglitazone is used in the management of type 2 diabetes. Pharmacological studies
`indicate that pioglitazone improves sensitivity to insulin in muscle and adipose tissue and
`inhibits hepatic gluconeogenesis. Pioglitazone improves glycemic control while reducing
`circulating insulin levels.
`
` Pioglitazone (±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione
`monohydrochloride belongs to a different chemical class and has a different pharmacological
`action than the sulfonylureas, biguanides, or the α-glucosidase inhibitors. The molecule contains
`one asymmetric center, and the synthetic compound is a racemate. The two enantiomers of
`pioglitazone interconvert in vivo. The structural formula is as shown:
`
`
`
`
`C H3
`
`N
`
`S
`
`O
`• HCl
`
`
`
`N H
`O
`O
`pioglitazone hydrochloride
`
`Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular
`formula of C19H20N2O3S•HCl and a molecular weight of 392.90. 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 not
`chemically or pharmacologically related to any other classes of oral antihyperglycemic agents.
`Metformin 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:
`
`
`CH3
`
`· HCl
`
`NH2
`
`HN
`
`N
`
`H3C
`
`
`
`NH
`NH
`metformin hydrochloride
`
`ACTOPLUS MET is available as a tablet for oral administration containing pioglitazone
`hydrochloride and metformin hydrochloride equivalent to 15 mg pioglitazone and 500 mg
`
`metformin hydrochloride (ACTOPLUS MET 15 mg/500 mg) or 850 mg metformin
`hydrochloride (ACTOPLUS MET 15 mg/850 mg). ACTOPLUS MET is formulated with the
`following excipients: povidone, microcrystalline cellulose, croscarmellose sodium, magnesium
`
`stearate, hypromellose 2910, polyethylene glycol 8000, titanium dioxide, and talc.
`
`
`ACTOPLUS MET XR is available as a tablet for once-a-day oral administration containing
`pioglitazone hydrochloride and metformin hydrochloride equivalent to 15 mg pioglitazone and
`1000 mg metformin hydrochloride (ACTOPLUS MET XR 15 mg/1000 mg) or 30 mg
`
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`pioglitazone and 1000 mg metformin hydrochloride (ACTOPLUS MET XR 30 mg/1000 mg).
`ACTOPLUS MET XR is 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.
`
`ACTOPLUS MET XR: SYSTEM COMPONENTS AND PERFORMANCE
`ACTOPLUS MET XR consists of an extended-release metformin core coated tablet with an
`immediate-release pioglitazone layer. The metformin core tablet is an extended-release
`formulation using the patented single composition osmotic technology (SCOT™) for once-daily
`(q.d.) oral administration. The tablet is similar in appearance to other film-coated oral
`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.
`
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`
`ACTOPLUS MET and ACTOPLUS MET XR
`
`ACTOPLUS MET and ACTOPLUS MET XR combine two antihyperglycemic agents with
`complementary mechanisms of action to improve glycemic control in patients with type 2
`diabetes: pioglitazone, a member of the thiazolidinedione class, and metformin hydrochloride, a
`member of the biguanide class. 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 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. Unlike sulfonylureas,
`pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective 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.
`
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`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.
`
`Since 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. Unlike sulfonylureas, metformin does not produce
`hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special
`circumstances, see PRECAUTIONS, General: Metformin hydrochloride) 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.
`
`Pharmacokinetics and Drug Metabolism
`Absorption and Bioavailability:
`ACTOPLUS MET
`In bioequivalence studies of ACTOPLUS MET 15 mg/500 mg and 15 mg/850 mg, the area
`under the curve (AUC) and maximum concentration (Cmax) of both the pioglitazone and the
`immediate-release metformin component following a single dose of the combination tablet were
`bioequivalent to pioglitazone (ACTOS®) 15 mg concomitantly administered with immediate-
`release metformin (Glucophage®) 500 mg or 850 mg tablets, respectively, under fasted
`conditions in healthy subjects (Table 1).
`
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`
` Table 1. Mean (SD) Pharmacokinetic Parameters for ACTOPLUS MET®
`
`
`Regimen
`N AUC(0-inf)
`Tmax
`N
`Cmax
`N
`(ng•h/mL)
`(ng/mL)
`(h)
`
`pioglitazone
`
`15 mg/500 mg
`ACTOPLUS MET®
`15 mg pioglitazone
`
`and 500 mg
`immediate-release
`metformin
`15 mg/850 mg
`ACTOPLUS MET®
`15 mg pioglitazone
`
`and 850 mg
`immediate-release
`metformin
`metformin
`15 mg/500 mg
`ACTOPLUS MET®
`15 mg pioglitazone
`
`and 500 mg
`immediate-release
`metformin
`15 mg/850 mg
`ACTOPLUS MET®
`15 mg pioglitazone
`and 850 mg
`
`immediate-release
`metformin
`
`51
`
`54
`
`52
`
`55
`
`59
`
`59
`
`47
`
`52
`
`5984
`(1599)
`
`5810
`(1472)
`
`5671
`(1585)
`
`5957
`(1680)
`
`7783
`(2266)
`
`7599
`(2385)
`
`11927
`(3311)
`
`11569
`(3494)
`
`63
`
`63
`
`60
`
`61
`
`63
`
`63
`
`60
`
`61
`
`585
`(198)
`
`608
`(204)
`
`569
`(222)
`
`603
`(239)
`
`1203
`(325)
`
`1215
`(329)
`
`1827
`(536)
`
`1797
`(525)
`
`63
`
`63
`
`60
`
`61
`
`63
`
`63
`
`60
`
`61
`
`1.8
`(0.9)
`
`1.7
`(0.9)
`
`1.9
`(0.8)
`
`2.0
`(1.5)
`
`2.3
`(0.9)
`
`2.5
`(0.9)
`
`2.4
`(0.9)
`
`2.3
`(0.8)
`
`N
`
`51
`
`54
`
`52
`
`55
`
`59
`
`59
`
`47
`
`52
`
`
`T1/2
`(h)
`
`8.7
`(3.9)
`
`7.9
`(3.1)
`
`7.2
`(1.8)
`
`7.2
`(1.8)
`
`.6
`8.6
`(14.3)
`
`6.7
`(5.9)
`
`17.6
`(20.1)
`
`17.0
`(18.1)
`
`
` Administration of ACTOPLUS MET 15 mg/850 mg with food resulted in no change in
`overall exposure of pioglitazone. With metformin there was no change in AUC; however, mean
`
`peak serum concentration of metformin was decreased by 28% when administered with food. A
`delayed time to peak serum concentration was observed for both components (1.9 hours for
`pioglitazone and 0.8 hours for metformin) under fed conditions. These changes are not likely to
`
`be clinically significant.
`
`ACTOPLUS MET XR
`In bioequivalence studies of ACTOPLUS MET XR 15 mg/1000 mg and 30 mg/1000 mg, the
`area under the curve (AUC) and maximum concentration (Cmax) of both the pioglitazone and the
`extended-release metformin components following a single dose of the combination tablet were
`bioequivalent to pioglitazone (ACTOS®)15 mg and 30 mg concomitantly administered with
`extended-release metformin hydrochloride (FORTAMET®) 1000 mg tablets under fed conditions
`
`in healthy subjects (Table 2).
`
`
`Table 2. Mean (SD) Pharmacokinetic Parameters for ACTOPLUS MET® XR
`
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`
`Regimen
`
`pioglitazone
`
`15 mg/1000 mg
`ACTOPLUS MET® XR
`15 mg pioglitazone and
`1000 mg extended-release
`metformin
`30 mg/1000 mg
`ACTOPLUS MET® XR
`30 mg pioglitazone and
`1000 mg extended-release
`metformin
`metformin
`15 mg/1000 mg
`ACTOPLUS MET® XR
`15 mg pioglitazone and
`1000 mg extended-release
`metformin
`30 mg/1000 mg
`ACTOPLUS MET® XR
`30 mg pioglitazone and
`1000 mg extended-release
`metformin
`
`
`
`N AUC(0-inf)
`(ng•h/mL)
`
`59
`
`59
`
`55
`
`55
`
`50
`
`50
`
`54
`
`54
`
`5113
`(1598)
`
`5979
`(1726)
`
`8242
`(2587)
`
`9177
`(2200)
`
`14454
`(3579)
`
`14787
`(3313)
`
`12705
`(3577)
`
`12796
`(3882)
`
`N
`
`60
`
`60
`
`57
`
`57
`
`60
`
`60
`
`58
`
`58
`
`Cmax
`
`(ng/mL)
`
`487
`(126)
`
`560
`(130)
`
`777
`(250)
`
`866
`(243)
`
`1551
`(404)
`
`1590
`(361)
`
`1322
`(335)
`
`1332
`(414)
`
`N
`
`60
`
`60
`
`57
`
`57
`
`60
`
`60
`
`58
`
`58
`
`Tmax
`
`(h)
`
`3.0
`(1.0)
`
`3.1
`(1.1)
`
`3.5
`(1.4)
`
`3.1
`(1.3)
`
`7.2
`(1.9)
`
`6.9
`(1.8)
`
`8.0
`(2.0)
`
`7.4
`(2.0)
`
`N
`
`60
`
`60
`
`55
`
`55
`
`50
`
`50
`
`54
`
`54
`
`T1/2
`
`(h)
`
`5.8
`(1.4)
`
`6.3
`(2.0)
`
`6.7
`(3.8)
`
`7.6
`(3.3)
`
`11.7
`(7.0)
`
`11.0
`(5.0)
`
`11.1
`(5.0)
`
`11.4
`(5.5)
`
`
`Administration of ACTOPLUS MET® XR 30 mg/1000 mg with food resulted in no change in
`total (AUC) exposure of pioglitazone; however, a decrease in Cmax by approximately 18% was
`
`observed. With the extended-release metformin component there was an increase in Cmax by
`approximately 98% and AUC exposure by approximately 85% when administered with food.
`These levels are comparable to exposures obtained with extended release metformin when
`administered with food. Time to peak serum concentration was prolonged by approximately 3
`and 2 hours for pioglitazone and extended-release metformin respectively, under fed conditions.
`
` Pioglitazone
`
` Following oral administration, in the fasting state, pioglitazone is first measurable in serum
`
`within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the
`
`time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption.
`
`Metformin hydrochloride
`The absolute bioavailability of a 500 mg immediate-release metformin tablet given under fasting
`conditions is approximately 50% - 60%. Studies using single oral doses of immediate-release
`metformin tablets of 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of
`dose proportionality with increasing doses, which is due to decreased absorption rather than an
`alteration in elimination. Food decreases the extent of and slightly delays the absorption of
`
`immediate-release metformin, as shown by approximately a 40% lower mean peak plasma
`concentration, a 25% lower AUC in plasma concentration versus time curve, and a 35 minute
`
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`prolongation of time to peak plasma concentration following administration of a single 850 mg
`tablet of immediate-release metformin with food, compared to the same tablet strength
`administered fasting. The clinical relevance of these decreases is unknown.
`
` The appearance of metformin in plasma from an extended-release metformin tablet is slower
`and more prolonged compared to immediate-release metformin (see FORTAMET prescribing
`information). In a multiple-dose crossover study, 23 patients with type 2 diabetes mellitus were
`administered either extended-release metformin hydrochloride 2000 mg once a day (after dinner)
`or immediate-release (IR) metformin hydrochloride 1000 mg twice a day (after breakfast and
`after dinner). After 4 weeks of treatment, steady-state pharmacokinetic parameters, area under
`the concentration-time curve (AUC), time to peak plasma concentration (Tmax), and maximum
`
`concentration (Cmax) were evaluated. Results are presented in Table 3.
`
`Table 3. Extended-Release Metformin vs. Immediate-Release Metformin Steady-State
`Pharmacokinetic Parameters at 4 Weeks
`
` Pharmacokinetic Parameters
`Extended-Release Metformin
`
`(mean ± SD)
` 2000 mg (administered daily with
`dinner)
`26,811 ± 7055
`6 (3-10)
`2849 ± 797
`
`Immediate-Release Metformin
` 2000 mg (administered as 1000 mg
`
`twice daily)
`27,371 ± 5,781
`3 (1-8)
`1820 ± 370
`
`AUC0-24 hrs (ng • hr/mL)
`
`
`Tmax (hr)
`
` Cmax (ng/mL)
`
`
`
` In four single-dose studies and one multiple-dose study, the bioavailability of extended-
`release metformin 2000 mg given once daily, in the evening, under fed conditions [as measured
`by the area under the plasma concentration versus time curve (AUC)] was similar to the same
`
`total daily dose administered as immediate-release metformin 1000 mg given twice daily. The
`geometric mean ratios (extended-release metformin/immediate-release metformin) of AUC0-24hr,
`AUC0-72hr, and AUC0-inf. for these five studies ranged from 0.96 to 1.08.
`
`
`In a single-dose, four-period replicate crossover design study, comparing two 500 mg
`extended-release metformin tablets to one 1000 mg extended-release metformin tablet
`administered in the evening with food to 29 healthy male subjects, two 500 mg extended-release
`metformin tablets were found to be equivalent to one 1000 mg extended-release metformin
`tablet.
`
`
`In a study carried out with extended-release metformin, there was a dose-associated increase
`in metformin exposure over 24 hours following oral administration of 1000, 1500, 2000, and
`2500 mg.
`
`
`In three studies with extended-release metformin using different treatment regimens (2000 mg
`after dinner, 1000 mg after breakfast and after dinner, and 2500 mg after dinner), the
`pharmacokinetics of metformin as measured by AUC appeared linear following multiple-dose
`administration.
`
`The extent of absorption (as measured by AUC) of extended-release metformin increased by
`approximately 60% when given with food. When extended-release metformin was administered
`
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`with food, Cmax was increased by approximately 30% and Tmax was more prolonged compared
`with the fasting state (6.1 versus 4.0 hours).
`
`Distribution:
`
` Pioglitazone
`The mean apparent volume of distribution (V/F) of pioglitazone following single-dose
`administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively
`protein bound (> 99%) in human serum, principally to serum albumin. Pioglitazone also binds to
`other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively
`bound (> 98%) to serum albumin.
`
`
`Metformin hydrochloride
`Distribution studies with extended-release metformin have not been conducted; however, the
`apparent volume of distribution (V/F) of metformin following single oral doses of immediate-
`release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma
`
`proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual
`clinical doses and dosing schedules of immediate-release metformin, steady-state plasma
`
`concentrations of metformin are reached within 24 - 48 hours and are generally <1 µg/mL.
`During controlled clinical trials of immediate-release metformin, maximum metformin plasma
`
`levels did not exceed 5 µg/mL, even at maximum doses.
`
`Metabolism, Elimination and Excretion:
`
`Pioglitazone
`
`Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also
`partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy
`derivatives of pioglitazone) and M-III (keto derivative of pioglitazone) are pharmacologically
`active in animal models of type 2 diabetes. In addition to pioglitazone, M-III and M-IV are the
`principal drug-related species found in human serum following multiple dosing. At steady-state,
`in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises
`approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total
`AUC.
`
`
`In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of
`pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree,
`CYP3A4 with additional contributions from a variety of other isoforms including the mainly
`extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and
`substrates have been performed (see PRECAUTIONS, Drug Interactions, Pioglitazone).
`Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed
`that pioglitazone is not a strong CYP3A4 enzyme inducer.
`
` Following oral administration, approximately 15% to 30% of the pioglitazone dose is
`recovered in the urine. Renal elimination of pioglitazone is negligible and the drug is excreted
`primarily as metabolites and their conjugates. It is presumed that most of the oral dose is
`excreted into the bile either unchanged or as metabolites and eliminated in the feces.
`
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`The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and
`16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to
`7 L/hr.
`
`Metformin hydrochloride
`Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted
`unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been
`identified in humans) nor biliary excretion. Renal clearance is approximately 3.5 times greater
`than creatinine clearance which indicates that tubular secretion is the major route of metformin
`elimination. Following oral administration, approximately 90% of the absorbed drug is
`eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of
`
`approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours,
`suggesting that the erythrocyte mass may be a compartment of distribution.
`
` Metabolism studies with extended-release metformin tablets have not been conducted.
`
`In healthy nondiabetic adults (N=18) receiving extended-release metformin 2500 mg daily, the
`
`percent of the metformin dose excreted in urine over 24 hours was 40.9% and the renal clearance
`was 542 ± 310 mL/min. After repeated administration of extended-release metformin, there is
`little or no accumulation of metformin in plasma, with most of the drug being eliminated via
`renal excretion over a 24-hour dosing interval.
`
`
`Special Populations
`Renal Insufficiency:
`
`Pioglitazone
`
`The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients
`with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30
`mL/min) renal impairment when compared to normal subjects.
`
`Metformin hydrochloride
`
`In patients with decreased renal function (based on creatinine clearance), the plasma and blood
`half-life of metformin is prolonged and the renal clearance is decreased in proportion to the
`decrease in creatinine clearance (see CONTRAINDICATIONS and WARNINGS, Metformin
`hydrochloride, also see GLUCOPHAGE® prescribing information, CLINICAL
`PHARMACOLOGY, Pharmacokinetics). Since metformin is contraindicated in patients with
`renal impairment, ACTOPLUS MET and ACTOPLUS MET XR are also contraindicated in
`these patients.
`
`Hepatic Insufficiency:
`
`Pioglitazone
`
`Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade
`B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak
`concentrations but no change in the mean AUC values.
`
`
` Therapy with ACTOPLUS MET or ACTOPLUS MET XR should not be initiated if the
`patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT)
`exceed 2.5 times the upper limit of normal (see PRECAUTIONS, General: Pioglitazone).
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`Metformin hydrochloride
`No pharmacokinetic studies of metformin have been conducted in subjects with hepatic
`insufficiency.
`
`Elderly:
`Pioglitazone
`
`In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are
`not significantly different, but AUC values are slightly higher and the terminal half-life values
`slightly longer than for younger subjects. These changes were not of a magnitude that would be
`considered clinically relevant.
`
`Metformin hydrochloride
`Limited data from controlled pharmacokinetic studies of immediate-release metformin in healthy
`elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is
`prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it
`
`appears that the change in metformin pharmacokinetics with aging is primarily accounted for by
`a change in renal function (see GLUCOPHAGE® prescribing information, CLINICAL
`
` PHARMACOLOGY, Special Populations, Geriatrics).
`
`ACTOPLUS MET or ACTOPLUS MET XR treatment should not be initiated in patients ≥ 80
`
`years of age unless measurement of creatinine clearance demonstrates that renal function is not
`reduced (see WARNINGS, Metformin hydrochloride and DOSAGE AND
`ADMINISTRATION; also see GLUCOPHAGE® prescribing information).
`
`Pediatrics:
`
`Pioglitazone
`Pharmacokinetic data in the pediatric population are not available. Use in pediatric patients is
`not recommended for the treatment of diabetes due to lack of long-term safety data. Risks
`
`including fractures and other adverse effects associated with pioglitazone, one of the components
`of ACTOPLUS MET and ACTOPLUS MET XR, have not been determined in this population
`(see WARNINGS and PRECAUTIONS).
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`Metformin hydrochloride
`After administration of a single oral immediate-release metformin 500 mg tablet with food,
`geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2
`diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45
`years of age), and all with normal renal function.
`
` Pharmacokinetic data for extended-release metformin tablets in the pediatric population are
`not available.
`
`Gender:
`
`Pioglitazone
`As monotherapy and in combination with sulfonylurea, metformin, or insulin, pioglitazone
`improved glycemic control in both males and females. The mean Cmax and AUC values were
`increased 20% to 60% in females. In controlled clinical trials, decreases from baseline in HbA1c
`were generally greater for females than for males (average mean difference in HbA1c 0.5%).
`Since therapy should be individualized for each patient to achieve glycemic control, no dose
`adjustment is recommended based on gender alone.
`
`Metformin hydrochloride
`Metformin pharmacokinetic parameters did not differ significantly between normal subjects and
`patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16).
`Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic
`effect of immediate-release metformin was comparable in males and females.
`
`
`Five studies indicated that with extended-release metformin treatment, the pharmacokinetic
`results for males and females were comparable.
`
`Ethnicity:
`Pioglitazone
`
`Pharmacokinetic data among various ethnic groups are not available.
`
`Metformin hydrochloride
`No studies of metformin pharmacokinetic parameters according to race have been performed. In
`controlled clinical studies of immediate-release metformin in patients with type 2 diabetes, the
`antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics
`(n=24).
`
`Drug-Drug Interactions
`
`Co-administration of a single dose of immediate-release metformin (1000 mg) and pioglitazone
`after 7 days of pioglitazone (45 mg) did not alter the pharmacokinetics of the single dose of
`metformin. Specific pharmacokinetic drug interaction studies with ACTOPLUS MET or
`ACTOPLUS MET XR have not been performed, although such studies have been conducted
`with the individual pioglitazone and metformin components.
`
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` Pioglitazone
`
` The following drugs were studied in healthy volunteers with co-administration of pioglitazone 45
`mg once daily. Results are listed below:
`
`Oral Contraceptives: Co-administration of pioglitazone (45 mg once daily) and an oral
`contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days,
`resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and Cmax respectively.
`There were no significant changes in norethindrone AUC (0-24h) and Cmax. In view of the high
`variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is
`unknown.
`
`Midazolam: Administration of pioglitazone for 15 days followed by a single 7.5 mg dose of
`midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC.
`
`
`Nifedipine ER: Co-administration of pioglitazone for 7 days with 30 mg nifedipine ER
`
`administered orally once daily for 4 days to male and female volunteers resulted in a ratio of
`least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 - 0.95) for Cmax and
`0.88 (0.80 - 0.96) for AUC. In view of the high variability of nifedipine pharmacokinetics, the
`clinical significance of this finding is unknown.
`
`Ketoconazole: Co-administration of pioglitazone for 7 days with ketoconazole 200 mg
`
`administered twice daily resulted in a ratio of least square mean (90% CI) values for unchanged
`pioglitazone of 1.14 (1.06 - 1.23) for Cmax, 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for
`Cmin.
`
` Atorvastatin Calcium: Co-administration of pioglitazone for 7 days with atorvastatin calcium
`
`(LIPITOR®) 80 mg once daily resulted in a ratio of least square mean (90% CI) values for
`unchanged pioglitazone of 0.69 (0.57 - 0.85) for Cmax, 0.76 (0.65 - 0.88) for AUC and 0.96 (0.87
`- 1.05) for Cmin. For unchanged atorvastatin the ratio of least square mean (90% CI) values were
`0.77 (0.66 - 0.90) for Cmax, 0.86 (0.78 - 0.94) for AUC and 0.92 (0.82 - 1.02) for Cmin.
`
`
`Cytochrome P450: See PRECAUTIONS, Drug Interactions, Pioglitazone
`
`Gemfibrozil: Concomitant administration of gemfibrozil (oral 600 mg twice daily), an inhibitor
`of CYP2C8, with pioglitazone (oral 30 mg) in 10 healthy volunteers pre-treated for 2 days prior
`with gemfibrozil (oral 600 mg twice daily) resulted in pioglitazone exposure (AUC0-24) being
`226% of the pioglitazone exposure in the absence of gemfibrozil (see PRECAUTIONS, Drug
`Interactions, Pioglitazone).1
`
`Rifampin: Concomitant administration of rifampin (oral 600 mg once daily), an inducer of
`CYP2C8 with pioglitazone (oral 30 mg) in 10 healthy volunteers pre-treated for 5 days prior
`with rifampin (oral 600 mg once daily) resulted in a decrease in the AUC of pioglitazone by 54%
`(see PRECAUTIONS, Drug Interactions, Pioglitazone).2
`
` In other drug-drug interaction studies, pioglitazone had no significant effect on the
`pharmacokinetics of fexofenadine, glipizide, digoxin, warfarin, ranitidine HCl or theophylline.
`
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`Metformin hydrochloride
`See PRECAUTIONS, Drug Interactions, Metformin hydrochloride
`
`Pharmacodynamics and Clinical Effects
`
`Pioglitazone
`Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant
`patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent
`glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose
`homeostasis. In patients with type 2 d