`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`
`22-024
`
`APPLICATION NUMBER:
`
`CLINICAL PHARMACOLOGY AND
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`BIOPHARMACEUTICS REVIEW! S 2
`
`
`
`
`
` 22-024
`
`
`
`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`
`NDA: 22-024
`Brand Name
`Generic Name
`
`Reviewer
`Team Leader (Acting)
`OCP Division
`OND Division
`Sponsor
`Submission Type
`Formulation; Strength(s)
`Indication
`
`
`
`
`
`
`
`Submission Date: 3/31/06
`ACTOPLUS MET XR
`and Metformin
`Pioglitazone Hydrochloride
`Hydrochloride Extended Release Tablets
`Jayabharathi Vaidyanathan, Ph.D.
`Jim Wei, Ph.D.
`DCP-2
`Division of Metabolic and Endocrine Products
`Takeda
`505 (b) (2)
`15 mg/ 1000 mg and 30 mg/ 1000 mg ; Oral tablets
`Treatment of Type 2 Diabetes Mellitus
`
`Table of Contents
`
`
`I. Executive Summary ................................................................................................... 2
`A. Recommendation................................................................................................... 2
`B.
`Phase IV Commitments......................................................................................... 3
` C. Summary of CPB Findings.. .................................................................................. 3
`II. QBR ............................................................................................................................. 3
`A. General Attributes.................................................................................................. 3
`B. General Clinical Pharmacology............................................................................. 5
`C.
`Intrinsic Factors ..................................................................................................... 5
`D.
`Extrinsic Factors.................................................................................................... 6
`E. General Biopharmaceutics..................................................................................... 6
`F. Analytical............................................................................................................. 15
`III. Labeling Comments ................................................................................................. 16
`IV. Appendix ................................................................................................................... 17
`A.
`Proposed Labeling ............................................................................................... 17
`B.
`Individual Study Synopsis................................................................................... 50
`C. OCP Filing Memo ............................................................................................... 66
`D. DSI Report........................................................................................................... 69
`
`
`
`
`
`
`
`
`
`1
`
`
`
`Executive Summary
`
`I
`
`Takeda has developed a fixed-dose combination tablet formulated as 15 mg/1000 mg and
`30 mg/1000 mg strengths from the following active ingredients from approved
`compounds Actos (pioglitazone HCl) NDA 21-073 held by Takeda Pharmaceuticals and
`Fortamet (metformin HCl extended release) NDA 21-574 held by Andrx Labs
`respectively.
`
`The efficacy and safety of the concomitant use of pioglitazone and metformin has
`previously been evaluated in controlled clinical trials (NDA 21-073). Concomitant
`administration of the separate commercial pioglitazone and metformin tablets in adult
`patients with type 2 diabetes was approved by the FDA in 1999 as a part of the original
`marketing approval of pioglitazone.
`
`Pioglitazone is approved for once-daily administration at doses of 15, 30 and 45 mg.
`Metformin extended release (Fortamet) is available in 500, and 1000 mg tablets and is
`approved for individualized treatment up to a maximum daily dose of 2500 mg in adults
`depending on effectiveness and tolerability. To improve gastrointestinal tolerability, it is
`recommended that Fortamet be administered with an evening meal. Fortamet has been
`shown to be bioequivalent to immediate release metformin under these dosing conditions.
`Pioglitazone can be administered regardless of meals.
`
`To aid in the approval of this application the sponsor has submitted 2 bioequivalence
`studies and 1 food effect study. There were no clinical studies done with the to-be
`marketed combination product and the pharmacokinetic studies were designed to bridge
`the proposed combination tablets to the clinical safety and efficacy database supporting
`the use of pioglitazone in combination with metformin existing under the approved NDA.
`
`Recommendation
`
` A
`
`
`
`
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology-2 (OCP/DCP-2)
`has reviewed the information provided in the NDA 22-024 for ACTOPLUS MET XR
`tablets and finds it acceptable. Recommendations and labeling comments should be sent
`to the sponsor as appropriate.
`
`_______________________
`Jaya Vaidyanathan, Ph.D.
`OCP/DCP-2
`
` clinical pharmacology briefing was held for NDA 22-024 on December 18, 2006; the
`attendees were Dr. Chandra Sahajwalla, Dr. Suresh Doddapaneni, Dr. Emmanuel
`Fadiran, Dr. Jim Wei, Dr. Robert Misbin, Dr. Jayabharathi Vaidyanathan and Carol
`Noory.
`
`
`
` A
`
`
`
`2
`
`
`
`Phase 4 Commitments
`
`Summary of CPB Findings
`
`B
`
`None.
`
` C
`
`
`
`
`The summary of results from the clinical pharmacology studies is provided below.
`
`Bioequivalence:
`
`Bioequivalence studies were conducted for the two strengths of combination tablet.
`Results indicate that the pioglitazone and metformin from ACTOPLUS MET XR 15
`mg/1000 mg and 30 mg/1000 mg tablets were bioequivalent to Actos and Fortamet
`commercial tablets given concomitantly under fed conditions. The conclusions are based
`on the findings that the 90% CI for the ratio of geometric means (test/reference) for AUC
`and Cmax were within the 80-125% interval.
`
`Food effect:
`
`
`The results demonstrated that after administration of the highest strength combination
`tablet (30 mg/1000 mg) under fed conditions, the AUC of pioglitazone was similar as
`compared to the fasted state while there was a decrease in Cmax by approximately 18%.
`While the metformin AUCinf and Cmax increased by 85% and 98% respectively in
`presence of food. Since metformin is indicated to be administered with food,
`ACTOPLUS MET XR is also recommended to be administered with food.
`
`
`
`
`II
`
`QBR
`
`General Attributes
`
`A
`
`What are the highlights of the chemistry and physico-chemical properties of
`ACTOPLUS MET XR?
`
`ACTOPLUS MET XR contains 2 oral antihyperglycemic drugs used in type 2 diabetes;
`pioglitazone hydrochloride and metformin hydrochloride. Pioglitazone ([(±)-5-[[4-[2-(5-
`ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-]
`thiazolidinedione monohydrochloride)
`(Figure 1) belongs to thiazolidinedione class. The molecule contains one asymmetric
`center, and the synthetic compound is a racemate. The two enantiomers of pioglitazone
`interconvert in vivo. Pioglitazone hydrochloride is an odorless white crystalline powder
`that has a molecular formula of C19H20N2O3S•HCl and a molecular weight of 392.90.
`
`Metformin hydrochloride (N, N-dimethylimidodicarbonimidic diamide hydrochloride) is
`not chemically or pharmacologically related to any other class of oral antihyperglycemic
`
`
`
`3
`
`
`
`agents. It is a white crystalline powder with a molecular formula of C4H11N5•HCl and a
`molecular weight of 165.62.
`
`Figure 1: Chemical structure of pioglitazone (top) and metformin (bottom).
`
`
`· HCl
`
`NH2
`
`HN
`
`CH3
`
`N
`
`H3C
`
`
`
`NH
`
`NH
`
`
`
`
`What is the proposed mechanism (s) of action and therapeutic indication?
`
`two antihyperglycemic agents with different
`ACTOPLUS MET XR combines
`mechanisms of action to improve glycemic control in patients with type 2 diabetes:
`pioglitazone hydrochloride, a member of thiazolidinedione class, and metformin, a
`member of the biguanide class. This is a 505 (b) (2) application. The proposed indication
`for the combination tablet is the same as that for the individual drugs.
`
`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.
`
`Metformin improves glucose tolerance in patients with type 2 diabetes, reducing both
`basal and postprandial plasma glucose levels. Metformin also decreases hepatic glucose
`production, decreases intestinal absorption of glucose and improves sensitivity by
`increasing peripheral glucose uptake and utilization.
`
`The proposed indication for ACTOPLUS MET XR is as an adjunct to diet and exercise to
`improve glycemic control in patients with type 2 diabetes who are already treated with a
`combination of pioglitazone and metformin 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.
`
`
`
`
`
`
`
`
`4
`
`S
`
`O
`
`• HCl
`
`
`
`NH
`
`O
`
`O
`
`H3C
`
`N
`
`
`
`
`
`
`What is the proposed dose and dosage form?
`
`ACTOPLUS MET XR is available in 15 mg pioglitazone hydrochloride (as the
`base)/1000 mg metformin hydrochloride extended-release and 30 mg pioglitazone
`hydrochloride (as the base)/1000 mg metformin hydrochloride extended-release tablets.
`
`ACTOPLUS MET XR is proposed be given once daily with the evening meal 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), ACTOPLUS MET XR
`is proposed to be initiated at either the 15 mg/1000 mg or 30 mg/1000 mg tablet strength
`once daily, and 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 (850 to 1000 mg total daily dose),
`ACTOPLUS MET XR is proposed to be initiated at either the 15 mg/1000 mg once daily
`or 30 mg/1000 mg tablet strength once daily, and titrated after assessing adequacy of
`therapeutic response.
`
`Starting dose for patients switching from combination therapy of pioglitazone plus
`metformin as separate tablets
`ACTOPLUS MET XR is proposed to be initiated with either the 15 mg/1000 mg or 30
`mg/1000 mg tablet strengths based on the dose of pioglitazone and metformin already
`being taken.
`
`
`
`General Clinical Pharmacology
`
` B
`
`
`What are the design features of the clinical pharmacology and clinical studies used
`to support dosing or claims?
`
`No clinical studies with the drug product were performed in support of this submission.
`Consistent with the requirements for a 505 (b) (2) application, the clinical pharmacology
`studies were performed to demonstrate the bioequivalence of the combined drug product
`to
`the
`commercially
`available
`reference
`products. Two
`doses
`of
`the
`pioglitazone/metformin extended release fixed dose tablet (15 mg/1000 mg and 30
`mg/1000 mg) were evaluated in 2 bioequivalence studies; the highest dose was evaluated
`in a food-effect study.
`
`Does this combination drug prolong QT or QTc interval?
`
`The sponsor has not submitted any study determining the effect of Actoplus Met XR on
`cardiac repolarization. However, both Actos® (pioglitazone) and Fortamet® (metformin
`
`
`
`5
`
`
`
`extended release) are approved drugs in the US and no reports of any adverse effects of
`these drugs due to their effect on cardiac repolarization has been reported thus far.
`
`
`
`Intrinsic Factors
`
` C
`
`
`The effects of various intrinsic factors (e.g., hepatic, renal, gender, elderly) were provided
`in the original NDA for each drug.
`
`Extrinsic Factors
`
`D
`
`Is there any drug-drug interaction between pioglitazone and metformin?
`
`Specific pharmacokinetic drug interaction studies with ACTOPLUS MET XR have not
`been performed, although such studies have been conducted with the individual
`pioglitazone and metformin components. The proposed label has the following statement:
`“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.”
`
`
`
`General Biopharmaceutics
`
` E
`
`
`What is the formulation of ACTOSPLUS MET XR tablets?
`
`ACTOPLUS MET XR tablets are a combination product containing either 15 mg + 1000
`mg or 30 mg + 1000 mg of pioglitazone hydrochloride (as the free base) and metformin
`extended release respectively. The composition of the tablets used in clinical
`pharmacology studies are shown in Table 1. The proposed tablets are white, round
`tablets that consist of a metformin extended-release core coated with an immediate-
`release pioglitazone layer. The 2 tablet strengths differ only in tablet weight. The tablets
`used in clinical pharmacology studies are identical in composition to those intended for
`commercial distribution except for the addition of imprinting with unique markings,
`utilizing different color inks for each of the tablet strength.
`
`
`Table 1: Composition of Actoplus Met XR tablets
`
`
`
`6
`
`
`
`
`
`
`
`The metformin extended-release component of the ACTOPLU MET XR is an extended
`release formulation of metformin for once-daily administration, which is based on the
`proprietary SCOT
`(single composition osmotic
`tablet)
`technology of Andrx
`Pharmaceuticals. This consists of an active core encased in a rate controlling semi-
`permeable membrane with 2 laser-drilled exit orifices. The rate of metformin release
`from the tablet is controlled by the osmotic gradient and the characteristics of the semi-
`permeable membrane.
`
` Pioglitazone is coated on the
`
`
`surface of metformin core using
`
`
`
`
`Is the dissolution method appropriate for ACTOPLUS MET XR tablets?
`
`Dissolution will be reviewed by Chemistry Reviewer. Please refer to CMC review for
`details.
`
`
`
`7
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`
`
`Bioequivalence Study:
`
`1) Is the combination tablet formulation of pioglitazone and metformin (15 mg/1000
`mg) bioequivalent to concomitant dosing of pioglitazone 15 mg and metformin
`extended release 1000 mg (15 mg + 1000 mg) commercial tablets in healthy
`subjects?
`
`Yes. Both pioglitazone and metformin components from the fixed dose combination tablet
`were bioequivalent to the individual commercial tablets (1 pioglitazone 15 mg + 1
`metformin XT 1000 mg).
`
`An open-label, randomized, 2-sequence, 2-period crossover BE study was conducted in
`healthy subjects (64 enrolled; 60 completed; 18-55 yrs) in the fed state (Study
`OPIXT002). The study drug was administered 30 minutes following a high fat evening
`meal. A washout interval of 7 days separated the 2 treatments. Blood samples were
`collected for pioglitazone and metformin PK analysis through 48 h following each
`treatment. The treatments were:
`
`
`
`The mean serum concentrations for pioglitazone from the two treatments are shown in
`Figure 2.
`
`
`Figure 2: Mean serum pioglitazone concentration-time profile following
`administration of the combination tablet and separate commercial tablets
`
`
`
`Mean serum concentrations of pioglitazone were lower after dosing with the test
`treatment (Fixed dose combination tablet) than after dosing with the reference treatment
`(Actos 15 mg + Fortamet 1000 mg). By 48 h, pioglitazone levels were below the limit of
`quantification following both treatments.
`
`
`
`
`8
`
`
`
`Statistical analysis of the PK parameters indicated that the 90% CI for the ratios of the LS
`means for AUClast, AUCinf, and Cmax of pioglitazone were well within the prespecified
`80-125% bounds and therefore met the criteria of bioequivalence (Table 1). The Tmax
`was also similar between the two treatments (~3 h).
`
`
`Table 2: Statistical summary of pioglitazone following administration of
`combination tablet (Test) and separate commercial tablets (Reference)
`
`
`The mean serum metformin concentrations are shown in Figure 3 below. Following both
`treatments, the serum metformin concentrations were identical. By 48 h post-dose the
`serum levels were near the lower limit of quantitation (10 ng/ml).
`
`Figure 3: Mean serum metformin concentration-time profile following
`administration of the combination tablet and separate commercial tablets
`
`
`
`
`
`The PK parameters of metformin following the two treatments were also similar. The
`median Tmax for metformin was 7 h for both treatments. The statistical analysis
`indicated that the 90% CI for the ratios of LS means for AUClast, AUCinf, and Cmax of
`metformin were within the 80-125% interval for establishing the bioequivalence (Table
`3).
`
`
`
`
`
`
`
`
`
`9
`
`
`
`Table 3: Statistical summary of metformin following administration of combination
`tablet (Test) and separate commercial tablets (Reference)
`
`
`Note: The sponsor conducted analysis after removal of subjects 36, 57 102, and 69.
`Subjects 36 and 57 discontinued after period 1 due to adverse events following test
`administration, while subjects 102 and 69 were withdrawn because of protocol violations
`of positive urine drug screen after reference treatment. Analysis including these subjects
`was conducted by the reviewer and resulted in comparable results to that presented in
`tables above (Table 4).
`
`
`
`
`Table 4: Statistical analysis of PK parameter data from all subjects enrolled
`
`
`Pioglitazone
`
`Metformin
`
`PK
`Parameter
`
`
`AUClast
`
`
`AUCinf
`
`
`Cmax
`
`LS Mean
`Reference
`
`5320.73
`
`
`5774.43
`
`
`546.18
`
`LS
`Mean
`Test
`4495.68
`
`
`4886.48
`
`
`471.61
`
`Ratio
`(90%CI)
`
`LS Mean
`Reference
`
`LS Mean
`Test
`
`Ratio (90%CI)
`
`84.49 (80.68 –
`88.49)
`
`84.62 (81.25 –
`88.14)
`
`85.79 (81.62 –
`90.17)
`
`14305.44
`
`
`14669.12
`
`
`1565.73
`
`13898.80
`
`
`14243.18
`
`
`1520.50
`
`(94.22 –
`97.16
`100.19)
`
`97.10 (94.20 –
`100.08)
`
`97.11
`
`
`
`
`
`
`
`
`
`2) Is the combination tablet formulation of pioglitazone and metformin extended
`release (30 mg/1000 mg) bioequivalent to concomitant dosing of pioglitazone 30 mg
`and metformin extended release 1000 mg (30 mg + 1000 mg) commercial tablets in
`healthy subjects?
`
`Yes. Both pioglitazone and metformin components from the fixed dose combination tablet
`were bioequivalent to the individual commercial tablets (1 pioglitazone 30 mg + 1
`metformin XT 1000 mg).
`
`
`
`
`10
`
`(b) (4)
`
`
`
`In order to address the bioequivalence of the 30 mg/1000 mg combination tablet, an
`open-label, randomized, 2-period crossover study (Study OPIXT003) was conducted in
`healthy subjects under fed conditions. As in the previous BE study the study drug was
`administered 30 minutes following a high fat evening meal. A washout interval of 7 days
`separated the 2 treatments. Blood samples were collected for pioglitazone and metformin
`PK analysis through 48 h following each treatment. The two treatments were:
`
`
`
`Results indicate that the serum pioglitazone concentrations were similar after dosing with
`both the test and reference treatments (Figure 4). By 48 h post dose mean pioglitazone
`concentrations were near or below the limit of quantification.
`
`
`Figure 4: Mean serum concentration-time profile for pioglitazone following
`administration of combination tablet (test) and separate commercial tablets
`(reference)
`
`
`Statistical analysis of the PK parameters indicated that the 90% CI for the ratios of the LS
`means for AUCinf, AUClast and Cmax of pioglitazone were within the 80-125% interval
`and therefore met the criteria for bioequivalence (Table 5). The median Tmax was similar
`for each treatment.
`
`
`Table 5: Statistical analysis of pharmacokinetic parameters for pioglitazone
`
`
`
`
`
`11
`
`
`
`
`
`Similarly, serum metformin concentrations were similar after administration of the
`combination tablet and the reference treatment (1 pioglitazone 30 mg + 1 metformin XT
`1000 mg commercial tablets). By 48 h post dose concentrations were below the limit of
`quantification. The statistical analysis of the PK parameters for metformin also indicated
`bioequivalence between the two treatments (Figure 5 & Table 6). The median Tmax for
`metformin was longer following the reference treatment.
`
`
`Figure 5: Mean serum metformin concentrations over time
`
`
`Table 6: Statistical analysis of PK parameters for metformin
`
`
`
`
`Note: The sponsor used data from subjects who finished both treatments. Subjects 12 and
`16 received the reference treatment in period 1 and voluntarily withdrew consent and
`discontinued in the study; Subject 50 received both treatments, then voluntarily withdrew
`consent and discontinued in period 2; Subject 5 received reference treatment in period 1,
`but was withdrawn due to protocol violation (positive urine drug result). In addition
`sponsor mentioned that subject 20’s serum concentration from reference pioglitazone
`treatment were all below the limit of quantification, therefore this subject was excluded
`from pioglitazone analysis. Analysis including these subjects was conducted by the
`reviewer and resulted in comparable results to that presented in tables above (Table 7).
`
`
`
`
`
`
`
`
`
`12
`
`
`
`Table 7: Statistical analysis of PK parameter data from all subjects enrolled
`
`
`Pioglitazone
`
`Metformin
`
`PK
`Parameter
`
`
`AUClast
`
`
`AUCinf
`
`
`Cmax
`
`LS Mean
`Reference
`
`8519.01
`
`
`8996.35
`
`
`836.36
`
`LS
`Mean
`Test
`7537.82
`
`
`7988.61
`
`
`740.52
`
`Ratio
`(90%CI)
`
`LS Mean
`Reference
`
`LS Mean
`Test
`
`Ratio (90%CI)
`
`88.48 (84.61 –
`92.53)
`
` 88.80 (85.01
`– 92.75)
`
` 88.54 (83.30
`–94.11)
`
`12004.49
`
`
`12311.58
`
`
`1290.19
`
`12012.95
`
`
`12319.75
`
`
`1292.29
`
` 100.07 (95.49 –
`104.87)
`
` 100.07 (95.67 –
`104.67)
`
` 100.16 (96.27 –
`104.21)
`
`
`
`What is the effect of food on the bioavailability of Actoplus Met XR?
`
`Food decreased the Cmax of pioglitazone from the combination tablet by 18% with no
`change in exposure. On the other hand in presence of food, there is about 85% - 100%
`increase in AUC and Cmax of metformin component from the combination tablet.
`
`In order to determine the effect of food on the absorption of pioglitazone and metformin
`from the combination tablet, an open-label, randomized, single-dose, 2-period, crossover
`design study was conducted. Subjects were randomly assigned to 1 of 2 sequences (12
`subjects per sequence) and received the fixed dose combination tablet (30 mg/1000 mg)
`in fasting state or after a high fat meal. There was a washout period of 7 days between
`treatments.
`
`The mean serum pioglitazone concentrations over time are shown in the Figure 6 below.
`Under fasting conditions, pioglitazone from the combination tablet was rapidly absorbed
`as compared to under fed conditions. Statistical comparisons of the PK parameters are
`presented in Table 8. For pioglitazone, the 90% CI of the fed/fasted LS mean ratios for
`AUClast, AUCinf were within the 80-125% interval indicating that the total exposure
`was not altered with food. However the Cmax decreased 18% in presence of food and
`this was statistically significant with the 90% CI being lower than the 80-125% range.
`Tmax increased by 3 h in presence of food.
`
`
`
`
`
`
`
`
`
`
`
`
`13
`
`
`
`Figure 6: Mean serum pioglitazone concentrations over time
`
`
`Table 8: Statistical comparisons of pioglitazone from combination tablet (30
`mg/1000 mg) administered in presence (T) and absence (R) of food.
`
`
`
`
`The mean serum metformin concentrations time profile is shown in Figure 7. As seen
`there is a delay in Tmax in presence of food, however food increases the exposure to
`metformin.
`
`
`
`
`
`
`
`
`Figure 7: Mean serum metformin concentrations over time
`
`
`
`14
`
`
`
`The statistical comparisons of the PK parameters are shown in Table 9. In presence of
`food there is approximately 85%, 100%, and 98% increases in AUCinf, AUClast and
`Cmax of the Actoplus met XR tablet. The 90% CI for the LS mean ratios for these PK
`parameters were all above the 80-125% range indicating that the peak and total exposure
`of metformin is increased when the combination tablet is administered with food.
`
`Table 9: Statistical comparisons of metformin from combination tablet (30 mg/1000
`mg) administered in presence (T) and absence (R) of food.
`
`
`
`
`Comment: The effect of food observed in this study on pioglitazone and metformin XR is
`similar to that observed for the individual components based on the package insert of
`Actos and Fortamet respectively. The delay in Tmax and decrease in Cmax for
`pioglitazone will most likely not have an impact on efficacy of pioglitazone since there
`was no change in exposure in presence of food. Metformin is indicated to be
`administered in presence of food to decrease the GI adverse events. The AUC and Cmax
`values obtained in presence of food in this study is similar to that (metformin component
`of reference and test product) seen in BE study OPIXT003 done under fed conditions.
`Therefore this suggests that absorption of metformin from the formulation is decreased in
`fasting state. The sponsor has proposed that the Actoplus met XR tablet be taken with an
`evening meal which is acceptable.
`
`Analytical
`
` F
`
`
`
`
`Have the analytical methods been sufficiently validated?
`
`Yes.
`
`An LC/MS/MS method for the quantification of pioglitazone in human serum was used.
`The internal standard for pioglitazone used was an analog
`. The analyte and
`internal standard were extracted from human serum using solid-phase extraction. The
`residue was reconstituted using mobile phase and injected onto an LC/MS/MS. The
`LLOQ was 25.0 ng/ml and the standard curve was linear up to 2500 ng/ml. Intra-assay
`and inter-assay precision were determined from the relative standard deviations of the
`quality control samples. The values were all below 6% (Table 10). The accuracy was
`
`
`
`15
`
`(b) (4)
`
`
`
`determined by comparing the mean measured concentrations of the quality control
`sample with their nominal concentrations (Table 10).
`
`
`Table 10: Intra-assay and inter-assay precision and accuracy for pioglitazone in
`serum
`
`
`An LC/MS/MS method was used for analysis of metformin in human serum. The internal
`standard used for metformin was
`. The analyte and internal standard
`were extracted using human serum using protein precipitation. The LLOQ was 10.0
`ng/ml and the standard curve was linear up to 3500 ng/ml. The values of assay precision
`and accuracy are shown in Table 11.
`
`Table 11: Intra-assay and inter-assay precision and accuracy for metfomin in serum
`
`
`
` Concentration
`
`
`III Labeling Recommendations
`
`
`
`
`
`
`
`
`16
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`
`
`IV Appendix
`
`
`
`Proposed Package Insert
`
`17
`
` A
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`32 pp withheld immediately after this page as (b)(4) draft labeling.
`
`(b) (4)
`
`
`
`
`
`
`
`NDC 64764-310-30
`NDC 64764-310-60
`NDC 64764-310-90
`
`Bottles of 30
`Bottles of 60
`Bottles of 90
`
`STORAGE
`ACTOPLUS MET
`Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
`Room Temperature]. Keep container tightly closed, and protect from moisture and
`humidity.
`ACTOPLUS MET XR
`Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Avoid excessive heat
`and humidity. Dispense in a tightly closed, light-resistant container.
`
`Individual Study Synopsis
`
`
`
` B
`
`
`1) Bioequivalence study
`
`
`
`
`
`50
`
`
`
`(b) (4)
`
`(b) (4)
`
`
`
`Title oi Study:
`
`Au Grunt-Label: Randomized. l-Feriod lll‘:"tssot'er Ensdy to Determine the Elioecuit'alence of 15 nag
`P:og|ita..tone and IEIIIIIII 111.; h-Iett'onnsn HE] Etctended Release {KT} When Administered as e Fined-Dose
`Conibiisaciou Product or [onccunitantly as Connnercial Tablets
`
`_...-......_
`
`new
`
`
`
`T= Testteatlnanttl .D—lEBi‘CT tablet].
`F'.=F.efee_'|ce ttss: :oent-l pLoeJ'.snans ii are canncin'cialtablet acdl nnecfiarinin 1. lb: llI in= conunetctal tsbl at:
`{:a Sable: snete admitted to theclInLc and closed onlliaj' 1 ofeacJ Fenod. acd tiara c'isc n'atgetl toln L"IE anLc an
`Day So:'eaclt Fertori
`
`Inmber of Subjects [Planned and Analyzed}:
`Planned: Ii-l E'.‘ll3_'|EC[E-; 32 s'.1l:_1e.cts per sec_uence
`Analyzed: Plsannacobtleucs—dll subjects; E-afery—IS—l s'.tb;e-.tts.
`
`Diagnosis and Main lllriteria ior Inclusion:
`'l'o q".telif1.. :'o: study petrictpazau. subjects inttst 'net‘e beeu healthy male subjects orliealdsy nonpregnaist.
`nonlactating feniale sub;ects aged 13 to ii years. inclusite; been willtug to signthe informed consent fol-tn;
`had clinical laboratory results within the.'eference reuges or that l‘. ere acceptable to LlLE intes1i sater:
`tse: alsed at least 1 113' poundsF"- l-tgi andLad a body :nas s index 5.30 It; 11'. and had neaa..se Lepetit‘.‘:-
`panel and human innnunodeficieucy virus eutibod1. test results at Ir:ic:eeuing.r
`
`Test Product: Dose and Mode of.-'Ld1ninistration:1ot Number:
`
`Diel
`AD—‘ESSF-E'l'
`
`Dose
`Pioglitaroue hydrochloride 15 mg
`nietfitlrnnnlsydroclfloride l'sl'l' 16-3-3 nag.r
`DnrtLrion oi Treatment:
`
`Form
`Fined-dose
`conibnsauou tablet
`
`'l'lse duration oftlie study 5:: a sLtbgect who completed bod; creatnaents was ll] days.
`
`Reference Therapy, Dose and Mode oi Administration, Lot anaber:
`
`Route
`I:ltral
`
`Lot No.
`578315339.
`
`Drug
`
`P:og|ita..tone liydrocl'Joride [ACTDEF]
`
`Dose
`
`l5 In;
`
`I'Iett'ornin; ':L1.'d:o-.tlilo1tde l.'=IT [FORTMET‘]
`
`lflflfl 1:1;
`
`Tonia
`
`Commercial
`tablet
`
`Commercial
`tablet
`
`
`
`
`
`51
`51
`
`
`
`Title of Study:
`A1: ISheet-Label. Randomized. l-Feriod Crossover |":irudy to Determine the Elioec_u.i1.'alence of 15 mg
`Ptoglitaaone and lSIZIIII mg l-Iet:'or1n:n HE] Extended Felease {KT} 1t‘i."l:en Administered as a Fined-Dose
`Combination Product or E onc omitantly as Commercial Tablets
`«C titetio for Evaluation:
`Pharmacolcinerit:
`
`The area under the conceutrat.on-r.me curve from tine CI to date oflast c_uant.fiable concentradon
`{ALTCDl-thcj. area under the conceutrat.on-t:n1e ctuve from t_me CI to infin:ty (AL'CDll-inij]. maximum
`observed concentration [Cmaxj. time at which I:l‘mau occurred fl'naaaj. terminal-phase elin1inar.on rate
`constant (it). andtermmal ejmination half-life {Tl 3] were calculated for each subject from serum
`conceutrat.ons oftmchangecl ptoglitaaone and naetfiormin :'or each 1rea1'ment using a noncompartmental
`approach Actual sambltng 1imes rather tnau scheduled samjflng times were used in the como'.uat.on_=. of
`pharmacohinelic parameters.
`Safety:
`'ariables were adverse eteuts. cjnical laboratory test results (hematology. serum chemisn'y. ancl
`_
`urinalysis}. vital stgu measuremeuts. ll-lead elecn'oc ardiogram {ECG} results. and physical examinattm:
`finding
`Statistical Methods:
`
`Pharmacolcineric Analysis:
`Descriptive stat.s1ics (eg. ntu11be: of subjects. mean. '33. median. nttinimtun. and maximum..." were used to
`summarize serum concentrations by treatment and scheduled lime of samplmg for pioghtazone and
`me1formi1:. The pharmacolctnetic parameters. ALTlCtIl-thc). ALTCfll-infl. Emaa. 'l'mau 3.2. aud T1 2 o:'
`piogluazone aud metformin were stumnattned for each treau11ent with the following descltpciue sta'Iiscics'
`number of subjects. mean. gemnetrtc mean [for AL'
`{El-tlcc}. AUCUll-ini} aud Cmaa only; SD. SE.
`coefEcLent o:'1.'ai.iat.on. minin1.m1._ Eith aud Tith perc endles. naed:an. and maximum.
`'l'he AUCIIZI-tlcc} ALT. [El-ind} ratio was determined for each subject; iftl'.e AUEIIZI-thc} value c omprtsed
`less than 50% of the AUCfiD—infj value :'or an '_1:d11.idualsub.'ect. that subject's AUCfiD—inf] was not
`included inthe desctiptve statist...s orbioec_u.i1.alence assessment. The r"' value was also calculated fitlr each
`subject; ifthe 1" value for 3-1 was less than CLSIJ. d:at subject's AUtlflll-infju. .‘-_r aud 1'1 2 values were not
`included inthe desctiptve statist.cs orbioec_u.i1.'alence assessment.
`A1: analysis ofvariauce with fitted effects for sequence. petiod. n'eatnaent. and random effect for sub;ect
`nested within sec_uence was performed on it: and the natural logatithms of ALTCIjJ-thc}. AUCfiG—mfl. aud
`Cmax ot' pioglitazoue and mett'ormin 'l'he 'd'ilcoxcln si med-rank test was performed on T‘maa.
`'l'he iii-3i: confidence intervals [Cls] :'orthe rat.os of d:e least-squares (LS: mean fin: d:e test treatment
`:1 AD 433355 tablet} to