CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
`
`APPLICATION NUMBER:
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`201281Orig1s000
`
`MEDICAL REVIEW(S)
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`Cross Discipline Team Leader Review
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`Cross-Discipline Team Leader Review
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`
`Date
`10/1 5/2011M
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`From
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`Ilan Ironm_ Cross-DisciMline Team Leader Review
`
`NDA/ Su lement#
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`201281/ Ori - inal submission
`
`Boehrin ' er In - elheim Pharmaceuticals, Inc.
`
`Date of Submission
`January 19, 2011
`
`PDUFA Goal Date
`November 19, 2011
`
`Established
`
`S ‘
`
`names
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`fixed dose combination
`
`Dosage forms / Strength
`
`Oral Tablets in the following dose strengths:
`Linagliptin 2.5 mg / metformin 500 mg,
`Linagliptin 2.5 mg / metfonnin 850 mg and
`/ metformin 1000 m-
`
`Com-lete Resonse
`
`Pro nosed Indication 5
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`Im rove l cemic controlm adults atients with T2DM
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`Cross Discipline Team Leader Review
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`1. Introduction
`
`This is an original New Drug Application (NDA) submitted under section 505(b)(2) of the
`Federal Food, Drug and Cosmetic Act. The reference listed drug is the US approved labeling
`for Glucophage (metformin). The NDA is for a fixed dose combination tablet (FDC) of
`linagliptin, a dipeptidyl peptidase 4 inhibitor (DPP4-i) and metformin, the only member of the
`biguanide class. Both components are approved in the US. When this NDA was submitted to
`FDA for review (January 2011), the original linagliptin NDA was still under review. This
`NDA was therefore considered as new molecular entity. Since linagliptin was approved in
`May 2011, the FDC NDA is no longer a new molecular entity. As a FDC between two
`approved products, approval is dependent on demonstration of bioequivalence (BE) between
`the two components (linagliptin and metformin) and the FDC, regarding specified
`pharmacokinetic and pharmacodynamic characteristics.
`2. Background
`
`Linagliptin is the third DPP4-i approved in the US. It improves glycemic control in patients
`with type 2 diabetes mellitus (T2DM) by inhibiting the inactivation of GLP-1 and GIP
`(incretin hormones) and prolonging the incretin effect on beta cells (serum glucose-dependent
`insulin stimulation) and alpha cells (glucagon suppression). GLP-1 in particular has other
`effects that contribute to improved glucose control in diabetics, such as appetite suppression
`and slowing of the rate of gastric emptying. Metformin is effective in decreasing hepatic
`glucose output and decreasing peripheral glucose utilization. Metformin gained a first line
`treatment recommendation by the American Diabetes Association and other diabetes
`professional organizations, and is widely used in the treatment of T2DM.
`To support the approval of linagliptin under NDA 201280, the applicant has conducted Phase
`2 and Phase 3 trials where the effect of linagliptin was assessed in subjects not adequately
`controlled with metformin alone. In addition, the applicant has demonstrated no drug-drug
`interaction between linagliptin and metformin. As a result of these aforementioned studies and
`their results, approval of a FDC for treatment of T2DM is dependent on demonstration of BE
`(geometric means ratio of Cmax and AUC of linagliptin and metformin in the FDC to the same
`parameters measured when linagliptin and metformin are administered separately fall within
`an interval (e.g., 80 - 125%] that is unlikely to incur clinically significant variations). The FDC
`then is approved for either patients already taking both linagliptin and metformin separately, or
`for patients whose glycemic control remains inadequate despite treatment with either
`
`linagliptin or metformin. To allow treatment with the FDC in patients
`the applicant must show that the coadministration (or alternatively, the FDC) is more effective
`than each component alone,
` Such
`factorial study was conducted by BI and submitted under the current NDA for review.
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`Cross Discipline Team Leader Review
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`3. CMC/Device
`
`Refer to Dr. Markofsky’s review for details of the CMC issues. CMC recommends a Complete
`Response, due to the Establishment Inspection recommendation. As of 11/7/11, the
`recommendation from the Office of Compliance/ Office of Manufacturing and Product Quality
`/ Division of GMP Assessment was for Withhold for the
` manufacturing site, with
`an “Official Action Indicated” for that site.
`The three dose strengths (linagliptin / metformin 2.5 mg / 500 mg, 2.5 mg / 850 mg and 2.5 mg
`/ 1000 mg) are packaged in HDPE bottles in the following presentations: 14-count (for
`physician samples), 60-count (for one month supply), 180-count (for 3-month supply, and
`2000-count (for mail-order pharmacies).
`Besides linagliptin and metformin HCL, the drug product contains the following inactive
`ingredients: arginine, corn starch, copovidone, colloidal silicon dioxide, magnesium stearate,
`titanium dioxide, propylene glycol, hypromellose, talc, yellow ferric oxide (2.5 mg/500 mg;
`2.5 mg/850 mg tablets) and/or red ferric oxide (2.5 mg/850 mg; 2.5 mg/1000 mg tablets). All
`of the inactive ingredients are compendial.
`Refer to linagliptin NDA 201280 for linagliptin drug substance information. Metformin
`hydrochloride (USP) is manufactured by
` BI referenced DMF
`for the CMC information related to the metformin HCl drug substance, and based on the
`Chemistry reviews of this DMF, this drug substance (metformin HCl) is adequate to support
`this NDA (201281). BI’s specification and testing procedures also comply with the USP
`monograph for metformin HCl.
`The stability studies support an expiration-dating period of 24 months for all strengths of the
`tablets when stored at room temperature [25°C (77°F)], with excursions permitted between 59
`°F to 86°F (15°C to 30°C) packaged in all of the proposed commercial container closure
`systems. Consequently, a 24 month expiry is granted.
`From a CMC standpoint, the initial recommendation for approval had been based on:
`• Adequate information was provided in the NDA for the synthesis, purification and controls
`of the drug substances
`• Adequate manufacturing information to support the proposed to-be-marketed drug product
`• Adequate specifications and controls for the drug product
`• Satisfactory methods to support lot release and stability monitoring of the drug product
`• Adequate stability package to support the recommended expiry period of the drug product.
`
`
`
`That initial recommendation was changed to a Complete Response as a result of the Office of
`Compliance recommendation for Withhold for one of the manufacturing sites.
`
`4. Nonclinical Pharmacology/Toxicology
`
`The nonclinical pharmacology / toxicology team recommends approval of the NDA. Please
`refer to Dr. Carlson’s review for details.
`A single, ‘proof of concept’ study in diabetic mice showed a slight improvement in baseline
`fasting glucose and improved glucose excursion after oral glucose tolerance test (oGTT) with
`combined linagliptin and metformin treatment compared to either drug alone. The study was
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`Cross Discipline Team Leader Review
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`limited to one week duration. Nevertheless, the diabetic mouse study supports the clinical
`finding of improved blood glucose control with coadministration of linagliptin plus metformin
`treatment over monotherapy treatments.
`Nonclinical toxicology studies were conducted with coadministration of linagliptin and
`metformin, where linagliptin was given once daily. These studies did not identify any efficacy
`or safety endpoints that may be affected by a change from QD to BID dosing of linagliptin
`(same AUC0-24h, with lower Cmax compared to QD dosing).
`Pivotal toxicity studies were conducted to bridge potential toxicity of the coadministration of
`linagliptin and metformin. No unexpected toxicity or significant supra-additive or synergistic
`interactions attributed to coadministration were identified that would alter previous
`pharmacology and toxicology conclusions about the safe use of linagliptin and metformin in
`the treatment of T2DM. Toxicity in nonclinical studies was driven by metformin, as expected
`based on dosing ratios and large safety margins with linagliptin. Major target organs of
`metformin were heart and liver, as evidenced by heart hypertrophy with immune cell
`infiltration/inflammation and liver hypertrophy with concomitant hepatic injury and elevated
`liver enzyme biomarkers, starting at approximately 10-times the expected clinical AUC
`exposures. Linagliptin coadministration did not have any apparent effect on heart, liver or
`other metformin-related toxicity on target organs including stomach and GI tract, salivary
`glands, lymphoreticular tissues, or reproductive tissues.
`No carcinogenicity studies were conducted with linagliptin and metformin coadministration.
`Neither linagliptin nor metformin are genotoxic and neither is considered to pose a significant
`carcinogenic risk at clinical exposures. Several linagliptin impurities, including potential or
`theoretical impurities and degradants, were identified and adequately qualified to show no
`significant toxicologic or carcinogenic risk. No further carcinogenicity testing with the
`combined drugs is necessary.
`A notable new toxicity issue was identified in the nonclinical program suggesting potential
`metformin-induced teratogenicity. Metformin is not listed as teratogenic at approximate
`clinical exposures (estimated based on body surface area) in current labels. Studies conducted
`by BI clearly demonstrated that metformin at 10- to 20-times human exposure caused skeletal
`malformations in Wistar Han rats (a rat species often used in European toxicology studies).
`The studies confirmed that metformin is not teratogenic at approximate clinical exposures
`(clear NOAELs were established). Linagliptin combination treatment did not have any
`remarkable effect on the metformin-related malformations. The use of Wistar Han rats seems
`significant because most embryofetal development studies are conducted in Sprague Dawley
`(SD) rats. The reference Glucophage® label does not note the rat strain used but it seems clear
`from the original pharmacology/toxicology review(s) that SD rats were used. Wistar rats are
`reported to be more sensitive to heart malformations than SD rats and they seem to be more
`susceptible to the rib and scapula malformations seen with metformin treatment. More
`importantly, metformin was clearly toxic to pregnant rats at the teratogenic doses, causing
`reduced body weight gain, modestly reduced plasma glucose (albeit not to marked
`hypoglycemic levels), and signs of metabolic acidosis (e.g., urine pH and serum electrolyte
`changes). Body weight decrements typically cause developmental delays (e.g., delayed skeletal
`ossification), but even maternal body weight loss does not seem to cause fetal malformations
`in rats. On the other hand, both hypoglycemia and metabolic acidosis are known to cause fetal
`malformations. Importantly, data from other DPP4 inhibitor development programs
`coadministered with metformin do not confirm metformin-induced skeletal malformations.
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`Several important trends were apparent from those recent studies: all were conducted in SD
`rats; all confirmed the absence of metformin teratogenicity at clinical exposures; all confirmed
`the absence of a significant effect of DPP4 inhibitor plus metformin combination treatment on
`embryofetal development; and, some of the studies confirmed metformin was not teratogenic
`at exposures up to approximately 10X MRHD.
`The mechanism of metformin-induced teratogenicity was not investigated in this NDA. At the
`time of this writing, FDA has requested from the applicant evidence supporting the
`explanation that the malformations were related to hypoglycemia in the pregnant rats. Clearly
`there are differences in the embryofetal study results for this NDA compared to those
`described on the existing metformin labels and in other DPP4 inhibitor nonclinical programs.
`It is likely the maternal toxicity at teratogenic doses contributed to fetal findings, since there
`were no fetal malformations in the absence of metformin-induced maternal toxicity. It is
`equally important to emphasize that both metformin alone and the combined linagliptin plus
`metformin treatment were not teratogenic at approximate clinical exposures (by AUC),
`consistent with the current metformin label. Nevertheless, the teratogenicity findings at
`maternally toxic metformin doses in Wistar Han rats should be noted in the label for the
`proposed linagliptin plus metformin FDC tablets. Based on this conclusion, the Pharmacology
`/ Toxicology team recommends a change in Pregnancy Category from the proposed “B” to a
`“C” category, while basically maintaining the descriptive language on bone malformations
`proposed by the applicant. However, FDA notified the applicant that information from
`adequate and well controlled clinical studies in pregnant women demonstrating that metformin
`is not a risk to the fetus may, upon review, support a designation of Pregnancy Category B.
`The applicant, in response, provided recent references regarding clinical trials and metanalyses
`of the use of metformin in diabetic women during pregnancy, gestational diabetics and first
`trimester exposure in women with polycystic ovaries treated with metformin. We acknowledge
`the references to these clinical trials and metanalyses, and believe they support a designation
`of Pregnancy Category B. The final descriptive language to summarize the clinical experience
`in the label is still under discussion, at the time of this writing.
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`Clinical Pharmacology
`
`The Clinical Pharmacology 2 review team (OCP/DCP-2) recommends NDA approval. For
`details, please refer to Dr. Khurana’s clinical pharmacology review.
`The key studies to support this NDA were:
`• Study 1288.1: BE between linagliptin 2.5 mg and metformin 1000 mg coadministration
`with linagliptin/metformin 2.5/1000 mg FDC
`• Study 1288.2: BE between linagliptin 2.5 mg and metformin 500 mg coadministration with
`linagliptin/metformin 2.5/500 mg FDC
`• Study 1288.3: BE between linagliptin 2.5 mg and metformin 850 mg coadministration with
`linagliptin/metformin 2.5/850 mg FDC
`• Study 1218.57: BE between the EU sourced Glucophage® formulation (used in the pivotal
`Phase 3 trial and all BE studies) and the US approved Glucophage® formulation at 500 mg
`and 1000 mg dose strengths of metformin.
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`For the clinical pharmacology assessments, linagliptin and metformin were quantitated in
`plasma using validated HPLC-MS/MS assay methods. The assay methods were validated for
`analyzing these 2 analytes in plasma samples in terms of range, accuracy, precision and
`sensitivity.
`BE was demonstrated between intended commercial FDC formulation and co-administration
`of individual tablet formulations for Linagliptin 2.5/Metformin 500 mg and Linagliptin
`2.5/Metformin 1000 mg FDC. BE was also demonstrated between intended commercial FDC
`formulation and coadministration of individual tablet formulations for Linagliptin 2.5/
`Metformin 850 mg, and also between the EU sourced Glucophage® formulation and the US
`approved Glucophage® formulation (Figure 1).
`
`Figure 1. Bioequivalence assessments between linagliptin/metformin FDc and individual components
`linagliptin and metformin, and between European sourced metformin and US-sourced metformin
`
`Source: Dr. Khurana’s Clinical Pharmacology review (Figure 2).
`
`Labeling changes proposed by the clinical pharmacology review team to the FDC professional
`label language are consistent with the language used in the linagliptin and metformin approved
`package insert language.
`
`Arindam Dasgupta, Ph.D., (Division of Bioequivalence and GLP Compliance [DBGC] /
`Office of Scientific Investigations [OSI] has conducted the following inspections related to
`studies 1288.1 and 1218.57:
`Clinical site: Boehringer Ingelheim Pharma GmbH & Co. KG, in Germany;
`Analytical sites:
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`Following the above inspections, the Division of Bioequivalence and GLP Compliance
`recommends that the clinical (NAI) and analytical data (VAI) of studies 1288.1 and 1218.57
`be accepted for Agency review.
`
`Biopharmaceutics
`
`Please refer to Dr. Mahayni’s review for details. The focus of the Biopharmaceutics review is
`to evaluate the information/data supporting the proposed dissolution method, dissolution
`acceptance criteria, and manufacturing site change and provide a recommendation regarding
`their acceptability.
`The dissolution method parameters and criteria for evaluation of linagliptin and metformin are
`acceptable. The dissolution data to support the change in manufacturing site is acceptable. The
`Biopharmaceutics reviewer recommends approval of the NDA.
`
`6. Clinical Microbiology
`
`There was no microbiology review. The product is not an antimicrobial and there are no issues
`regarding sterility.
`
`7. Clinical/Statistical- Efficacy
`
`Clinical Review
`
`The clinical review team recommends approval of the NDA. For details, please refer to Dr.
`Kwon’s clinical review of the NDA.
`
` linagliptin/metformin FDC can be used in patients
`
`whenever treatment with both components is considered appropriate,
` the applicant conducted and submitted the results of a factorial design trial 1218.46 to
`demonstrate that initiating both components of the FDC in subjects who are treatment naive
`provided superior glycemic control when compared to either linagliptin or metformin given as
`monotherapy.
`This was a multinational, multicenter, Phase 3, randomized, double-blind, placebo-controlled
`parallel group trial to compare the efficacy and safety of twice daily coadministration of
`linagliptin 2.5 mg and metformin 500 mg or of linagliptin 2.5 mg and metformin 1000 mg,
`with the individual components of metformin (500 mg or 1000 mg, BID) and linagliptin (5
`mg, once daily [QD]) over 24 weeks in drug naive or previously treated subjects (adequately
`washed out of the effect of their prior medications) with insufficient glycemic control. To be
`eligible, subjects in the treatment naïve category should have HbA1c in the range 7.5 to 11%
`and subjects previously treated with an oral antidiabetic drug should have an HbA1c in the
`range 7.5 to 10.5%. An uncontrolled, open-label arm evaluated the safety and efficacy of
`linagliptin and metformin (linagliptin 2.5 mg + metformin 1000 mg BID) for 24 weeks in
`subjects with poor glycemic control (HbA1c > 11%). The primary endpoint was the change in
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`HbAlc at week 24. Secondary endpoints frequently used in trials of T2DM were listed in the
`protocol.
`Subjects who completed the randomized part of this trial without receiving rescue therapy
`were offered to participate in an extension trial (trial 1218.52).
`A total of 791 subjects were randomized in 133 sites in Africa, Asia, Europe, North America,
`and South America in a 12222122222 ratio to either placebo (72 subjects), linagliptin 5 mg (142
`subjects), metformin 500 mg (144 subjects), metformin 1000 mg (147 subjects), linagliptin 2.5
`mg and metformin 500 mg (143 subjects), or linagliptin 2.5 mg and metformin 1000 mg (143
`subjects). Of the randomized subjects, 86.9 % completed the 24 weeks of trial duration. A total
`of 66 subjects entered the open-label arm of the trial and received linagliptin 2.5 mg and
`metformin 1000 mg.
`The results in the full analysis set (FAS) demonstrated a statistically and clinically meaningful
`reduction with coadministration of linagliptin and metformin compared to the treatment with
`corresponding doses of monotherapy (Table 1). Table 1 also shows the glycemic-related
`secondary endpoints of proportion of subjects reaching HbAlc < 7% (a therapy goal
`recommended by the American Diabetes Association for adults with T2DM) and the
`proportion of subjects in each arm receiving glycemic rescue therapy (sulfonylurea,
`thiazolidinedione or insulin) based on protocol-defined criteria.
`
`Table 1. Change in HbAlc (%) from baseline to week 24, responder analysis (proportion of subjects with
`HbAlc < 7%) and proportion receiving glycemic rescue in the FAS-LOCF population of Trial 1218.46
`Study population
`Placebo
`Lina 5 mg
`Met 500 mg
`Lina 2.5 mg +
`Met 1000 mg
`Lina 2.5 mg +
`Once Daily
`Twice Daily
`Met 500 mg
`Twice Daily
`Met 1000 mg
`Twice Dallv
`Twice Dally
`
`Wham ———m-m_
`Baseline (mean. SE)
`8.7 (0.1)
`8.7 (0.!)
`8.7 (0.1)
`8.7 (0.1)
`8.5 (0.l)
`8.7 (0.1)
`
`
`
`8.0 (11)
`
`.
`4.3 (6)
`
`
`
`————__
`——————
`v...)
`Patients (%. 11) receiving rescue
`medication
`
`29.2 (19)
`
`11.1 (15)
`
`13.5(19)
`
`.
`7..» (10)
`
`source: Dr. Lui‘s statistical review.
`
`Sensitivity analyses of the primary efficacy endpoint among completers (all subjects who
`completed 24 weeks of trial without glycemic rescue therapy) and among the per-protocol set
`(all randomized subjects without major protocol violations) yielded the same conclusions as
`the primary FAS/ITT analysis.
`The treatment effect was consistent across different subgroups based on demographic and
`baseline disease characteristics.
`
`In the open-label arm, the mean baseline HbAlc was 11.8 % at baseline and 7.9 % at the end
`of the trial, and the mean (SD) change fiom baseline to Week 24 was -3.7% (1.7). No formal
`hypothesis testing was done for this arm, as this was uncontrolled.
`(m4)
`
`The graphical representation of changes in HbAlc over time for all controlled groups in the
`FAS dataset over the 24—week trial period is shown in Figure 2.
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`Figure 2. Change in adjusted mean HbA1c (%) from baseline over time - FAS (LOCF)
`
`Source: Applicant’s CTR 1218.46, Figure 15.2.1.2.2.1
`
`Our statistical review team prefers that figures showing HbA1c changes over time in a trial be
`based on completer’s data. Therefore we have requested that the applicant include in the label
`a figure based on completers, with regard to the results of the factorial trial 1218.46.
`
`Change in fasting plasma glucose (FPG) from baseline to week 24, an important secondary
`endpoint to support the efficacy of coadministration of linagliptin and metformin, is shown in
`Table 2.
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`Table 2. Change in fasting plasma glucose (mg/dL) from baseline to week 24 in the FAS population in
`Study 1218.46
`
`Source: Applicant’s SCE, Table 3.2.1.2:1
`
`Mean effects of the coadministration of linagliptin and metformin on the 2-hour glucose
`following a mixed meal tolerance test were small, but the trial was clearly underpowered to
`demonstrate an effect. Nonetheless, the individual components have been shown to have an
`effect on postprandial glucose, and there is no reason to suspect that the coadministration
`would not behave similarly.
`
`Two clinical sites in India were inspected by the Division of Good Clinical Practice
`Compliance / OSI. The two sites contributed 54 subjects to trial 1218.46. While the final
`classification is pending, Dr. Leibenhaut’s conclusion was that the clinical data in support of
`the NDA is considered reliable and should be accepted.
`
`There were few data on the glycemic effect of linagliptin and metformin coadministration in
`the extension trial 1218.52, and the applicant has not proposed to include them in the current
`label, so I will not be discussing these data in the CDTL review memo.
`
`Statistical Review
`
`Please refer to Dr. Liu’s review for details of the statistical review. The team recommends
`approval of the NDA. Study 1218.46 provided the only data included in the statistical review.
`In addition to the sensitivity analyses conducted by the applicant and reviewed by Dr. Kwon,
`Dr. Liu has conducted new analyses; among them the mixed-effects model repeated measures.
`The results from the sensitivity analyses (such as MMRM, completers, and per protocol) of the
`primary efficacy endpoint and the key secondary endpoint, FPG, support the superiority of the
`combination to placebo and to each corresponding component treatment on both HbA1c and
`FPG reductions after 24 weeks treatment at a 0.05 level (two-sided).
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`In Dr. Liu’s review, he noted that the efficacy of linagliptin 5 mg monotherapy compared to
`placebo in Trial 1218.46 through analyses other than FAS-LOCF was questionable, primarily
`due to a greater than average reduction in glycemic parameters in the placebo group (-0.3 to -
`0.4% mean change from baseline in the placebo group). This effect in Trial 1218.46 is
`inconsistent with the evidence supporting the efficacy of linagliptin 5 mg monotherapy as
`reviewed in the linagliptin NDA 201280: a 18-week trial and a 24-week trial have
`demonstrated placebo-adjusted changes in HbA1c (95% CI) of -0.6 % (-0.9, -03) and -0.7% (-
`0.9, -0.5), respectively, in a combined pool of 716 subjects, who were randomized 2:1 to
`linagliptin 5 mg versus placebo.
`
`Subgroup analyses suggest that females derive greater benefit from the coadministration of
`linagliptin and metformin compared to males.
`
`8. Safety
`
`Of the clinical study reports submitted, only trials 1218.46 and 1218.52 were not previously
`reviewed under NDA 201280 for linagliptin.
`A total of 3084 subjects with T2DM were exposed to the coadministration of linagliptin and
`metformin across Phase 2 and 3 trials of linagliptin, providing a total of 3006 patient-years of
`exposure.
`There are no new safety issues related to the coadministration of linagliptin and metformin,
`based on Study 1218.46, the scant data from its extension study and the 4-month safety update.
`The only noteworthy exception is the metformin-related embryofetal malformations described
`in the reproductive toxicology studies using Wistar Han rats; refer to Dr. Carlson’s
`pharmacology / toxicology review.
`9. Advisory Committee Meeting
`
`This linagliptin / metformin FDC NDA was not referred to an advisory committee because the
`drugs are not first in class and the safety profile is similar to that of other drugs approved for
`this indication. Evaluation of the safety data did not raise significant unexpected safety or
`efficacy issues. We concluded outside expertise was not necessary for this review.
`
`10.
`
`Pediatrics
`
`There is no need for new PREA-related PMRs for pediatric studies for this NDA. The
`approval letter will have a statement that refers to the existing linagliptin PREA PMRs (listed
`below): e.g., "We remind you of your requirements under PREA for....."), and that also
`indicates that these requirements apply to both forms of the drug.
`PeRC, the Safety Requirement Team and Pediatric Maternal Health Staff concurred with this
`approach.
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`201280 Tradjenta
`(linagliptin)
`
`201280 Tradjenta
`(linagliptin)
`
`A randomized, placebo-controlled, dose-finding study under
`PREA evaluating at least two doses of linagliptin as monotherapy
`in pediatric patients ages 10 to 16 years (inclusive).
`Deferred randomized and controlled pediatric study under PREA
`to evaluate efficacy, safety, and pharmacokinetics of linagliptin
`for the treatment of type 2 diabetes mellitus in pediatric patients
`ages 10 to 16 years (inclusive) as monotherapy and when added
`to metformin therapy.
`
`Final Protocol: by 11/ 30/11
`Trial Completion: by 2/28/14
`Final Report Submission: by 8/31/14
`Final Protocol: by 6/30/14
`Trial Completion: by 3/31/17
`Final Report Submission: by 9/30/17
`
`11.
`
`Other Relevant Regulatory Issues
`
`At the time of this writing, this application is being discussed by the 505(b)(2) clearance group
`in the Office of New Drugs. The main issue being discussed is that the reference listed drug in
`this NDA is Glucophage; however, we recommended the applicant incorporate the language
`describing metformin-related lactic acidosis and drug interactions to be based on the Glumetza
`label converted to conform to the Physician Labeling Rule and approved in April 2011.
`12.
`Labeling
`
`At the time of this CDTL memo, the proprietary name review by DMEPA is pending. The
`current trade name under consideration is Jentadueto;
` have been
`rejected by DMEPA.
`Labeling is being discussed with the applicant, specifically for the summary description of
`metformin clinical trials used to support a Pregnancy Category “C” designation.
`
`13.
`
`Recommendations/Risk Benefit Assessment
`
`I recommend a Complete Response to the linagliptin / metformin FDC NDA. This fixed dose
`combination tablet is a convenience product, so that patients who need both linagliptin and
`metformin for glycemic control can take only one pill twice daily. But there are no additional
`risks for the FDC, compared to coadministration of these two drugs separately. Thus, this
`recommendation for action is based on the manufacturing inspection at one of the sites. The
`Office of Compliance had issued a “Withhold” recommendation for the
` site.
`
`Page 12 of 12
`
`Reference ID: 3037366
`
`12
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`ILAN IRONY
`11/07/2011
`This version was revised to reflect the OC/OMPQ recommendation.
`
`MARY H PARKS
`11/08/2011
`
`Reference ID: 3037366
`
`

`

`CLINICAL REVIEW
`
`Application Type 505(b)(2)
`Application Number(s) NDA 201281
`Priority or Standard Standard
`
`January 19, 2011
`Submit Date(s)
`January 19, 2011
`Received Date(s)
`PDUFA Goal Date November 19, 2011
`Division / Office DMEP/ODE II
`
`Reviewer Name(s) Hyon J. Kwon, PharmD, MPH
`Review Completion Date October 14, 2011
`
`Established Name Linagliptin/Metformin
`(Proposed) Trade Name
`Therapeutic Class DPP4 inhibitor and biguanide
`Applicant Boehringer Ingelheim
`
`Formulation(s) Linagliptin (L)/Metformin (M) film-
`coated FDC tablets at dosages of 2.5
`mg L/500 mg M, 2.5 mg L/850 mg M,
`and 2.5 mg L/1000 mg M
`Dosing Regimen Twice daily
`Indication(s) As an adjunct to diet and exercise to
`improve glycemic control in adults
`with T2DM where treatment with
`linagliptin/metformin is appropriate
`Intended Population(s) Type 2 diabetes mellitus
`
`Reference ID: 3029467
`
`(b) (4)
`
`

`

`Clinical Review
`Hyon J. Kwon, PharmD, MPH
`NDA 201281
`Linagliptin/metformin FDC
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT.............................................. 8
`1.1 Recommendation on Regulatory Action .......................................................................... 8
`1.2 Risk Benefit Assessment .................................................................................................. 8
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies................ 9
`1.4 Recommendations for Postmarket Requirements and Commitments .............................. 9
`INTRODUCTION AND REGULATORY BACKGROUND............................................ 9
`2.1 Product Information.......................................................................................................... 9
`2.2 Tables of Currently Available Treatments for Proposed Indications............................. 10
`2.3 Availability of Proposed Active Ingredient in the United States ................................... 10
`2.4
`Important Safety Issues With Consideration to Related Drugs...................................... 11
`2.5 Summary of Presubmission Regulatory Activity Related to Submission ...................... 11
`2.6 Other Relevant Background Information ....................................................................... 11
`3 ETHICS AND GOOD CLINICAL PRACTICES ............................................................ 11
`3.1 Submission Quality and Integrity................................................................................... 11
`3.2 Compliance with Good Clinical Practices...................................................................... 12
`3.3 Financial Disclosures........................................................................................