CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`202343Orig1s000
`
`
`SUMMARY REVIEW
`
`
`
`
`
`

`

`Cross Discipline Team Leader Review
`
`Cross-Discipline Team Leader Review
`
`
`Date
`8/15/201 1
`
`Ilan Iron , M.D.
`From
`m_ Cross-Disci line Team Leader Review
`202343 Ori - inal submission under 505 0
`
`1
`
`
`Date of Submission
`07/12/2010
`
`PDUFA Goal Date
`10/07/2011
`
`Proprietary Name /
`Established
`S ‘
`
`Juvisync / sitagliptin simvastatin fixed dose combination
`tablets
`
`Dosage forms / Strength
`
`Sitagliptin simvastatin 100 mg / 10 mg, 100 mg / 20 mg
`and 100 m- /40 111
`
`
`
`Proposed Indieation(s)
`
`Recommended:
`
`.
`
`Improve glycemic control in adults with T2DM
`Reduce risk of cardiovascular mortality, non—fatal MI,
`stroke and need for revascularization procedures
`Reduce elevated total cholesterol, LDL-cholesterol,
`apo-B lipoprotein, and triglycerides in settings for
`which simvastatin is approved.
`A o uroval
`
`Page 1 of 15
`
`Reference ID: 301 6527
`
`1
`
`

`

`Cross Discipline Team Leader Review
`
`
`
`1. Introduction
`
`
`This is a new drug application for a fixed dose combination tablet (FDC) of sitagliptin, an oral
`antidiabetic drug for the treatment of adults with type 2 diabetes (T2DM) and simvastatin (a
`lipid lowering drug. Both components are approved and marketed drugs in the US. While
`FDCs where both drug components treat the same indication are common, there is precedent
`within CDER and OND for approval of a FDC with each component treating a separate
`indication (Caduet is a FDC of amlodipine, an antihypertensive drug and atorvastatin, a lipid
`lowering statin drug).
`From a scientific and regulatory standpoint, this is a fairly straightforward application. The
`two drugs that comprise the FDC are approved in the US, and each carries substantial
`postmarketing experience.
`Recent published studies and metanalyses 1,2,3 have suggested a small interference of statins as
`a class (with the exception of pravastatin) on glycemic control, and among pre-diabetics, a
`slightly higher tendency to progress to overt diabetes among users of statins.
`A large rosuvastatin outcome trial (n = 17802 subjects) conducted in patients with elevated C
`reactive protein and normal LDL cholesterol levels (JUPITER) also showed a small increase in
`investigator-reported diabetes (2.8 % vs. 2.3% for placebo, HR = 1.27) and an increase in
`HbA1c among diabetics (refer to Dr. Mary Roberts review of Rosuvastatin NDA 21366
`supplement 16, filed on 2/5/2010).
`In SPARCL (atorvastatin 80 mg vs placebo), diabetes was reported as an AE in 144 subjects
`(6.1%) in the atorvastatin group and 89 subjects (3.8%) in the placebo group. The reported
`percentage of diabetes was 8.9% in the atorvastatin and 5.3% in the placebo group in subjects
`with a medical history of diabetes, and 5.5% and 3.5%, respectively, in subjects without a
`medical history of diabetes.
`In ASCOT-LLA (atorvastatin 10 mg vs placebo), a slightly larger percentage of patients in the
`atorvastatin group also developed diabetes during the course of the study, although the
`difference did not achieve statistical significance. At 12 months, there was a small statistically
`significant difference in mean blood sugar change, slightly favoring the placebo group. This
`difference (mean % increase of 0.26% for the atorvastatin group vs 0.16% for the placebo
`group) was small.
`But the conclusion from these metanalyses, JUPITER, SPARCL and ASCOTT-LLA has been
`that the benefits of a statin treatment in diabetics far outweigh the risks, and such treatment
`continues to be recommended for patients with T2DM, due to major impact cardiovascular
`disease has on the morbidity, mortality and health care costs in the diabetic population. For
`this particular NDA, a dedicated trial to examine the magnitude of the simvastatin interference
`with sitagliptin-promoted glycemic control will be a postmarketing requirement, already
`
`
`1 Sattar N, Preiss D Murray HM et al. Statins and risk of incident diabetes: a collaborative meta-analysis of
`randomised statin trials. Lancet 2010; 375: 735–42
`2 Rajpathak SN, Kumbhani DJ, Crandall J et al. Statin Therapy and Risk of Developing Type 2 Diabetes: A Meta-
`Analysis. Diabetes Care 2009; 32:1924 – 1929
`3 Koh KK, Quon MJ, Han SH at al. Atorvastatin causes insulin resistance and increased ambient glycemia in
`hypercholesterolemic patients. Journal of the American College of Cardiology 2010; 55: 1209-1216
`
`Page 2 of 15
`
`Reference ID: 3016527
`
`2
`
`

`

`Cross Discipline Team Leader Review
`
`discussed with the applicant during a teleconference in May 2010 and repeated at the pre-NDA
`meeting.
`So the main issue for this application is the demonstration of bioequivalence (BE) between the
`to-be-marketed formulation of the FDC and its components namely, sitagliptin and
`simvastatin.
`As reported in Dr. Chung’s Clinical Pharmacology review, BE was established in a study
`conducted in healthy volunteers. However, inspection of the clinical and analytical sites by the
`Division of Bioequivalence and GLP Compliance (DBGC) in the Office of Scientific
`Investigations (OSI) uncovered violations of the handling of reserve samples of tablets at the
`clinical study site, Icon Development Solutions in San Antonio TX. DBGC recommended
`rejecting the BE data,
` The
`clinical and clinical pharmacology review teams discussed these recommendations with
`DBGC, and learned that the lots inspected and used for the BE studies were the same as those
`submitted in the NDA, and passed all specifications. The applicant received a biowaiver from
`Bipharmacology with regard to the minor differences between these lots and the to-be-
`marketed lots.
`2. Background
`
`
`Sitagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, has been approved for treatment of
`T2DM in the US since October 2006 under NDA 21995. The recommended dose is 100 mg
`daily for subjects with normal renal function, 50 mg daily for subjects with moderate renal
`impairment, and 25 mg daily for subjects with severe and end stage renal disease (ESRD).
`Simvastatin, a hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin),
`was approved in December 1991 under NDA 19766 and currently has five lipid lowering and
`cardiovascular (CV) indications (refer to Zocor label).
`The filing of the sitagliptin/simvastatin FDC NDA is based on the demonstration of BE
`between the FDC tablets and coadministration of corresponding doses of sitagliptin and
`simvastatin (for the latter, 10 and 80 mg to bracket the dose range). Although no phase 3
`clinical studies were conducted with the sitagliptin/simvastatin FDC or with the co-
`administration of sitagliptin and simvastatin, seven clinical pharmacology studies support
`registration of the FDC.
`Although the FDC tablet can be regarded as a convenience product (i.e., taking only one tablet
`daily, rather than two separate tablets), many diabetics have indications for the use of a statin
`drug, due to their prevalent dyslipidemia and higher cardiovascular risks, and this combination
`makes sense for the targeted population. The FDC has the disadvantage that patients for whom
`sitagliptin is being considered as the antidiabetic drug will also be taking a statin (simvastatin)
`associated with significant interactions with other drugs, as well as the added cost, when
`compared to adding generic simvastatin to a regimen of brand sitagliptin.
`Prior to submitting NDA, the applicant reached agreement with FDA on two issues:
`• The 100/80 mg tablet is not approvable because of the recently identified safety issue
`(increased risk of rhabdomyolysis) associated with the 80 mg simvastatin dose.
`• Submission of a NDA without the 50 mg sitagliptin dose for use in subjects with moderate
`renal insufficiency is both a review and safety issue. If not contained in the original NDA, the
`development of the 50 mg sitagliptin doses may be a post-marketing requirement (PMR).
`
`Page 3 of 15
`
`Reference ID: 3016527
`
`3
`
`(b) (4)
`
`

`

`Cross Discipline Team Leader Review
`
`Thus, the current NDA 202-343 proposes sitagliptin/simvastatin 100/ 10, 100/20, and 100/40
`mg FDC tablets, as previously agreed. The applicant is now developing 50/10, 50/20, and
`50/40 mg FDC dose strengths and plans to submit a supplemental NDA (sNDA) for them by
`(m4)
`
`3. CMC/Device
`
`The proposed formulation is a bilayer tablet comprised of:
`l) A sitagliptin layer (layer weight
`M”), which is based on
`JANUVIA® Tablet formulation, and
`2) A
`(m4) simvastatin layer
`simvastatin
`(war This
`ZOCOR® Tablets.
`
`09(4) from a common
`a“) is the same as that used in the manufacture of
`
`(I'm
`
`During review, CMC noted that the stability analysis of samples of sitagliptin 100 mg /
`simvastatin 80 mg were out of the applicant’s self-defined range of 95 to 105% at release and
`during the 52 week stability period. In response to an information request, Merck expanded the
`specification range to 90 — 110% (as allowed per US regulations), and the assay data fell
`within the range.
`Based on the provided real—time stability data, a two and a half (2 1/2) year expiry period is
`granted for the 100/ 10, 100/20 and 100/40 mg /mg sitagliptin/ simvastatin FDC tablets
`supplied in 30 and 90 count bottles.
`Based on the provided real—time stability data, a one (1) year expiry period is granted for the
`100/10, 100/20 and 100/40 mg /mg sitagliptin/ simvastatin FDC tablets supplied in the 1000
`count bottle.
`
`The CMC review team recommends approval; a final review of the facility inspection in ESS
`is pending at the time of this review.
`
`4. Nonclinical Pharmacology/1'oxicology
`
`Due to the concern of possible toxicologic interactions between sitagliptin and simvastatin,
`especially regarding adverse effects on the skeletal muscle, the sponsor conducted a 3-month
`toxicology study in rats to assess the potential toxicity due to coadministration of sitagliptin
`and simvastatin. There was no mortality or significant adverse effects associated with the
`coadministration of sitagliptin and simvastatin at exposures greater than 20 times those at the
`maximum clinical dose of either drug in the FDC. Although there were no adverse muscle or
`pancreas effects associated with either drug administered alone or in combination,
`coadministration of sitagliptin and simvastatin did cause an increase in adverse liver effects.
`Administration of the simvastatin high dose (60 mg/kg; ~47—114X MHRD; based on AUC)
`caused an increase in liver weight, hepatocellular hypertrophy, and an increase in ALT levels
`(~2-3X compared to controls). Although these effects were not observed in animals
`administered sitagliptin alone, the coadministration of sitagliptin (180 mg/kg; ~20X MHRD;
`based on AUC) and simvastatin caused a slightly greater dose—related increase in liver weight
`(females only) and ALT levels with both the low (30 mg/kg; ~20-66X MHRD; based on AUC)
`and high (60 mg/kg; ~47-114X MHRD; based on AUC) simvastatin doses suggesting a
`
`Page 4 of 15
`
`Reference ID: 3016527
`
`4
`
`

`

`Cross Discipline Team Leader Review
`
`possible drug-drug interaction between sitagliptin and simvastatin with regards to liver
`toxicity. Although the sponsor did not establish a NOAEL for the additional increases in liver
`weight and ALT levels, these adverse liver effects are clinically monitorable. Co-
`administration of the simvastatin high dose (60 mg/kg; ~47X MHRD; based on AUC) and
`sitagliptin (180 mg/kg; ~20X MHRD; based on AUC) also caused bile duct hyperplasia. Given
`that there were no similar findings in animals administered the simvastatin high dose or
`sitagliptin alone and that bile duct proliferation/hyperplasia was previously observed in rats in
`studies conducted under NDA 21995 (sitagliptin) and NDA 19766 (simvastatin), this finding
`suggests a potential drug-drug interaction. However, as a NOEL (30 mg simvastatin/180 mg
`sitagliptin) was established for this finding at approximately 20 times the human exposure at
`the MRHD, this is of minimal concern clinically.
`Simvastatin treatment was associated with adverse effects in the nonglandular stomach and
`thyroid. These findings were not markedly affected by the coadministration of sitagliptin.
`Moreover, they are consistent with those observed in the rat in toxicology studies conducted in
`support of simvastatin and are not considered to be clinically relevant.
`Information from the genotoxicity, carcinogenicity, and reproductive studies conducted under
`the sitagliptin) and simvastatin NDAs support chronic administration. Pregnancy category X is
`recommended for the FDC drug product given that simvastatin is classified in pregnancy
`category X because lipid lowering drugs offer no benefit during pregnancy when cholesterol
`and cholesterol derivatives are needed for normal fetal development.
`
`The Pharmacology / Toxicology team recommends approval of the NDA.
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`Clinical Pharmacology
`
`As agreed with the applicant, demonstration of BE between the FDC and each component
`(sitagliptin and simvastatin) was the pivotal element to support approval of the NDA.
`Simvastatin is an inactive pro-drug and needs to be converted to its active form, simvastatin
`acid, after oral administration. Therefore, pharmacokinetic (PK) parameters of simvastatin acid
`should be considered the primary endpoint for the BE assessment of simvastatin in addition to
`those of sitagliptin.
`
`The proposed strengths are 100/10, 100/20 and 100/40 mg (mg sitagliptin / mg simvastatin,
`respectively). The tablet strengths containing 50 mg sitagliptin (i.e., 50/10, 50/20 and 50/40
`mg) are currently in development and the applicant agreed to submit a supplement for these
`dose strengths
`. FDCs containing 50 mg of sitagliptin target the group of
`diabetics with hyperlipidemia who have moderate renal impairment.
`Merck conducted eight clinical pharmacology studies in support of the sitagliptin/simvastatin
`FDC NDA, as follows:
`
` Two BE studies - one using the lowest strength (Study P255: sitagliptin 100 mg / simvastatin
`10 mg) and the other one using the highest strength (Study P153 Part I and Part II: sitagliptin
`100 mg / simvastatin 80 mg)
`• One study for the food effect on sitagliptin 100 mg / simvastatin 80 mg
`
` •
`
`Page 5 of 15
`
`Reference ID: 3016527
`
`5
`
`(b) (4)
`
`

`

`Cross Discipline Team Leader Review
`
`• Two relative bioavailability studies to explore preliminary formulations
`• Two studies for assessment of drug-drug interaction
`
`The BE study for the high simvastatin dose of 80 mg was conducted prior to awareness of
`safety issues associated with that dose strength and prior to the safety labeling changes
`imposed on simvastatin 80 mg. However, for the purpose of the bracketing approach to BE of
`the entire dose range of the FDC, the study is valid and data from that study should be
`accepted to support the BE of lower dose strengths of simvastatin in the FDC tablets, with
`biowaiver being granted for the lower doses of simvastatin.
`
`The two BE studies (Study P153 Part I and Part II and Study P255) showed BE between
`sitagliptin / simvastatin FDC and its individual components, because the primary PK
`parameters (AUC and Cmax) of sitagliptin, simvastatin and simvastatin acid met the regulatory
`BE goal post of 90% confidence interval (90% CI) (Table 1).
`
`Table 1. Summary results (geometric mean ratio) of bioequivalence studies of sitagliptin and simvastatin
`
`
`
`Source: Dr. Chung’s Clinical Pharmacology review
`
` A
`
` high fat breakfast did not affect sitagliptin exposure following sitagliptin / simvastatin FDC
`administration (refer to the Clinical Pharmacology review for data). Meanwhile, simvastatin
`AUC decreased by 24% and its Cmax increased by 20% with the high fat breakfast. In addition,
`high fat breakfast resulted in increase in simvastatin acid AUC and Cmax by 37% and 116%,
`respectively. The clinical significance of the above exposure change in simvastatin and
`simvastatin acid is not known; our proposed recommendation is for evening administration,
`similar to the simvastatin labeling.
`
`There was no significant drug interaction between sitagliptin and simvastatin. Digoxin
`exposure was significantly increased by sitagliptin + simvastatin. Patients receiving digoxin
`should be monitored when sitagliptin / simvastatin FDC is co-administered.
`
`Clinical Pharmacology recommends approval of the NDA.
`
`Office of Scientific Investigation report and recommendation
`
`
`Page 6 of 15
`
`Reference ID: 3016527
`
`6
`
`

`

`Cross Discipline Team Leader Review
`
`At our request, DBGC / OSI conducted inspections of clinical and analytical portions of the
`following studies:
`
`Study: 255: “A Single-Dose Study to Evaluate Definitive Bioequivalence of MK-043 1D and
`Co-administration of Sitagliptin and Simvastatin”
`
`Study: 153: “A 2-Part Single-Dose Study to Evaluate a Probe Formulation of MK-043 1D and
`Evaluate Definitive Bioequivalence of MK-043 1D and Co-adrninistration of Sitagliptin and
`Simvastatin”.
`(I'm was inspected, and the few minor deficiencies were
`The analytical site
`resolved. The clinical inspection occurred at Icon Development Solutions, in San Antonio TX,
`where both BE studies took place. Inspectors identified the following deficiencies:
`Icon returned the retained sitagliptin / simvastatin FDC samples to Merck (those bottles not
`used for dosing in Study P153); Merck, in turn, returned them to Icon. However, the FDA
`inspector considered Icon’s action as failure to meet the regulatory requirements for retention
`of reserve samples for bioavailability or study (21 CFR 320.38 and 320.63).
`In addition, Icon informed the inspector that for both Studies P255 and P153, Merck pre-
`identified the sample bottles to be retained, by numbering these kits with different serial
`numbers as the bottles actually used in dosing the subjects. The regulations specify that the
`clinical site has to randomly select drug products for dosing or for reserve, and therefore, the
`authenticity of the products could not be verified.
`The studies fail to meet the regulatory requirements for retention of reserve samples for
`bioavailability or study (21 CFR 320.38 and 320.63). The Final Rule for Retention of
`Bioavailability and Bioequivalence Testing Samples (Federal Register, Vol. 58, No. 80, Pages
`25918-25928, 1993) clarifies that:
`“The study sponsor should provide to the testing facility batches of the test product and
`reference standard packages such that the reserve samples can be randomly selected to ensure
`that they are in fact representative of the batches provided by the study sponsor. . .”
`Since Icon did not randomly select reserve samples and maintain their custody, DBGC could
`not verify the authenticity of the study drugs tested. Thus, DBGC recommended rejecting data
`from these two BE studies.
`
`DBGC cited another example where similar findings resulted in a Complete Response action.
`The Complete Response letter to
`M0
`
`cites:
`
`(we)
`
`Page 7 of 15
`
`Reference ID: 301 6527
`
`7
`
`

`

`Cross Discipline Team Leader Review
`
`
`Resolution of the conflicting recommendations
`The CMC, clinical and clinical pharmacology teams identified the manufactured lots of study
`drug and contacted Merck to confirm (the lot numbers listed in the inspection report and those
`listed in the NDA were different). Merck explained that these lot numbers for the clinical site
`were the identification of bottles to be used in the BE study. Furthermore, Dr. Sung’s review
`showed that the variability of specification ranges among lots and within lots was very small,
`and could not result in effects on BE sufficient large to change the conclusion of
`bioequivalence. This was discussed with DBGC/OSI on September 13th, 2011, and all
`disciplines agreed that acceptance of the BE data was reasonable, but that OSI must convey
`these regulatory violations to Merck and to Icon independently of the regulatory action on this
`NDA.
`
`Biopharmaceutics
`Biopharmaceutics granted the requested biowaiver for the minor differences between the final
`market composition tablets used in the Definitive Bioequivalence studies P153 and P255 and
`the commercial tablets (lighter brown color and a different manufacturing site). A biowaiver
`for the intermediate strength tablets of sitagliptin 100 mg / simvastatin 20 mg and sitagliptin
`100 mg / simvastatin 40 mg was also granted. Dissolution profiles and criteria for both
`components were acceptable.
`6. Clinical Microbiology
`
`
`Not applicable. The product is not an anti-microbial.
`
`
`7. Clinical/Statistical- Efficacy
`
`
`No Phase 3 clinical trials were conducted to support the sitagliptin / simvastatin FDC. We had
`agreed with Merck, in several interactions during the IND development of this product, that
`such trial would not be required to demonstrate a glycemic and lipid lowering effect, as long as
`PK bioequivalence is demonstrated against each component of the FDC. Due to the findings
`from the JUPITER trial and the two metanalyses demonstrating slight worsening of glycemia
`among diabetics using statins, we asked Merck to conduct a metanalysis of their simvastatin
`studies to assess effects on glycemic control in the diabetic subset of these CV risk-enriched
`study populations, and to conduct a metanalysis of the sitagliptin trials, comparing the effects
`on glycemia in patients using simvastatin or other statins who were randomized to sitagliptin
`or placebo comparator in the sitagliptin trials conducted in support of the Januvia NDA.
`These analyses were described in Dr. Pratt’s review and I will reproduce here only top level
`results and conclusion (under the Safety heading, below).
`8. Safety
`
`
`Please refer to Dr. Pratt’s clinical review, for details regarding the safety analyses of the
`coadministration of simvastatin and sitagliptin.
`
`Page 8 of 15
`
`Reference ID: 3016527
`
`8
`
`

`

`Cross Discipline Team Leader Review
`
`
`The safety and glycemic assessment focused on data from subjects in sitagliptin trials who
`were coadministered sitagliptin and simvastatin. Subjects treated with simvastatin and placebo
`or an active-comparator served as control for these analyses. To explore potential class effects
`of statins in general when coadministered with sitagliptin, safety was also assessed in subjects
`who were coadministered sitagliptin and other statins in a pool of sitagliptin studies.
`
`The applicant demonstrated that there was no clinically significant difference in the change in
`HbA1c in subjects with T2DM randomized to simvastatin compared to placebo in the
`simvastatin clinical development program.
`• Heart Protection Study (Lancet 360(9326): 7-22, 2002): This trial was conducted in the
`United Kingdom among subjects at high CV risk, age 40 to 80 years, randomized to
`simvastatin 40 mg or placebo and followed for 5 years, as endpoint-driven. In a random
`sample of subjects with T2DM (5963 of the 20,536 subjects) who had HbA1c recorded at
`baseline (n = 1,087), there was no significant difference (Table 2) between treatment
`groups in the change in HbA1c.
`
`
`Table 2. HPS: Change from baseline in HbA1c in a random sample of T2DM
`
`
`
`
`There were also no meaningful differences in the reporting rate of hospital admissions for
`unstable diabetes (3.1% simvastatin vs. 3.2% placebo) or laser treatment for retinopathy
`(1.4% simvastatin vs. 1.2% placebo). For the 4,867 T2DM subjects for whom
`antihyperglycemic agent (AHA) information was available at baseline and follow up, there
`were no meaningful differences between the simvastatin and placebo groups in the number
`(%) of subjects who initiated or stopped AHAs.
`As Dr. Pratt correctly pointed out in her review, the study was not designed and powered
`to detect the small differences detected in the published metanalyses.
`• Study MK-0733-P187 compared the effect of simvastatin 40 mg versus placebo on the
`change from baseline to week 24 in LDL cholesterol in 253 diabetics with LDL > 100
`mg/dL and HbA1c ≤ 9% (on TZDs) at baseline. There was no significant difference
`between the simvastatin 40 mg and placebo groups in the change in HbA1c at week 24 (LS
`Mean for the difference simvastatin minus placebo: 0.2%, 95% CI -0.1, 0.4).
`
`
`
`Page 9 of 15
`
`Reference ID: 3016527
`
`9
`
`

`

`Cross Discipline Team Leader Review
`
`The HbA1c-lowering efficacy of sitagliptin versus placebo/ active comparator was analyzed in
`the following subgroups in the 19 sitagliptin clinical trials (the same 19 sitagliptin studies that
`were included in the SCS): simvastatin users, statin users, and non-statin users. The results
`were generally similar between the groups, although few subjects were on simvastatin or any
`statin in some of the studies. This resulted in wide 95% CI intervals. These results, and their
`variability, are best illustrated by the forest plots in Merck’s Summary of Clinical Efficacy
`(Figure 1 and Figure 2).
`
`Page 10 of 15
`
`Reference ID: 3016527
`
`10
`
`

`

`Cross Discipline Team Leader Review
`
`Figure 1. Analysis of Change from Baseline in A1C (%) by Simvastatin/Statin Use in the Primary Analysis
`Population of Each Study (Protocols 010 to 036)
`
`
`
`
`Page 11 of 15
`
`Reference ID: 3016527
`
`
`
`11
`
`

`

`Cross Discipline Team Leader Review
`
`Figure 2. Analysis of Change from Baseline in A1C (%) by Simvastatin/Statin Use in the Primary Analysis
`Population of Each Study (Protocols 040 to 801)
`
`
`
`Page 12 of 15
`
`Reference ID: 3016527
`
`
`
`12
`
`

`

`Cross Discipline Team Leader Review
`
`• Review of the change from baseline HbA1c in patients who initiated simvastatin (n = 95)
`or other statins (n = 177) during the treatment period in the sitagliptin clinical development
`program did not suggest a clinically significant effect on the initiation of simvastatin or
`another statin on glycemic control. This analysis is flawed due to the different times
`treatment with statins was initiated after randomization, and the relatively strong glycemic
`effect of sitagliptin or other active comparators against the small expected changes due to
`statins, based on the metanalyses.
`
`
`At the Pre-NDA stage, we agreed with Merck that a FDC containing simvastatin 80 mg would
`not be marketed, due to the risks of severe myopathy and rhabdomyolysis detected with that
`dose in the SEARCH trial and from other sources of safety data. On June 7, 2011, FDA
`approved new safety labeling for Zocor regarding the risk of myopathy, including
`rhabdomyolysis, in patients treated with 80 mg simvastatin.
`
`We also agreed with Merck that manufacturing of FDC doses containing sitagliptin 25 mg or
`simvastatin 5 mg would not be required due to the low usage rate (2.2% and 0.6%,
`respectively) in the US.
`
`The applicant analyzed sitagliptin and simvastatin coadministration data from the following 19
`sitagliptin trials and studies which were included in the Summary of Clinical Safety (SCS):
`• Phase 1 study 061
`• Phase 2 studies 010 and 014
`• Phase 3 trials 019, 020, 021, 023, 024, 035, 036, 040, 047, 049, 051, 052, 053, 064, 079, and
`801.
`
`Although the applicant assessed safety and tolerability “in patients who were coadministered
`sitagliptin and simvastatin in a pool of sitagliptin studies,” it did not clearly state why the
`above studies were chosen for inclusion in the SCS.
`
`The exposure to sitagliptin in combination with simvastatin or any statin in this metanalysis
`population was acceptable (n=827 and n=1,938, respectively). The mean duration of exposure
`was ~280 days, (range < 14 to ≥ 720 days). The majority of subjects treated with simvastatin
`received doses of 20 or 40 mg daily.
`
`Exposure to sitagliptin in combination with simvastatin did not increase one’s risk of death,
`SAEs, or discontinuation compared to non-exposed subjects.
`• Thirteen of the 3,691 subjects included in the all statins pooled analysis died (6 sitagliptin, 7
`non-exposed). Seven of these subjects had been exposed to simvastatin (2 sitagliptin, 5 non-
`exposed).
`• The incidence of nonfatal SAEs in the simvastatin population in the controlled portions of
`pooled studies was similar between the sitagliptin and non-exposed groups (7.0% vs. 7.2%,
`respectively).
`• The rate of discontinuations due to AEs was similar between treatment groups in both the
`simvastatin and all statin analyses (range 3.3 - 4.2%), despite an increase in the gastrointestinal
`SOC that was more prevalent in the non-exposed (i.e. simvastatin population: sitagliptin 0.2%
`vs. non-exposed 1.3%).
`
`Page 13 of 15
`
`Reference ID: 3016527
`
`13
`
`

`

`Cross Discipline Team Leader Review
`
`
`Comparing subjects on both sitagliptin and simvastatin or other statins to subjects on these
`statins not exposed to sitagliptin, there were no increases in reports of myopathy or the
`preferred term of “blood CPK increased” or increases in liver aminotransferases. There were
`also no increases noted in subjects receiving both sitagliptin and simvastatin or other statins
`for adverse reactions listed in the Januvia label: pancreatitis, hypoglycemia, renal impairment,
`or hypersensitivity reactions, compared to subjects on these lipid lowering agents not exposed
`to sitagliptin.
`9. Advisory Committee Meeting
`
`
`This sitagliptin/simvastatin 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
`these indications. 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
`
`
`The sponsor submitted a full waiver for the pediatric assessment for the following aspects:
`• The product fails to represent a meaningful therapeutic benefit over existing therapies for
`pediatric patients and is unlikely to be used in a substantial number of all pediatric age groups
`or the pediatric age group(s) for which a waiver is being requested,
`• DMEP has not required sponsors of lipid-lowering medications to evaluate drugs’
`effectiveness in the general pediatric population to satisfy the requirements of PREA.
`• Pediatric studies with sitagliptin are ongoing.
`The PeRC meeting was held on August 17, 2011 and the committee agreed with DMEP’s
`position to grant a full waiver from PREA requirements.
`11.
`Other Relevant Regulatory Issues
`
` •
`
`
`
` We sent Merck a REMS retraction letter. The product, once approved, will only carry a
`Medication Guide.
`
`• The DSI audit is described under the Clinical Pharmacology section of this memo.
`
`• The two postmarketing requirements (PMRs) to be listed in the approval letter are:
`PMR 1: Development of fixed dose combination strengths of sitagliptin/simvastatin of 50/10,
`50/20, and 50/40 to permit dosing of patients with moderate renal impairment with this
`combination product.
`PMR 2: A randomized, double-blind, active-controlled clinical trial to study the effect of
`sitagliptin/simvastatin FDC versus sitagliptin on glycemic control in type 2 diabetic patients on
`background metformin therapy.
`
`Page 14 of 15
`
`Reference ID: 3016527
`
`14
`
`

`

`Cross Discipline Team Leader Review
`
`12.
`
`Labefing
`
`At the time of this writing, the proprietary name under consideration for this FDC is Juvisync,
`after
`(hm had been rejected by DIS/[EPA and / or DDMAC. We are currently
`negotiating the PI and the Medication Guide with the applicant.
`Although Merck had agreed to a number of revisions we proposed to the label, they had not
`agreed to implement changes (listed in the paragraph below) we had requested in order to align
`this PI with the Supplemental Request Letter for Zocor we issued on 8/11/11. Merck wants to
`discuss and agree on changes to the Zocor label first, and then align the new changes to the
`Juvisync label as a labeling supplement to the Juvisync NDA.
`
`These disputed changes are listed below:
`0
`
`(b) (4)
`
`Although DRISK’s comments and suggested revisions to the Medication Guide were minor,
`we have not worked on the Medication Guide with the applicant, until we reach agreement on
`the substantive PI changes listed above.
`
`13.
`
`Recommendations/Risk Benefit Assessment
`
`I recommend approval of the sitagliptin/simvastatin FDC NDA. I fully recognize that this is a
`convenience product, so that patients who need sitagliptin and simvastatin can take only one
`pill daily. But there are no additional risks for the FDC, compared to coadministration of these
`two drugs separately.
`My reconnnended PMRS are listed in Section 11 of this memo, and the labeling issues we need
`to reach agreement with the applicant are listed in Section 12 of this memo.
`
`Page 15 of 15
`
`Reference ID: 301 6527
`
`15
`
`

`

`---------------------------------------------------------------