SCIENTIFIC DISCUSSION
`
`Introduction
`
`
`1.
`
`The pathophysiology of Type 2 diabetes mellitus (T2DM) is characterised by deficient insulin activity
`arising from decreased insulin secretion secondary to beta cell failure, and/or compromised insulin
`action in peripheral target tissues (insulin resistance). This abnormal metabolic state is exacerbated by
`excess hepatic glucose production and altered metabolism of proteins and lipids, which along with
`hyperglycaemia, contribute to microvascular and macrovascular complications.
`T2DM accounts for approximately 85% to 95% of diabetes cases in developed regions like the
`European Union. Age and weight are established risk factors for T2DM. The majority of patients with
`T2DM are overweight or obese. Diet modification and exercise is the first line of treatment for T2DM.
`Pharmacologic intervention with one oral antidiabetic drug (OAD) is usually the next step in
`treatment. After 3 to 9 years of OAD monotherapy, patients typically require an additional
`intervention. The recommended first line treatment is metformin, which restrains hepatic glucose
`production and decreases peripheral insulin resistance. Sulphonylureas, which are insulin
`secretagogues, may be used as an alternative to patients intolerant to metformin, or as an addition to
`metformin. Other second line oral treatment alternatives include alpha-glucosidase inhibitors,
`meglitinides and thiazolidinediones. Recently the first GLP-1 analogue, exenatide, and the first DPP-4
`inhibitors, sitagliptin and vildagliptin, were approved by the CHMP.
`
`Vildagliptin belongs to a new class of oral anti-diabetic drugs and is a selective and reversible
`inhibitor of Dipeptidyl peptidase 4 (DPP-4), the enzyme which inactivates the incretin hormones,
`glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), hormones
`which significantly contribute to the maintenance of glucose homeostasis.
`Metformin is an established first line treatment for T2DM. While the exact mechainsm of action is not
`fully understood, metformin is thought to act primarily to increase intestinal glucose utilization and
`enhance hepatic and peripheral insulin sensitivity .
`
`The combination of vildagliptin and metformin is intended for use in patients with T2DM as fixed
`combination tablets.
`
`The therapeutic indication granted is:
`The treatment of type 2 diabetes mellitus patients who are unable to achieve sufficient glycaemic
`control at their maximally tolerated dose of oral metformin alone or who are already treated with the
`combination of vildagliptin and metformin as separate tablets.
`
`The tablets are available in 2 strengths: vildagliptin 50 mg and metformin 850 mg, and vildagliptin 50
`mg and metformin 1000 mg. In all cases, the recommended daily dose is 100 mg vildagliptin, allowing
`a daily dose of 1700 to 2000 mg metformin.
`
`The combination of two classes of antihyperglycaemic agents in one single tablet can improve
`compliance with treatment, and thus eventually glycaemic control. Currently, no fixed dose
`combination of a DPP4 inhibitor and metformin is available in Europe.
`
`Vildagliptin (Galvus) has received a positive opinion for granting a marketing authorization on 19 July
`2007. Metformin was initially granted national authorisations in the EU from 1959 to 1997. Following
`a referral to the CPMP under Article 11 of Council Directive 75/319, as amended, a decision on a
`harmonised SPC for metformin was issued in February 2001. The indication proposed for Eucreas is
`fully consistent with that already approved for Vildagliptin (Galvus) in combination with metformin.
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`Quality aspects
`
`
`2.
`
`Introduction
`
`Eucreas is presented as immediate release film-coated tablets containing vildagliptin and metformin
`hydrochloride as active substances in the strength combination 50 mg/850 mg and 50 mg/1000mg.
`The other ingredients are hydroxypropyl cellulose and magnesium stearate. The film consists of
`hypromellose, macrogol, talc, titanium dioxide, purified water and colorants.
`The film-coated tablets are marketed in Aluminium/Aluminium (PA/Al/PVC/Al) blister.
`
`Active Substance
`
`Two active substances are used in this fixed combination product, vildagliptin and metformin
`hydrochloride
`
`Vildagliptin
`
`is (S)-1-[2-(3-Hydroxyadamantan-1-ylamino)acetyl]pyrrolidine-2-carbonitrile
`Its chemical name
`according to the IUPAC nomenclature.
`Vildagliptin is a white to slightly yellowish or slightly greyish crystalline powder and no polymorphs
`or solvates have been identified so far. Vildagliptin is non-hygroscopic and freely soluble in water and
`polar organic solvents. The above-mentioned active substance has one chiral centre and is used as a
`single enantiomer (S).
`
` •
`
` Manufacture
`
`
`Vildagliptin is synthesised in two reactions steps followed by purification (recrystallisation). The
`manufacturing process has been adequately described. Critical parameters have been identified and
`adequate in-process controls included. Specifications for starting materials, reagents, and solvents
`have been provided. Adequate control of critical steps and intermediates has been presented. Structure
`elucidation has been performed by elemental analysis, ultraviolet spectroscopy, infrared absorption
`spectroscopy, 1H-NMR spectroscopy, 13C-NMR spectroscopy, and mass spectroscopy. The molecular
`weight was determined by elemental analysis which is in agreement with the expected molecular
`weight. The proposed molecular structure was confirmed by X-ray powder diffraction and X-ray
`single crystal structural analysis.
`
` •
`
` Specification
`
`
`The Vildagliptin specifications include tests for appearance (slightly yellowish or slightly greyish
`powder), particle size (by laser light diffraction), identification (by IR-KBr, IR-ATR and X-ray
`diffraction), related substances (HPLC and IC), R-enantiomer of vidagliptin (HPLC), residual solvents
`(Head-space GC), loss on drying (thermogravimetry), sulphated ash, heavy metals, clarity of solution,
`colour of solution, assay (HPLC) and microbiological limit tests.
`It was verified that all specifications reflect the relevant quality attributes of the vildagliptin. The
`analytical methods, which were used in the routine controls, were well described and their validations
`are in accordance with the relevant ICH guidelines.
`Impurities were described, classified as process related impurities and possible degradation products,
`and qualified. Residual solvents were satisfactorily controlled in the active substance according to the
`relevant ICH requirements. Batch analysis data for the vildagliptin active substance were provided and
`all results comply with the specifications and show a good uniformity from batch to batch.
`
` •
`
` Stability
`
`
`The stability results from long-term accelerated and stress studies were completed according to ICH
`guidelines demonstrated adequate stability of the vildagliptin. This active substance is not susceptible
`to degradation under the influence of light and temperature exposure. The results of the long-term and
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`accelerated studies fulfil the proposed specification and for that reason support the proposed retest
`period.
`
`Metformin hydrochloride
`
`Metformin hydrochloride’s chemical name is 1,1-Dimethylbiguanide monohydrochloride according to
`the IUPAC nomenclature. This active substance is described in the Ph.Eur. It is a white crystalline
`powder that is odourless. The compound is freely soluble in water, slightly soluble in ethanol and
`practically insoluble in acetone, diethylether and dichloromethane. It has a specific crystalline form
`and has not demonstrated polymorphism or solvates. Particle size does not significantly influence
`dissolution of metformin hydrochloride, because it is freely soluble in water.
`
`The chemistry, manufacturing and control information on metformin hydrochloride has been evaluated
`by the EDQM and a European Certificate of Suitability of the Monograph of the European
`Pharmacopoeia (CEP) has been issued. It was noticed that two additional supplementary tests (Other
`impurities and residual solvents) were included in the CEP.
`
`Metformin hydrochloride specifications includes tests for appearance (white, crystalline powder),
`particle size (laser light diffraction), clarity and colour of the solution (Ph.Eur), identification (IR and
`XRPD), impurities (HPLC), residual solvents (GC), loss on drying (Ph.Eur), sulphated ash (Ph.Eur),
`heavy metals (Ph.Eur), assay (HPLC) and microbiological limit tests.
`
`The tests and limits in the specifications are considered appropriate for controlling the quality of this
`active substance.
`
`Batch analysis data for the metformin hydrochloride drug substances were provided and all batch
`analysis results comply with the specifications and show consistency from batch to batch.
`
`The stability results from long-term accelerated and stress studies were completed according to ICH
`guidelines demonstrated adequate stability of the metformin hydrochloride. The re-test period
`proposed was considered acceptable according to the stability data submitted.
`
`Medicinal Product
`
` •
`
` Pharmaceutical Development
`
`
`All information regarding the choice of the drug substance and the excipients are sufficiently justified.
`Well known excipients were used in the formulation, selected based on their suitability for use in a
`melt granulation process.
`
`Several tablet strengths of vildagliptin / metformin hydrochloride were developed for Eucreas film-
`coated tablets and were used either in clinical trials or in stability program. However, only two tablet
`strengths (50 mg/850 and 50 mg/1000 mg) will be marketed.
`
`The main aim of the applicant was to develop robust final formulation that would be suitable for
`routine manufacturing at the production scale of film-coated tablets which contain 2 active substances.
`In this context, different formulation containing slightly different excipients were investigated and
`optimised. Having investigated different formulations the applicant selected for commercialisation the
`melt granulation
`
`It was noticed that during the scale up minor changes were made to the formulation. However, it was
`verified that these changes do not have an impact on the formulation quality and performance.
`In order to differentiate the two strengths the colorant used in the film-coating system was slightly
`different.
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` •
`
` Manufacture of the Product
`
`
`The proposed commercial manufacturing process involves standard technology using standard
`manufacturing processes such as mixing/kneading, melt granulation, compressing and film coating.
`Furthermore, the equipment used is commonly available in the pharmaceutical industry. It was
`demonstrated that melt granulation step is critical in the manufacturing process.
`The batch analysis results show that the medicinal product can be manufactured reproducibly
`according the agreed finished product specifications.
`
` •
`
` Product Specification
`
`
`The drug product specifications were established according the ICH guidelines and include the
`following tests: appearance, identification (TLC and HPLC), mean mass, dissolution (Ph.Eur., HPLC),
`water (Karl Fischer), degradation products (HPLC), uniformity of dosage units by content uniformity
`(HPLC), assay (HPLC), microbial limits (Ph Eur).
`All analytical procedures that were used for testing the drug product were properly described.
`Moreover, all relevant methods were satisfactorily validated in accordance with the relevant ICH
`guidelines.
`The batch analysis results show that the medicinal product can be manufactured reproducibly
`according the agreed finished product specifications.
`
` •
`
` Stability of the Product
`
`
`The stability studies were conducted according to the relevant ICH guidelines. The stability program
`was based on bracketing between the lowest (1:20) and highest (1:5) ratio of vildagliptin / metformin
`hydrochloride. For the extremes the following batches were included: three batches are at 25/500
`(1:20) and three at 50/250 (1:5). Moreover, one batch each of all the other strengths was also included.
`It was verified that all batches have been stored at long term and accelerated conditions in the
`proposed market packaging. One batch each of the extremes was stored under elevated temperature
`conditions for 3 months and at ICH conditions, another batch each of the extremes was stored under
`low temperature conditions for 6 months and finally another batch each of the extremes was stored for
`photostability at ICH conditions.
`Based on the available stability data, the proposed shelf life and storage conditions as stated in the
`SPC are acceptable.
`
`Discussion on chemical, pharmaceutical and biological aspects
`
`Information on development, manufacture, control of the active substance and the finished product
`have been presented in a satisfactory manner and justified in accordance with relevant CHMP and ICH
`guidelines. The results of tests carried out indicate satisfactory consistency and uniformity of the
`finished product. Therefore, this medicinal product should have a satisfactory and uniform
`performance in the clinic.
`
`3.
`
`Introduction
`
`All pivotal toxicology and safety pharmacology studies were conducted in compliance with Good
`Laboratory Practices. A facility inspection has been performed of one laboratory site by an EMEA
`GLP inspection team. The audit did not result in any objections to the use of the audited studies for the
`safety evaluation.
`Non-clinical studies with the combination of vildagliptin and metformin were limited to studies on
`repeat-dose toxicity and embryo-foetal toxicity.
`
`The non-clinical data relating to vildagliptin consisted mostly of original data from the applicant and
`was largely identical to the data submitted for the approval of vildagliptin (Galvus).
`
`Non-clinical aspects
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`
`There is a limited amount of non-clinical data on metformin, and no new original data was submitted.
`The applicant performed an extensive review of the literature. In the light of the longstanding clinical
`use of metformin, this was considered to be acceptable by the CHMP.
`
`Pharmacology
`
`Vildagliptin
`
` •
`
` Primary pharmacodynamics
`
`
`In vitro studies
`The non-clinical pharmacology program has demonstrated that vildagliptin is a selective and potent
`inhibitor of DPP-4. The IC50 value for inhibition of human DPP-4 is about 3 nM and similar activity
`was observed with the rat enzyme, demonstrating the lack of species selectivity. Vildagliptin showed
`some activity at the related enzymes DPP-8 and DPP-9 (Ki values of 506 nM and 65 nM,
`respectively). Although these values are 253 and 32 times higher than the Ki for DPP-4, activity at
`Cmax in humans (2.3 µM) is likely. No assays exist allowing evaluation of DPP-8/DPP-9 inhibition in
`vivo. The possibility of activity at one or both of these targets is considered a safety concern in
`relation to the occurrence of skin lesions in monkeys (see below). No, or minimal, inhibition was seen
`with other related enzymes.
`
`In vivo studies
`In vivo pharmacodynamic studies were performed in rats and monkeys. These studies demonstrated
`the in vivo inhibition of DPP-4 and increased plasma levels of GLP-1. Studies in diabetic rats and in
`insulin-resistant monkeys demonstrated a glucose-lowering effect of vildagliptin. Chronic effects of
`vildagliptin were studied in pre-diabetic and insulin-treated diabetic monkeys. Beneficial effects were
`observed on HbA1c, fasting insulin, fibrinogen and PAI-1.
`
`Vildagliptin increased β-cell mass in neonatal rats, and improved β-cell function in streptozotocin-
`induced diabetic mice. These data could suggest that vildagliptin has the potential to mitigate the
`progressive loss of islet function in type 2 diabetes patients.
`
` •
`
` Secondary pharmacodynamics
`
`
`Vildagliptin showed no significant effect on gastric emptying in monkeys. This is in contrast to what
`has been observed with exogenously-administered GLP-1 and GLP-1 analogues.
`
`As discussed above, activity at the related enzymes DPP-8 and/or DPP-9 can not be excluded at
`clinical exposures. Concerns related to secondary pharmacology can also arise from the importance of
`DPP-4 in enzymatic and non-enzymatic functions other than inhibiting the inactivation of GLP-1 and
`GIP.
`
`DPP-4 (CD26) is present as a cell surface molecule on immune cells and has been characterised as an
`important costimulatory molecule in immune activation. Although some studies applying DPP-4
`inhibitors have suggested a role for the enzyme activity for the immune function, other studies have
`suggested costimulation to be unrelated to the enzyme activity. The studies performed with
`vildagliptin and discussed in the dossier support the view that the immune function of CD26 is
`independent of its enzyme activity.
`
`There are no indications for safety issues related to other DPP-4 substrates than GLP-1 and GIP.
`
`Potential effects on the immune system, resulting in an increased risk for infections and on substance
`P and neurokinin resulting in an increased risk of angioedema are discussed in the Risk Management
`Plan. No increased risk has been observed during clinical development for any of these adverse events.
`
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`Metformin and Eucreas
`
`No pharmacological studies with metformin or the combination vildagliptin-metformin has been
`performed by the applicant. The applicant has discussed the pharmacology of metformin based on
`literature data. While the exact mechanism of the in vivo glucose-lowering by metformin is not fully
`understood, the primary effects are attributed to a decrease of hepatic glucose production, a delay of
`intestinal glucose absorption and in increase of glucose disposal in peripheral tissues. All of these
`effects of metformin are reported in preclinical animal models.
`
` •
`
` Safety pharmacology programme
`
`
`Safety pharmacology studies have been conducted to evaluate neuropharmacological, respiratory and
`cardiovascular effects of vildagliptin in animals.
`Cardiovascular changes were observed in dogs at high doses, occasionally resulting in mortality.
`Possible mechanisms were examined in an extensive battery of in vitro and in vivo studies of
`cardiovascular parameters. These effects are possibly related to inhibition of SCN5A sodium channels
`which was observed in in vitro studies. Based on dog exposure data (Cmax > 7-fold higher at NOAEL
`than seen at maximum dose in humans) and the in vitro IC50 for sodium channels (365 µM versus
`clinical Cmax of 2 µM), a clinical effect is unlikely. However, conduction disturbances were further
`investigated in humans.
`No formal safety pharmacology program has been performed with metformin since its development in
`the 1950s. This was considered acceptable taking into account the extensive accumulated experience
`with its use since then.
`
` •
`
` Pharmacodynamic drug interactions
`
`
`The effects of combinations of vildagliptin with the rapid-onset insulinotropic agent, nateglinide
`(Starlix®) and with the insulin sensitizer, pioglitazone (Actos®) were assessed in Zucker fatty rats and
`resulted in an additive or more than additive effect on several plasma glucose-related parameters.
`No specific interaction studies with vildagliptin and metformin had been performed.
`
`Pharmacokinetics
`
`Vildagliptin
`
`Vildagliptin was rapidly absorbed with a high bioavailability in all species. There were no important
`differences in pharmacokinetic parameters between the tested animal species and humans.
`
`Vildagliptin showed low binding to plasma proteins in all species (<10%). In a whole body
`autoradiography study in rats, vildagliptin-related radioactivity was widely distributed to most tissues.
`Drug-related radioactivity was bound to melanin. There was a low passage for drug-related
`radioactivity across the blood-brain barrier. No radioactivity was detected in any tissue at 48 h post-
`dose. Studies in pregnant rats and rabbits demonstrated placental transfer of vildagliptin.
`
`
`The parent compound was one of the major circulating components in all species and all metabolites
`observed in humans were also found in the animal species. Hydrolysis was the main mechanism of
`vildagliptin metabolism in all species and exposure to the major metabolites was broadly similar in the
`rat, dog and human. In humans, the predominant metabolic pathway was hydrolysis at the cyano
`moiety to form a carboxylic acid metabolite (M20.7/LAY151), accounting for approximately 55% of
`circulating drug-related material following an oral dose. M20.7 was the main metabolite both in the rat
`(54%) and the dog (33%). In the rabbit, another hydrolysis product M15.3 was the main metabolite
`(53%).
`
`Vildagliptin is produced as a pure S-enantiomer. A clinical study showed that chiral conversion in vivo
`is unlikely.
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`Urinary excretion was the main route in all species except the rat, where equal amounts were excreted
`with urine and faeces. Milk transfer of vildagliptin and metabolites were demonstrated in the rat,
`which is therefore mentioned in the SPC section 4.6, with a milk/plasma ratio for total radioactivity of
`4.
`
`In vitro studies demonstrated that vildagliptin is unlikely to exhibit a potential for pharmacokinetic
`drug interactions. Vildagliptin did not inhibit Pgp or any of a series of CYP enzymes. There was no
`evidence for enzyme induction.
`
`Metformin and Eucreas
`
`Metformin is a highly polar, highly water soluble bi-substituted guanidine derivative that most likely
`exists as a positively charged molecule under physiological conditions. Consequently, metformin
`absorption in humans and animals is incomplete. Metformin shows negligible plasma protein binding.
`Metformin is believed to be a substrate for rodent organic anion transport proteins which may play a
`part in its distribution to various tissues. Metformin is excreted mainly as unchanged drug in the urine.
`
`Toxicokinetic analysis from toxicity studies with multiple fixed dose combinations of vildagliptin and
`metformin were conducted in rats and dogs. The results demonstrated the absence of any effect of
`metformin on vildagliptin, or LAY151 (vildagliptin metabolite) exposure. Exposure to metformin
`appeared to be slightly increased when coadministered with vildagliptin in some dog and rat studies.
`Toxicokinetic evaluations were performed in embryo-foetal development studies conducted in rats and
`rabbits. In general, exposure to vildagliptin and metformin in the foetus was low in both species and
`metformin exposure was similar in the presence and absence of vildagliptin.
`
`Toxicology
`
`Vildagliptin
`
` •
`
` Single dose toxicity
`
`
`Vildagliptin exhibits low acute toxicity. In mice and rats no toxicological signs were observed after a
`single oral dose of 2000 mg/kg.
`
` •
`
` Repeat dose toxicity (with toxicokinetics)
`
`
`Repeat dose toxicity studies were performed in rats (up to 26 weeks) and dogs (up to 52 weeks). These
`models are considered relevant, based on the lack of species specificity for the pharmacological
`activity of vildagliptin, and the similarities in metabolism to humans.
`
`The main toxicological effect noted in rats was the accumulation of clusters of foamy alveolar
`macrophages in the lung. Similar observations were made in mice. This finding was proposed to be
`due to an exaggerated pharmacological effect of DPP-4 inhibition in the rat. The clinical relevance of
`the lung findings in rats cannot be fully excluded. There is a considerable safety margin (5 x human
`AUC at NOAEL) and the findings are considered of limited importance.
`
`The most consistent toxicological finding in the dog was the appearance of gastrointestinal symptoms,
`particularly soft faeces, mucoid faeces, diarrhea and at higher doses, faecal blood. These signs were
`observed at relatively low systemic exposures (observed already at lowest dose representing 2 x
`human AUC). GI findings were not observed in any other species and according to the applicant no GI
`disorders have been observed in clinical trials. The CHMP was of the opinion, that these findings are
`unlikely to be of clinical importance.
`
` •
`
` Genotoxicity
`
`
`The data from genotoxicity studies conducted with vildagliptin in several standard genotoxicity tests
`do not indicate a genotoxic potential.
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` •
`
` Carcinogenicity
`
`
`Life-time carcinogenicity studies were performed in mice and rats. No evidence for a carcinogenic
`potential was observed in the rat. An increased incidence of hemangiosarcomas was observed at the
`highest dose in female rats while in male rats, the incidence was slightly decreased. Given the mouse
`findings discussed below, a relation to treatment cannot be fully excluded. In the mouse there was an
`increased incidence of hemangiosarcomas and mammary carcinoma. The increased incidence of
`hemangiosarcoma in mice occurred only in organs where this tumour occurs as a relatively common
`spontaneous finding in the mouse (liver, spleen, uterus etc.). It is suggested that a predisposition to
`spontaneous hemangiosarcoma at the affected site is needed for vildagliptin to promote an increased
`incidence. A study in the mouse demonstrated that vildagliptin inhibits VEGF-induced angiogenesis.
`Based on these mechanistic data the applicant proposes a mechanism whereby inhibition of VEGF-
`induced angiogenesis over a long period exerts selection pressure in favour of endothelium that
`proliferates independently of VEGF and hence increases the likelihood of endothelial neoplasia. There
`was a disproportionate increase in hemangiosarcoma involving the liver in treated male mice at ≥ 250
`mg/kg/day. At the same time there was a decreased incidence of hepatocellular carcinoma in male
`mice. The applicant hypothesizes that hemangiosarcomas may originate within early hepatocellular
`tumours or preneoplastic lesions followed by obliteration of the hepatocellular tumour and its
`replacement with the more aggressive hemangiosarcoma. There is a substantial safety margin
`(exposure margin at NOAEL = 16). It was considered that vildagliptin is likely to act by promoting
`development of a tumour form that appears commonly mice, and that the data do not suggest an
`increased risk for hemangiosarcoma development in humans where this tumour form is uncommon.
`The fact that the incidences of other common spontaneous tumours were not increased by vildagliptin
`treatment supports the view that a more general tumour promoting effect of vildagliptin is unlikely.
`The applicant will further study the mechanism for tumour development in the liver of mice, and the
`findings were considered by the CHMP not to represent a significant risk to humans.
`
`In the case of mammary adenocarcioma, the applicant suggested that tumours noted in the mouse
`carcinogenicity study are likely the result of an effect on the pituitary-gonadal axis that is unlikely to
`be of relevance to humans. In mammary tissue from mice treated with vildagliptin for 53 weeks there
`was a dramatic upregulation of genes related to milk production, such as casein-beta, casein-gamma
`and lactalbumin, suggesting that hormonally-driven changes are occurring in the mammary gland of
`mice treated with vildagliptin. The CHMP was of the opinion that these effects are unlikely to be of
`relevance to humans.
`
` •
`
` Reproduction Toxicity
`
`
`Vildagliptin showed no effects on fertility, reproductive performance or early embryonic development
`in the rat. Embryo-foetal toxicity was evaluated in rats and rabbits. In the rat, an increased incidence of
`wavy ribs was observed at ≥ 225 mg/kg/day, in association with reduced maternal body weight
`parameters. Although classified as a malformation, literature data suggest that wavy ribs in the rat may
`be reversible. In rabbits, decreased foetal weight and skeletal variations indicative of developmental
`delays were noted in rabbits at 150 mg/kg/day, in the presence of severe maternal toxicity (including
`mortality). It is concluded that vildagliptin is not selectively embryotoxic and does not exhibit a
`teratogenic potential. In the peri- and postnatal toxicity study in rats, maternal toxicity was observed at
`all doses. Transient decrease in F1 generation body weight and a decreased number of central beam
`breaks in open-field motor activity tests were observed at ≥ 150 mg/kg/day.
`
` •
`
` Local tolerance
`
`
`Local tolerance of vildagliptin was investigated as part of the intravenous toxicity. No local effects due
`to vildagliptin were observed in either species. A skin irritation study conducted in rabbits did not
`indicate any dermal irritant properties.
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`• Other toxicity studies
`
`Vildagliptin showed no effect on the immune response in KLH-immunised rats. As discussed in the
`section on Pharmacology, the lack of immunotoxicity supports the view that the immune function of
`DPP-4/CD26 is independent of its enzymatic activity.
`
`No toxicity studies with metabolites were performed. The main human metabolites were present at
`similar amounts in the toxicology species. In patients with renal impairment, the exposure to the
`pharmacologically inactive metabolite LAY151 may be increased up to 6 times. There are no
`indications for any toxicity related to the metabolite and no further studies are warranted.
`
`Drug impurities requiring toxicological qualification were tested in repeat-dose toxicity and
`genotoxicity studies with a vildagliptin preparation spiked with the impurities at levels of 2-3%. There
`were no findings suggesting a change in toxicity profile.
`
`Available data indicate that the administration of DPP-4 inhibitors to monkeys results in dose and
`duration-dependent increases in necrotic lesions of the tail, digits, ears, nose and scrotum. The
`mechanism is unknown and such lesions have not been described in humans, rats or dogs. Data from
`the safety pharmacology study in monkeys suggest that vildagliptin may cause skin lesions in the
`monkey. A 13-week toxicology in cynomolgus monkeys shows occurrence of necrotic lesions with a
`lack of safety margin and lack of reversibility at higher doses. The skin lesions are proposed to result
`from peripheral vasoconstriction.The skin lesions were observed at doses that produced a tachycardic
`and a prohypertensive action indicating a sympathomimetic effect of vildagliptin at these doses in
`monkeys.The applicant argues that these findings were related to DPP4 inhibition, and that monkeys
`are much more sensitive to DPP4 inhibition than humans. The lack of skin lesions with sitagliptin in
`rhesus monkeys speaks against this proposal suggesting that other factors may be involved in causing
`the skin lesions result, such as inhibition of DPP8 and or DPP9, the occurrence of which in vivo is not
`known.
`
`Based on mechanistic considerations, no firm conclusion on the relevance of the skin lesions in
`monkeys for clinical safety can be drawn at this time. The CHMP considered these findings acceptable
`for a market authorisation, considering the clinical safety documented so far, and appropriate means
`taken by the applicant to identify any signals in the post-marketing phase. Further studies on the
`mechanism of skin lesions in the monkeys will be performed as follow-up measures. In addition to
`describing the findings in SPC section 5.3, a warning is included in section 4.4 with a reference to
`section 5.3.
`
`Eucreas
`
`Toxicology information for metformin, beyond what is in the product labelling information, is
`not publicly available. No studies have been performed by the applicant. This is acceptable, given the
`long clinical experience with metformin.
`
`Repeat-dose toxicity studies up to 13 weeks with the combination vildagliptin and metformin were
`performed in rats and dogs. No important safety concerns were identified. The effect of the
`combination of vildagliptin and metformin on embryo-foetal development was studied in rats and
`rabbits. There was no evidence of teratogenicity in either the rat or rabbit. Adverse effects on the
`foetus (slight decreases in ossification in rats and increased early resoprtion in rabbits) were associated
`with metformin-induced maternal toxicity, which included mort