WARNING: RISK OF THYROID C CELL TUMORS

Transcription

1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use VICTOZA sfely nd effectively. See full prescriing informtion for VICTOZA. VICTOZA (lirglutide) injection, for sucutneous use Initil U.S. Approvl: 2010 WARNING: RISK OF THYROID C CELL TUMORS See full prescriing informtion for complete oxed wrning. Lirglutide cuses thyroid C-cell tumors t cliniclly relevnt exposures in oth genders of rts nd mice. It is unknown whether VICTOZA cuses thyroid C-cell tumors, including medullry thyroid crcinom (MTC), in humns, s the humn relevnce of lirglutide-induced rodent thyroid C-cell tumors hs not een determined (5.1, 13.1). VICTOZA is contrindicted in ptients with personl or fmily history of MTC or in ptients with Multiple Endocrine Neoplsi syndrome type 2 (MEN 2). Counsel ptients regrding the potentil risk of MTC nd the symptoms of thyroid tumors (4, 5.1). RECENT MAJOR CHANGES Indictions nd Usge (1) /2017 Contrindictions (4) /2017 Wrnings nd Precutions (5.2, 5.6, 5.7) /2017 INDICATIONS AND USAGE VICTOZA is glucgon like peptide 1 (GLP 1) receptor gonist indicted: s n djunct to diet nd exercise to improve glycemic control in dults with type 2 dietes mellitus (1). to reduce the risk of mjor dverse crdiovsculr events in dults with type 2 dietes mellitus nd estlished crdiovsculr disese (1). Limittions of Use: Not for tretment of type 1 dietes mellitus or dietic ketocidosis. Hs not een studied in comintion with prndil insulin. DOSAGE AND ADMINISTRATION Inject sucutneously in the domen, thigh or upper rm (2.1). Administer once dily t ny time of dy, independently of mels (2.2). Initite t 0.6 mg per dy for one week then increse to 1.2 mg. Dose cn e incresed to 1.8 mg for dditionl glycemic control (2.2). DOSAGE FORMS AND STRENGTHS Injection: 6 mg/ml solution in pre-filled, multi-dose pen tht delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg (3). CONTRAINDICATIONS VICTOZA is contrindicted in ptients with personl or fmily history of medullry thyroid crcinom or in ptients with Multiple Endocrine Neoplsi syndrome type 2 (4). VICTOZA is contrindicted in ptients with prior serious hypersensitivity rection to VICTOZA or ny of the product components (4). WARNINGS AND PRECAUTIONS Thyroid C-cell Tumors: See Boxed Wrning (5.1). Pncretitis: Postmrketing reports, including ftl nd non-ftl hemorrhgic or necrotizing pncretitis. Discontinue promptly if pncretitis is suspected. Do not restrt if pncretitis is confirmed (5.2). Never shre VICTOZA pen etween ptients, even if the needle is chnged (5.3). Serious Hypoglycemi: When VICTOZA is used with n insulin secretgogue (e.g. sulfonylure) or insulin, consider lowering the dose of the insulin secretgogue or insulin to reduce the risk of hypoglycemi (5.4). Renl Impirment: Postmrketing, usully in ssocition with nuse, vomiting, dirrhe, or dehydrtion which my sometimes require hemodilysis. Use cution when inititing or esclting doses of VICTOZA in ptients with renl impirment (5.5). Hypersensitivity: Postmrketing reports of serious hypersensitivity rections (e.g., nphylctic rections nd ngioedem). Discontinue VICTOZA nd promptly seek medicl dvice (5.6). Acute Gllldder Disese: If cholelithisis or cholecystitis re suspected, gllldder studies re indicted (5.7) ADVERSE REACTIONS The most common dverse rections, reported in 5% of ptients treted with VICTOZA re: nuse, dirrhe, vomiting, decresed ppetite, dyspepsi, constiption (6.1). Immunogenicity-relted events, including urticri, were more common mong VICTOZA -treted ptients (0.8%) thn mong comprtor-treted ptients (0.4%) in clinicl trils (6.2). To report SUSPECTED ADVERSE REACTIONS, contct Novo Nordisk Inc. t or FDA t FDA 1088 or DRUG INTERACTIONS VICTOZA delys gstric emptying. My impct sorption of concomitntly dministered orl medictions. (7). USE IN SPECIFIC POPULATIONS Renl Impirment: No dose djustment recommended (2.4, 8.6, 12.3). Pregnncy: VICTOZA should e used during pregnncy only if the potentil enefit justifies the potentil risk to the fetus (8.1). See 17 for PATIENT COUNSELING INFORMATION nd FDA-Approved Mediction Guide. Revised: 08/2017 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF THYROID C CELL TUMORS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Importnt Administrtion Instructions 2.2 Generl Dosing nd Administrtion 2.3 Concomitnt Use with n Insulin Secretgogue (e.g. Sulfonylure) or with Insulin 2.4 Dosge in Ptients with Renl Impirment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-cell Tumors 5.2 Pncretitis 5.3 Never Shre VICTOZA Pen Between Ptients 5.4 Use with Medictions Known to Cuse Hypoglycemi 5.5 Renl Impirment 5.6 Hypersensitivity Rections 5.7 Acute Gllldder Disese 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 6.2 Immunogenicity 6.3 Post-Mrketing Experience 7 DRUG INTERACTIONS 7.1 Orl Medictions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.2 Lcttion 8.4 Peditric Use 8.5 Geritric Use 8.6 Renl Impirment 8.7 Heptic Impirment 8.8 Gstropresis 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 14 CLINICAL STUDIES 14.1 Glycemic Control Trils in Adults with Type 2 Dietes Mellitus 14.2 Crdiovsculr Outcomes Tril in Ptients with Type 2 Dietes Mellitus nd Atherosclerotic Crdiovsculr Disese 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Recommended Storge 17 PATIENT COUNSELING INFORMATION *Sections or susections omitted from the full prescriing informtion re not listed. 1

2 FULL PRESCRIBING INFORMATION WARNING: RISK OF THYROID C CELL TUMORS Lirglutide cuses dose-dependent nd tretment-durtion-dependent thyroid C-cell tumors t cliniclly relevnt exposures in oth genders of rts nd mice. It is unknown whether VICTOZA cuses thyroid C-cell tumors, including medullry thyroid crcinom (MTC), in humns, s the humn relevnce of lirglutideinduced rodent thyroid C-cell tumors hs not een determined [see Wrnings nd Precutions (5.1) nd Nonclinicl Toxicology (13.1)]. VICTOZA is contrindicted in ptients with personl or fmily history of MTC nd in ptients with Multiple Endocrine Neoplsi syndrome type 2 (MEN 2). Counsel ptients regrding the potentil risk for MTC with the use of VICTOZA nd inform them of symptoms of thyroid tumors (e.g. mss in the neck, dysphgi, dyspne, persistent horseness). Routine monitoring of serum clcitonin or using thyroid ultrsound is of uncertin vlue for erly detection of MTC in ptients treted with VICTOZA [see Contrindictions (4) nd Wrnings nd Precutions (5.1)]. 1 INDICATIONS AND USAGE VICTOZA is indicted: s n djunct to diet nd exercise to improve glycemic control in dults with type 2 dietes mellitus, to reduce the risk of mjor dverse crdiovsculr events (crdiovsculr deth, non-ftl myocrdil infrction, or non-ftl stroke) in dults with type 2 dietes mellitus nd estlished crdiovsculr disese [see Clinicl Studies (14.2)]. Limittions of Use: VICTOZA is not sustitute for insulin. VICTOZA should not e used in ptients with type 1 dietes mellitus or for the tretment of dietic ketocidosis, s it would not e effective in these settings. The concurrent use of VICTOZA nd prndil insulin hs not een studied. 2 DOSAGE AND ADMINISTRATION 2.1 Importnt Administrtion Instructions Inspect visully prior to ech injection. Only use if solution is cler, colorless, nd contins no prticles. Inject VICTOZA sucutneously in the domen, thigh or upper rm. No dose djustment is needed if chnging the injection site nd/or timing. When using VICTOZA with insulin, dminister s seprte injections. Never mix. It is cceptle to inject VICTOZA nd insulin in the sme ody region ut the injections should not e djcent to ech other. 2.2 Generl Dosing nd Administrtion Inject VICTOZA sucutneously once-dily t ny time of dy, independently of mels. Initite VICTOZA with dose of 0.6 mg per dy for one week. The 0.6 mg dose is strting dose intended to reduce gstrointestinl symptoms during initil titrtion, nd is not effective for glycemic control. After one week t 0.6 mg per dy, the dose should e incresed to 1.2 mg. If the 1.2 mg dose does not result in cceptle glycemic control, the dose cn e incresed to 1.8 mg. If dose is missed, resume the once-dily regimen s prescried with the next scheduled dose. Do not dminister n extr dose or increse in dose to mke up for the missed dose. If more thn 3 dys hve elpsed since the lst VICTOZA dose, reinitite VICTOZA t 0.6 mg to mitigte ny gstrointestinl symptoms ssocited with reinitition of tretment. Upon reinitition, VICTOZA should e titrted t the discretion of the prescrier. 2.3 Concomitnt Use with n Insulin Secretgogue (e.g., Sulfonylure) or with Insulin When inititing VICTOZA, consider reducing the dose of concomitntly dministered insulin secretgogues (such s sulfonylures) to reduce the risk of hypoglycemi [see Wrnings nd Precutions (5.4) nd Adverse Rections (6)]. 2.4 Dosge in Ptients with Renl Impirment No dose djustment is recommended for ptients with renl impirment. 3 DOSAGE FORMS AND STRENGTHS Injection: 6 mg/ml solution in pre-filled, multi-dose pen tht delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg. 4 CONTRAINDICATIONS Medullry Thyroid Crcinom VICTOZA is contrindicted in ptients with personl or fmily history of medullry thyroid crcinom (MTC) or in ptients with Multiple Endocrine Neoplsi syndrome type 2 (MEN 2). Hypersensitivity VICTOZA is contrindicted in ptients with prior serious hypersensitivity rection to VICTOZA or to ny of the product components. Serious hypersensitivity rections including nphylctic rections nd ngioedem hve een reported with VICTOZA [see Wrnings nd Precutions (5.6)]. 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-cell Tumors Lirglutide cuses dose-dependent nd tretment-durtion-dependent thyroid C-cell tumors (denoms nd/or crcinoms) t cliniclly relevnt exposures in oth genders of rts nd mice [see Nonclinicl Toxicology (13.1)]. Mlignnt thyroid C-cell crcinoms were detected in rts nd mice. It is unknown whether VICTOZA will cuse thyroid C-cell tumors, including medullry thyroid crcinom (MTC), in humns, s the humn relevnce of lirglutide-induced rodent thyroid C-cell tumors hs not een determined. VICTOZA (lirglutide) injection, for sucutneous use 2 Cses of MTC in ptients treted with VICTOZA hve een reported in the postmrketing period; the dt in these reports re insufficient to estlish or exclude cusl reltionship etween MTC nd VICTOZA use in humns. VICTOZA is contrindicted in ptients with personl or fmily history of MTC or in ptients with MEN 2. Counsel ptients regrding the potentil risk for MTC with the use of VICTOZA nd inform them of symptoms of thyroid tumors (e.g. mss in the neck, dysphgi, dyspne, persistent horseness). Routine monitoring of serum clcitonin or using thyroid ultrsound is of uncertin vlue for erly detection of MTC in ptients treted with VICTOZA. Such monitoring my increse the risk of unnecessry procedures, due to low test specificity for serum clcitonin nd high ckground incidence of thyroid disese. Significntly elevted serum clcitonin my indicte MTC nd ptients with MTC usully hve clcitonin vlues >50 ng/l. If serum clcitonin is mesured nd found to e elevted, the ptient should e further evluted. Ptients with thyroid nodules noted on physicl exmintion or neck imging should lso e further evluted. 5.2 Pncretitis Bsed on spontneous postmrketing reports, cute pncretitis, including ftl nd non-ftl hemorrhgic or necrotizing pncretitis, hs een oserved in ptients treted with VICTOZA. After initition of VICTOZA, oserve ptients crefully for signs nd symptoms of pncretitis (including persistent severe dominl pin, sometimes rditing to the ck nd which my or my not e ccompnied y vomiting). If pncretitis is suspected, VICTOZA should promptly e discontinued nd pproprite mngement should e initited. If pncretitis is confirmed, VICTOZA should not e restrted. In glycemic control trils of VICTOZA, there hve een 13 cses of pncretitis mong VICTOZA - treted ptients nd 1 cse in comprtor (glimepiride) treted ptient (2.7 vs. 0.5 cses per 1000 ptient-yers). Nine of the 13 cses with VICTOZA were reported s cute pncretitis nd four were reported s chronic pncretitis. In one cse in VICTOZA -treted ptient, pncretitis, with necrosis, ws oserved nd led to deth; however clinicl cuslity could not e estlished. Some ptients hd other risk fctors for pncretitis, such s history of cholelithisis or lcohol use. VICTOZA hs een studied in limited numer of ptients with history of pncretitis. It is unknown if ptients with history of pncretitis re t higher risk for development of pncretitis on VICTOZA. 5.3 Never Shre VICTOZA Pen Between Ptients VICTOZA pens must never e shred etween ptients, even if the needle is chnged. Pen-shring poses risk for trnsmission of lood-orne pthogens. 5.4 Use with Medictions Known to Cuse Hypoglycemi Ptients receiving VICTOZA in comintion with n insulin secretgogue (e.g., sulfonylure) or insulin my hve n incresed risk of hypoglycemi. The risk of hypoglycemi my e lowered y reduction in the dose of sulfonylure (or other concomitntly dministered insulin secretgogues) or insulin [see Dosge nd Administrtion (2.2), Adverse Rections (6.1)]. 5.5 Renl Impirment VICTOZA hs not een found to e directly nephrotoxic in niml studies or clinicl trils. There hve een postmrketing reports of cute renl filure nd worsening of chronic renl filure, which my sometimes require hemodilysis in VICTOZA -treted ptients [see Adverse Rections (6.2)]. Some of these events were reported in ptients without known underlying renl disese. A mjority of the reported events occurred in ptients who hd experienced nuse, vomiting, dirrhe, or dehydrtion [see Adverse Rections (6.1)]. Some of the reported events occurred in ptients receiving one or more medictions known to ffect renl function or hydrtion sttus. Altered renl function hs een reversed in mny of the reported cses with supportive tretment nd discontinution of potentilly custive gents, including VICTOZA. Use cution when inititing or esclting doses of VICTOZA in ptients with renl impirment [see Use in Specific Popultions (8.6)]. 5.6 Hypersensitivity Rections There hve een postmrketing reports of serious hypersensitivity rections (e.g., nphylctic rections nd ngioedem) in ptients treted with VICTOZA. If hypersensitivity rection occurs, discontinue VICTOZA ; tret promptly per stndrd of cre, nd monitor until signs nd symptoms resolve. Do not use in ptients with previous hypersensitivity rection to VICTOZA [see Contrindictions (4)]. Anphylxis nd ngioedem hve een reported with other GLP-1 receptor gonists. Use cution in ptient with history of nphylxis or ngioedem with nother GLP-receptor gonist ecuse it is unknown whether such ptients will e predisposed to these rections with VICTOZA. 5.7 Acute Gllldder Disese In the LEADER tril [see Clinicl Studies (14.2)], 3.1% of VICTOZA -treted ptients versus 1.9% of plceo-treted ptients reported n cute event of gllldder disese, such s cholelithisis or cholecystitis. The mjority of events required hospitliztion or cholecystectomy. If cholelithisis is suspected, gllldder studies nd pproprite clinicl follow-up re indicted. 6 ADVERSE REACTIONS The following serious dverse rections re descried elow or elsewhere in the prescriing informtion: Risk of Thyroid C-cell Tumors [see Wrnings nd Precutions (5.1)] Pncretitis [see Wrnings nd Precutions (5.2)] Use with Medictions Known to Cuse Hypoglycemi [see Wrnings nd Precutions (5.4)] Renl Impirment [see Wrnings nd Precutions (5.5)] Hypersensitivity Rections [see Wrnings nd Precutions (5.6)] 6.1 Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes oserved in the clinicl trils of drug cnnot e directly compred to rtes in the clinicl trils of nother drug nd my not reflect the rtes oserved in prctice. Common Adverse Rections The dt in Tle 1 re derived from 5 glycemic control, plceo-controlled trils [see Clinicl Studies (14.1)]. These dt reflect exposure of 1673 ptients to VICTOZA nd men durtion of exposure to VICTOZA of 37.3 weeks. The men ge of ptients ws 58 yers, 4% were 75 yers or older nd 54%

3 VICTOZA (lirglutide) injection, for sucutneous use 3 were mle. The popultion ws 79% White, 6% Blck or Africn Americn, 13% Asin; 4% were of Hispnic or Ltino ethnicity. At seline the popultion hd dietes for n verge of 9.1 yers nd men HA 1c of 8.4%. Bseline estimted renl function ws norml or mildly impired in 88.1% nd modertely impired in 11.9% of the pooled popultion. Tle 1 shows common dverse rections, excluding hypoglycemi, ssocited with the use of VICTOZA. These dverse rections occurred more commonly on VICTOZA thn on plceo nd occurred in t lest 5% of ptients treted with VICTOZA. Tle 1 Adverse rections reported in 5% of VICTOZA -treted ptients Plceo N = 661 Lirglutide 1.2 mg N = 645 Lirglutide 1.8 mg N = 1024 Adverse Rection (%) (%) (%) Nuse Dirrhe Hedche Nsophryngitis Vomiting Decresed ppetite Dyspepsi Upper Respirtory Trct Infection Constiption Bck Pin Cumultive proportions were clculted comining studies using Cochrn-Mntel-Henszel weights. In n nlysis of plceo- nd ctive-controlled trils, the types nd frequency of common dverse rections, excluding hypoglycemi, were similr to those listed in Tle 1. Other Adverse Rections Gstrointestinl Adverse Rections In the pool of 5 glycemic control, plceo-controlled clinicl trils, withdrwls due to gstrointestinl dverse rections, occurred in 4.3% of VICTOZA -treted ptients nd 0.5% of plceo-treted ptients. Withdrwl due to gstrointestinl dverse events minly occurred during the first 2-3 months of the trils. Injection site rections Injection site rections (e.g., injection site rsh, erythem) were reported in pproximtely 2% of VICTOZA -treted ptients in the five doule-lind, glycemic control trils of t lest 26 weeks durtion. Less thn 0.2% of VICTOZA -treted ptients discontinued due to injection site rections. Hypoglycemi Hypoglycemi requiring the ssistnce of nother person in plceo-controlled trils In 5 glycemic control, plceo-controlled clinicl trils of t lest 26 weeks durtion, hypoglycemi requiring the ssistnce of nother person for tretment occurred in 8 VICTOZA -treted ptients (7.5 events per 1000 ptient-yers). Of these 8 VICTOZA -treted ptients, 7 ptients were concomitntly using sulfonylure. Tle 2 Incidence (%) nd Rte (episodes/ptient yer) of Hypoglycemi in 26-Week Comintion Therpy Plceo-controlled Trils Plceo Comprtor VICTOZA Tretment Add-on to Metformin Plceo + Metformin (N = 121) VICTOZA + Metformin (N = 724) Ptient not le to self-tret (0.001) Ptient le to self-tret 2.5 (0.06) 3.6 (0.05) Add-on to Plceo + (N = 114) VICTOZA + (N = 695) Ptient not le to self-tret (0.003) Ptient le to self-tret 2.6 (0.17) 7.5 (0.38) Not clssified (0.05) Add-on to Metformin + Rosiglitzone Plceo + Metformin + Rosiglitzone (N = 175) VICTOZA + Metformin + Rosiglitzone (N = 355) Ptient not le to self-tret 0 0 Ptient le to self-tret 4.6 (0.15) 7.9 (0.49) Not clssified 1.1 (0.03) 0.6 (0.01) Add-on to Metformin + Plceo + Metformin + (N = 114) VICTOZA + Metformin + (N = 230) Ptient not le to self-tret (0.06) Ptient le to self-tret 16.7 (0.95) 27.4 (1.16) Not clssified 0 0 Ptient not le to self-tret is defined s n event requiring the ssistnce of nother person for tretment. Ppillry thyroid crcinom In glycemic control trils of VICTOZA, there were 7 reported cses of ppillry thyroid crcinom in ptients treted with VICTOZA nd 1 cse in comprtor-treted ptient (1.5 vs. 0.5 cses per 1000 ptient-yers). Most of these ppillry thyroid crcinoms were <1 cm in gretest dimeter nd were dignosed in surgicl pthology specimens fter thyroidectomy prompted y findings on protocolspecified screening with serum clcitonin or thyroid ultrsound. Cholelithisis nd cholecystitis In glycemic control trils of VICTOZA, the incidence of cholelithisis ws 0.3% in oth VICTOZA - treted nd plceo-treted ptients. The incidence of cholecystitis ws 0.2% in oth VICTOZA - treted nd plceo-treted ptients. In the LEADER tril [see Clinicl Studies (14.2)], the incidence of cholelithisis ws 1.5% (3.9 cses per 1000 ptient yers of oservtion) in VICTOZA -treted nd 1.1% (2.8 cses per 1000 ptient yers of oservtion) in plceo-treted ptients, oth on ckground of stndrd of cre. The incidence of cute cholecystitis ws 1.1% (2.9 cses per 1000 ptient yers of oservtion) in VICTOZA -treted nd 0.7% (1.9 cses per 1000 ptient yers of oservtion) in plceo-treted ptients. Lortory Tests Biliruin In the five glycemic control trils of t lest 26 weeks durtion, mildly elevted serum iliruin concentrtions (elevtions to no more thn twice the upper limit of the reference rnge) occurred in 4.0% of VICTOZA -treted ptients, 2.1% of plceo-treted ptients nd 3.5% of ctive-comprtor-treted ptients. This finding ws not ccompnied y normlities in other liver tests. The significnce of this isolted finding is unknown. Clcitonin Clcitonin, iologicl mrker of MTC, ws mesured throughout the clinicl development progrm. At the end of the glycemic control trils, djusted men serum clcitonin concentrtions were higher in VICTOZA -treted ptients compred to plceo-treted ptients ut not compred to ptients receiving ctive comprtor. Between group differences in djusted men serum clcitonin vlues were pproximtely 0.1 ng/l or less. Among ptients with pretretment clcitonin <20 ng/l, clcitonin elevtions to >20 ng/l occurred in 0.7% of VICTOZA -treted ptients, 0.3% of plceo-treted ptients, nd 0.5% of ctive-comprtor-treted ptients. The clinicl significnce of these findings is unknown. Lipse nd Amylse In one glycemic control tril in renl impirment ptients, men increse of 33% for lipse nd 15% for mylse from seline ws oserved for VICTOZA -treted ptients while plceo-treted ptients hd men decrese in lipse of 3% nd men increse in mylse of 1%. In the LEADER tril, serum lipse nd mylse were routinely mesured. Among VICTOZA -treted ptients, 7.9% hd lipse vlue t ny time during tretment of greter thn or equl to 3 times the upper limit of norml compred with 4.5% of plceo-treted ptients, nd 1% of VICTOZA -treted ptients hd n mylse vlue t ny time during tretment of greter thn or equl to 3 times the upper limit of norml versus 0.7% of plceo-treted ptients. The clinicl significnce of elevtions in lipse or mylse with VICTOZA is unknown in the sence of other signs nd symptoms of pncretitis [see Wrnings nd Precutions (5.2)]. Vitl signs VICTOZA did not hve dverse effects on lood pressure. Men increses from seline in hert rte of 2 to 3 ets per minute hve een oserved with VICTOZA compred to plceo. 6.2 Immunogenicity Consistent with the potentilly immunogenic properties of protein nd peptide phrmceuticls, ptients treted with VICTOZA my develop nti-lirglutide ntiodies. The detection of ntiody formtion is highly dependent on the sensitivity nd specificity of the ssy. Additionlly, the oserved incidence of ntiody (including neutrlizing ntiody) positivity in n ssy my e influenced y severl fctors including ssy methodology, smple hndling, timing of smple collection, concomitnt medictions, nd underlying disese. For these resons, the incidence of ntiodies to lirglutide cnnot e directly compred with the incidence of ntiodies of other products. Approximtely 50-70% of VICTOZA -treted ptients in five doule-lind clinicl trils of 26 weeks durtion or longer were tested for the presence of nti-lirglutide ntiodies t the end of tretment. Low titers (concentrtions not requiring dilution of serum) of nti-lirglutide ntiodies were detected in 8.6% of these VICTOZA -treted ptients. Cross-recting nti-lirglutide ntiodies to ntive glucgon-like peptide-1 (GLP-1) occurred in 6.9% of the VICTOZA -treted ptients in the doulelind 52-week monotherpy tril nd in 4.8% of the VICTOZA -treted ptients in the doule-lind 26-week dd-on comintion therpy trils. These cross-recting ntiodies were not tested for neutrlizing effect ginst ntive GLP-1, nd thus the potentil for cliniclly significnt neutrliztion of ntive GLP-1 ws not ssessed. Antiodies tht hd neutrlizing effect on lirglutide in n in vitro ssy occurred in 2.3% of the VICTOZA -treted ptients in the doule-lind 52-week monotherpy tril nd in 1.0% of the VICTOZA -treted ptients in the doule-lind 26-week dd-on comintion therpy trils. Antiody formtion ws not ssocited with reduced efficcy of VICTOZA when compring men HA 1c of ll ntiody-positive nd ll ntiody-negtive ptients. However, the 3 ptients with the highest titers of nti-lirglutide ntiodies hd no reduction in HA 1c with VICTOZA tretment. In five doule-lind glycemic control trils of VICTOZA, events from composite of dverse events potentilly relted to immunogenicity (e.g. urticri, ngioedem) occurred mong 0.8% of VICTOZA - treted ptients nd mong 0.4% of comprtor-treted ptients. Urticri ccounted for pproximtely one-hlf of the events in this composite for VICTOZA -treted ptients. Ptients who developed ntilirglutide ntiodies were not more likely to develop events from the immunogenicity events composite thn were ptients who did not develop nti-lirglutide ntiodies. In the LEADER tril [see Clinicl Studies (14.2)], nti-lirglutide ntiodies were detected in 11 out of the 1247 (0.9%) VICTOZA -treted ptients with ntiody mesurements. Of the 11 VICTOZA -treted ptients who developed nti-lirglutide ntiodies, none were oserved to develop neutrlizing ntiodies to lirglutide, nd 5 ptients (0.4%) developed cross-recting ntiodies ginst ntive GLP Post-Mrketing Experience The following dditionl dverse rections hve een reported during post-pprovl use of VICTOZA. Becuse these events re reported voluntrily from popultion of uncertin size, it is generlly not possile to relily estimte their frequency or estlish cusl reltionship to drug exposure. Medullry thyroid crcinom [see Wrnings nd Precutions (5.1)] Dehydrtion resulting from nuse, vomiting nd dirrhe. [see Wrnings nd Precutions (5.5) nd Ptient Counseling Informtion (17)]

4 VICTOZA (lirglutide) injection, for sucutneous use 4 Incresed serum cretinine, cute renl filure or worsening of chronic renl filure, sometimes requiring hemodilysis. [see Wrnings nd Precutions (5.5) nd Ptient Counseling Informtion (17)] Angioedem nd nphylctic rections. [see Contrindictions (4), Wrnings nd Precutions (5.6), Ptient Counseling Informtion (17)] Allergic rections: rsh nd pruritus Acute pncretitis, hemorrhgic nd necrotizing pncretitis sometimes resulting in deth [see Wrnings nd Precutions (5.2)] Heptoiliry disorders: elevtions of liver enzymes, hyperiliruinemi, cholestsis, heptitis [see Adverse Rections (6.1)] 7 DRUG INTERACTIONS 7.1 Orl Medictions VICTOZA cuses dely of gstric emptying, nd therey hs the potentil to impct the sorption of concomitntly dministered orl medictions. In clinicl phrmcology trils, VICTOZA did not ffect the sorption of the tested orlly dministered medictions to ny cliniclly relevnt degree. Nonetheless, cution should e exercised when orl medictions re concomitntly dministered with VICTOZA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy Risk Summry Bsed on niml reproduction studies, there my e risks to the fetus from exposure to VICTOZA during pregnncy. VICTOZA should e used during pregnncy only if the potentil enefit justifies the potentil risk to the fetus. Animl reproduction studies identified incresed dverse developmentl outcomes from exposure during pregnncy. Lirglutide exposure ws ssocited with erly emryonic deths nd n imlnce in some fetl normlities in pregnnt rts dministered lirglutide during orgnogenesis t doses tht pproximte clinicl exposures t the mximum recommended humn dose (MRHD) of 1.8 mg/ dy. In pregnnt rits dministered lirglutide during orgnogenesis, decresed fetl weight nd n incresed incidence of mjor fetl normlities were seen t exposures elow the humn exposures t the MRHD [see Animl Dt]. The estimted ckground risk of mjor irth defects for women with uncontrolled pre-gesttionl dietes (Hemogloin A 1C >7) is 6 to 10%. The mjor irth defect rte hs een reported to e s high s 20 to 25% in women with Hemogloin A 1C >10. In the U.S. generl popultion, the estimted ckground risk of mjor irth defects nd miscrrige in cliniclly recognized pregnncies is 2-4% nd 15-20%, respectively. Clinicl Considertions Disese-ssocited mternl nd/or emryo/fetl risk Poorly controlled dietes in pregnncy increses the mternl risk for dietic ketocidosis, preeclmpsi, spontneous ortions, preterm delivery, stillirth nd delivery complictions due to fetl mcrosomi (e.g., perinel injury nd lcertions, need for cesren section, nd post-prtum hemorrhge). Poorly controlled dietes increses the fetl risk for neurl tue defects, crdiovsculr mlformtions, orl clefts, still irth, mcrosomi relted moridity (e.g., rchil plexus injury, hypoxi), nd neontl hyperglycemi. Animl Dt Femle rts given sucutneous doses of 0.1, 0.25 nd 1.0 mg/kg/dy lirglutide eginning 2 weeks efore mting through gesttion dy 17 hd estimted systemic exposures 0.8-, 3-, nd 11-times the humn exposure t the MRHD sed on plsm AUC comprison. The numer of erly emryonic deths in the 1 mg/kg/dy group incresed slightly. Fetl normlities nd vritions in kidneys nd lood vessels, irregulr ossifiction of the skull, nd more complete stte of ossifiction occurred t ll doses. Mottled liver nd minimlly kinked ris occurred t the highest dose. The incidence of fetl mlformtions in lirglutide-treted groups exceeding concurrent nd historicl controls were misshpen orophrynx nd/or nrrowed opening into lrynx t 0.1 mg/kg/dy nd umilicl herni t 0.1 nd 0.25 mg/kg/dy. Pregnnt rits given sucutneous doses of 0.01, nd 0.05 mg/kg/dy lirglutide from gesttion dy 6 through dy 18 inclusive, hd estimted systemic exposures less thn the humn exposure t the MRHD of 1.8 mg/dy t ll doses, sed on plsm AUC. Lirglutide decresed fetl weight nd dose-dependently incresed the incidence of totl mjor fetl normlities t ll doses. The incidence of mlformtions exceeded concurrent nd historicl controls t 0.01 mg/kg/dy (kidneys, scpul), 0.01 mg/kg/dy (eyes, forelim), mg/kg/dy (rin, til nd scrl vertere, mjor lood vessels nd hert, umilicus), mg/kg/dy (sternum) nd t 0.05 mg/kg/dy (prietl ones, mjor lood vessels). Irregulr ossifiction nd/or skeletl normlities occurred in the skull nd jw, vertere nd ris, sternum, pelvis, til, nd scpul; nd dose-dependent minor skeletl vritions were oserved. Viscerl normlities occurred in lood vessels, lung, liver, nd esophgus. Biloed or ifurcted gllldder ws seen in ll tretment groups, ut not in the control group. In pregnnt femle rts given sucutneous doses of 0.1, 0.25 nd 1.0 mg/kg/dy lirglutide from gesttion dy 6 through wening or termintion of nursing on lcttion dy 24, estimted systemic exposures were 0.8-, 3-, nd 11-times humn exposure t the MRHD of 1.8 mg/dy, sed on plsm AUC. A slight dely in prturition ws oserved in the mjority of treted rts. Group men ody weight of neontl rts from lirglutide-treted dms ws lower thn neontl rts from control group dms. Bloody scs nd gitted ehvior occurred in mle rts descended from dms treted with 1 mg/kg/ dy lirglutide. Group men ody weight from irth to postprtum dy 14 trended lower in F 2 genertion rts descended from lirglutide-treted rts compred to F 2 genertion rts descended from controls, ut differences did not rech sttisticl significnce for ny group. 8.2 Lcttion Risk Summry There re no dt on the presence of VICTOZA in humn milk, the effects on the restfed infnt, or the effects on milk production. Lirglutide ws present in milk of lctting rts [see Dt]. Developmentl nd helth enefits of restfeeding should e considered long with the mother s clinicl need for VICTOZA nd ny potentil dverse effects on the restfed infnt from VICTOZA or from the underlying mternl condition. Dt In lctting rts, lirglutide ws present unchnged in milk t concentrtions pproximtely 50% of mternl plsm concentrtions. 8.4 Peditric Use Sfety nd effectiveness of VICTOZA hve not een estlished in peditric ptients. VICTOZA is not recommended for use in peditric ptients. 8.5 Geritric Use In the VICTOZA tretment rms of the glycemic control trils, totl of 832 (19.3%) of the ptients were 65 to 74 yers of ge nd 145 (3.4%) were 75 yers of ge nd over. No overll differences in sfety or efficcy were oserved etween these ptients nd younger ptients, ut greter sensitivity of some older individuls cnnot e ruled out. In the VICTOZA tretment rm of the LEADER tril [see Clinicl Studies (14.2)], totl of 1738 (37.2%) ptients were 65 to 74 yers of ge, 401 (8.6%) were 75 to 84 yers of ge, nd 17 (0.4%) were 85 yers of ge or older t seline. No overll differences in sfety or efficcy were oserved etween these ptients nd younger ptients. 8.6 Renl Impirment No dose djustment of VICTOZA is recommended for ptients with renl impirment [see Clinicl Phrmcology (12.3)]. The sfety nd efficcy of VICTOZA ws evluted in 26-week clinicl study tht included ptients with moderte renl impirment (egfr 30 to 60 ml/min/1.73m 2 ) [see Clinicl Studies (14.1)]. In the VICTOZA tretment rm of the LEADER tril [see Clinicl Studies (14.2)], 1932 (41.4%) ptients hd mild renl impirment, 999 (21.4%) ptients hd moderte renl impirment nd 117 (2.5%) ptients hd severe renl impirment t seline. No overll differences in sfety or efficcy were seen in these ptients compred to ptients with norml renl function. There is limited experience with VICTOZA in ptients with end stge renl disese. There hve een postmrketing reports of cute renl filure nd worsening of chronic renl filure, which my sometimes require hemodilysis [see Wrnings nd Precutions (5.5) nd Adverse Rections (6.2)]. Use cution in ptients who experience dehydrtion. 8.7 Heptic Impirment There is limited experience in ptients with mild, moderte or severe heptic impirment. Therefore, VICTOZA should e used with cution in this ptient popultion. No dose djustment of VICTOZA is recommended for ptients with heptic impirment [see Clinicl Phrmcology (12.3)]. 8.8 Gstropresis VICTOZA slows gstric emptying. VICTOZA hs not een studied in ptients with pre existing gstropresis. 10 OVERDOSAGE Overdoses hve een reported in clinicl trils nd post-mrketing use of VICTOZA. Effects hve included severe nuse nd severe vomiting. In the event of overdosge, pproprite supportive tretment should e initited ccording to the ptient s clinicl signs nd symptoms. 11 DESCRIPTION VICTOZA contins lirglutide, n nlog of humn GLP-1 nd cts s GLP-1 receptor gonist. The peptide precursor of lirglutide, produced y process tht includes expression of recominnt DNA in Scchromyces cerevisie, hs een engineered to e 97% homologous to ntive humn GLP-1 y sustituting rginine for lysine t position 34. Lirglutide is mde y ttching C-16 ftty cid (plmitic cid) with glutmic cid spcer on the remining lysine residue t position 26 of the peptide precursor. The moleculr formul of lirglutide is C 172H 265N 43O 51 nd the moleculr weight is Dltons. The structurl formul (Figure 1) is: His Al Glu Gly Thr Phe Thr Ser Asp C-16 ftty cid (plmitoyl) Glu Vl Ser Lys Al Al Gln Gly Glu Leu Tyr Ser Glu Phe Ile Al Trp Leu Vl Arg Gly Lys Figure 1 Structurl Formul of lirglutide VICTOZA is cler, colorless or lmost colorless solution. Ech 1 ml of VICTOZA solution contins 6 mg of lirglutide nd the following inctive ingredients: disodium phosphte dihydrte, 1.42 mg; propylene glycol, 14 mg; phenol, 5.5 mg; nd wter for injection. Ech pre-filled pen contins 3 ml solution of VICTOZA equivlent to 18 mg lirglutide (free-se, nhydrous). 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action Lirglutide is n cylted humn Glucgon-Like Peptide-1 (GLP-1) receptor gonist with 97% mino cid sequence homology to endogenous humn GLP-1(7-37). GLP-1(7-37) represents <20% of totl circulting endogenous GLP-1. Like GLP-1(7-37), lirglutide ctivtes the GLP-1 receptor, memrne-ound cell-surfce receptor coupled to denylyl cyclse y the stimultory G-protein, Gs, in pncretic et cells. Lirglutide increses intrcellulr cyclic AMP (camp) leding to insulin relese in the presence of elevted glucose concentrtions. This insulin secretion susides s lood glucose concentrtions decrese nd pproch euglycemi. Lirglutide lso decreses glucgon secretion in glucose-dependent mnner. The mechnism of lood glucose lowering lso involves dely in gstric emptying. Arg Gly

5 VICTOZA (lirglutide) injection, for sucutneous use 5 GLP-1(7-37) hs hlf-life of minutes due to degrdtion y the uiquitous endogenous enzymes, dipeptidyl peptidse IV (DPP-IV) nd neutrl endopeptidses (NEP). Unlike ntive GLP-1, lirglutide is stle ginst metolic degrdtion y oth peptidses nd hs plsm hlf-life of 13 hours fter sucutneous dministrtion. The phrmcokinetic profile of lirglutide, which mkes it suitle for once dily dministrtion, is result of self-ssocition tht delys sorption, plsm protein inding nd stility ginst metolic degrdtion y DPP-IV nd NEP Phrmcodynmics VICTOZA s phrmcodynmic profile is consistent with its phrmcokinetic profile oserved fter single sucutneous dministrtion s VICTOZA lowered fsting, premel nd postprndil glucose throughout the dy [see Clinicl Phrmcology (12.3)]. Fsting nd postprndil glucose ws mesured efore nd up to 5 hours fter stndrdized mel fter tretment to stedy stte with 0.6, 1.2 nd 1.8 mg VICTOZA or plceo. Compred to plceo, the postprndil plsm glucose AUC 0-300min ws 35% lower fter VICTOZA 1.2 mg nd 38% lower fter VICTOZA 1.8 mg. Glucose dependent insulin secretion The effect of single dose of 7.5 mcg/kg (~ 0.7 mg) VICTOZA on insulin secretion rtes (ISR) ws investigted in 10 ptients with type 2 dietes during grded glucose infusion. In these ptients, on verge, the ISR response ws incresed in glucose-dependent mnner (Figure 2). 14 VICTOZA Plceo Plsm Glucose (mg/dl) Figure 2 Men Insulin Secretion Rte (ISR) versus Glucose Concentrtion Following Single-Dose VICTOZA 7.5 mcg/kg (~ 0.7 mg) or Plceo in Ptients with Type 2 Dietes (N=10) During Grded Glucose Infusion Glucgon secretion VICTOZA lowered lood glucose y stimulting insulin secretion nd lowering glucgon secretion. A single dose of VICTOZA 7.5 mcg/kg (~ 0.7 mg) did not impir glucgon response to low glucose concentrtions. Gstric emptying VICTOZA cuses dely of gstric emptying, therey reducing the rte t which postprndil glucose ppers in the circultion. Crdic Electrophysiology (QTc) The effect of VICTOZA on crdic repolriztion ws tested in QTc study. VICTOZA t stedy stte concentrtions with dily doses up to 1.8 mg did not produce QTc prolongtion Phrmcokinetics Asorption - Following sucutneous dministrtion, mximum concentrtions of lirglutide re chieved t 8-12 hours post dosing. The men pek (C mx) nd totl (AUC) exposures of lirglutide were 35 ng/ml nd 960 ng h/ml, respectively, for sucutneous single dose of 0.6 mg. After sucutneous single dose dministrtions, C mx nd AUC of lirglutide incresed proportionlly over the therpeutic dose rnge of 0.6 mg to 1.8 mg. At 1.8 mg VICTOZA, the verge stedy stte concentrtion of lirglutide over 24 hours ws pproximtely 128 ng/ml. AUC 0- ws equivlent etween upper rm nd domen, nd etween upper rm nd thigh. AUC 0- from thigh ws 22% lower thn tht from domen. However, lirglutide exposures were considered comprle mong these three sucutneous injection sites. Asolute iovilility of lirglutide following sucutneous dministrtion is pproximtely 55%. Distriution - The men pprent volume of distriution fter sucutneous dministrtion of VICTOZA 0.6 mg is pproximtely 13 L. The men volume of distriution fter intrvenous dministrtion of VICTOZA is 0.07 L/kg. Lirglutide is extensively ound to plsm protein (>98%). Metolism - During the initil 24 hours following dministrtion of single [ 3 H]-lirglutide dose to helthy sujects, the mjor component in plsm ws intct lirglutide. Lirglutide is endogenously metolized in similr mnner to lrge proteins without specific orgn s mjor route of elimintion. Elimintion - Following [ 3 H]-lirglutide dose, intct lirglutide ws not detected in urine or feces. Only minor prt of the dministered rdioctivity ws excreted s lirglutide-relted metolites in urine or feces (6% nd 5%, respectively). The mjority of urine nd feces rdioctivity ws excreted during the first 6-8 dys. The men pprent clernce following sucutneous dministrtion of single dose of lirglutide is pproximtely 1.2 L/h with n elimintion hlf-life of pproximtely 13 hours, mking VICTOZA suitle for once dily dministrtion. Specific Popultions Elderly - Age hd no effect on the phrmcokinetics of VICTOZA sed on phrmcokinetic study in helthy elderly sujects (65 to 83 yers) nd popultion phrmcokinetic nlyses of ptients 18 to 80 yers of ge [see Use in Specific Popultions (8.5)]. Gender - Bsed on the results of popultion phrmcokinetic nlyses, femles hve 25% lower weight-djusted clernce of VICTOZA compred to mles. Bsed on the exposure response dt, no dose djustment is necessry sed on gender. Rce nd Ethnicity - Rce nd ethnicity hd no effect on the phrmcokinetics of VICTOZA sed on the results of popultion phrmcokinetic nlyses tht included Cucsin, Blck, Asin nd Hispnic/ Non-Hispnic sujects. ISR (pmol/kg/min) Body Weight - Body weight significntly ffects the phrmcokinetics of VICTOZA sed on results of popultion phrmcokinetic nlyses. The exposure of lirglutide decreses with n increse in seline ody weight. However, the 1.2 mg nd 1.8 mg dily doses of VICTOZA provided dequte systemic exposures over the ody weight rnge of kg evluted in the clinicl trils. Lirglutide ws not studied in ptients with ody weight >160 kg. Peditric - VICTOZA hs not een studied in peditric ptients [see Use in Specific Popultions (8.4)]. Renl Impirment - The single-dose phrmcokinetics of VICTOZA were evluted in sujects with vrying degrees of renl impirment. Sujects with mild (estimted cretinine clernce ml/min) to severe (estimted cretinine clernce <30 ml/min) renl impirment nd sujects with end-stge renl disese requiring dilysis were included in the tril. Compred to helthy sujects, lirglutide AUC in mild, moderte, nd severe renl impirment nd in end-stge renl disese ws on verge 35%, 19%, 29% nd 30% lower, respectively [see Use in Specific Popultions (8.6)]. Heptic Impirment - The single-dose phrmcokinetics of VICTOZA were evluted in sujects with vrying degrees of heptic impirment. Sujects with mild (Child Pugh score 5-6) to severe (Child Pugh score > 9) heptic impirment were included in the tril. Compred to helthy sujects, lirglutide AUC in sujects with mild, moderte nd severe heptic impirment ws on verge 11%, 14% nd 42% lower, respectively [see Use in Specific Popultions (8.7)]. Drug Interctions In vitro ssessment of drug drug interctions VICTOZA hs low potentil for phrmcokinetic drug-drug interctions relted to cytochrome P450 (CYP) nd plsm protein inding. In vivo ssessment of drug drug interctions The drug-drug interction studies were performed t stedy stte with VICTOZA 1.8 mg/dy. Before dministrtion of concomitnt tretment, sujects underwent 0.6 mg weekly dose increse to rech the mximum dose of 1.8 mg/dy. Administrtion of the intercting drugs ws timed so tht C mx of VICTOZA (8-12 h) would coincide with the sorption pek of the co-dministered drugs. Digoxin A single dose of digoxin 1 mg ws dministered 7 hours fter the dose of VICTOZA t stedy stte. The concomitnt dministrtion with VICTOZA resulted in reduction of digoxin AUC y 16%; C mx decresed y 31%. Digoxin medin time to mximl concentrtion (T mx) ws delyed from 1 h to 1.5 h. Lisinopril A single dose of lisinopril 20 mg ws dministered 5 minutes fter the dose of VICTOZA t stedy stte. The co-dministrtion with VICTOZA resulted in reduction of lisinopril AUC y 15%; C mx decresed y 27%. Lisinopril medin T mx ws delyed from 6 h to 8 h with VICTOZA. Atorvsttin VICTOZA did not chnge the overll exposure (AUC) of torvsttin following single dose of torvsttin 40 mg, dministered 5 hours fter the dose of VICTOZA t stedy stte. Atorvsttin C mx ws decresed y 38% nd medin T mx ws delyed from 1 h to 3 h with VICTOZA. Acetminophen VICTOZA did not chnge the overll exposure (AUC) of cetminophen following single dose of cetminophen 1000 mg, dministered 8 hours fter the dose of VICTOZA t stedy stte. Acetminophen C mx ws decresed y 31% nd medin T mx ws delyed up to 15 minutes. Griseofulvin VICTOZA did not chnge the overll exposure (AUC) of griseofulvin following co-dministrtion of single dose of griseofulvin 500 mg with VICTOZA t stedy stte. Griseofulvin C mx incresed y 37% while medin T mx did not chnge. Orl Contrceptives A single dose of n orl contrceptive comintion product contining 0.03 mg ethinylestrdiol nd 0.15 mg levonorgestrel ws dministered under fed conditions nd 7 hours fter the dose of VICTOZA t stedy stte. VICTOZA lowered ethinylestrdiol nd levonorgestrel C mx y 12% nd 13%, respectively. There ws no effect of VICTOZA on the overll exposure (AUC) of ethinylestrdiol. VICTOZA incresed the levonorgestrel AUC 0- y 18%. VICTOZA delyed T mx for oth ethinylestrdiol nd levonorgestrel y 1.5 h. Insulin Detemir No phrmcokinetic interction ws oserved etween VICTOZA nd insulin detemir when seprte sucutneous injections of insulin detemir 0.5 Unit/kg (single-dose) nd VICTOZA 1.8 mg (stedy stte) were dministered in ptients with type 2 dietes. 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility A 104-week crcinogenicity study ws conducted in mle nd femle CD-1 mice t doses of 0.03, 0.2, 1.0, nd 3.0 mg/kg/dy lirglutide dministered y olus sucutneous injection yielding systemic exposures 0.2-, 2-, 10- nd 45-times the humn exposure, respectively, t the MRHD of 1.8 mg/dy sed on plsm AUC comprison. A dose-relted increse in enign thyroid C-cell denoms ws seen in the 1.0 nd the 3.0 mg/kg/dy groups with incidences of 13% nd 19% in mles nd 6% nd 20% in femles, respectively. C-cell denoms did not occur in control groups or 0.03 nd 0.2 mg/ kg/dy groups. Tretment-relted mlignnt C-cell crcinoms occurred in 3% of femles in the 3.0 mg/kg/dy group. Thyroid C-cell tumors re rre findings during crcinogenicity testing in mice. A tretment-relted increse in firosrcoms ws seen on the dorsl skin nd sucutis, the ody surfce used for drug injection, in mles in the 3 mg/kg/dy group. These firosrcoms were ttriuted to the high locl concentrtion of drug ner the injection site. The lirglutide concentrtion in the clinicl formultion (6 mg/ml) is 10-times higher thn the concentrtion in the formultion used to dminister 3 mg/kg/dy lirglutide to mice in the crcinogenicity study (0.6 mg/ml). A 104-week crcinogenicity study ws conducted in mle nd femle Sprgue Dwley rts t doses of 0.075, 0.25 nd 0.75 mg/kg/dy lirglutide dministered y olus sucutneous injection with exposures 0.5-, 2- nd 8-times the humn exposure, respectively, resulting from the MRHD sed on plsm AUC comprison. A tretment-relted increse in enign thyroid C-cell denoms ws seen in mles in 0.25 nd 0.75 mg/kg/dy lirglutide groups with incidences of 12%, 16%, 42%, nd 46% nd in ll femle lirglutide-treted groups with incidences of 10%, 27%, 33%, nd 56% in 0 (control), 0.075, 0.25, nd 0.75 mg/kg/dy groups, respectively. A tretment-relted increse in mlignnt thyroid

6 C-cell crcinoms ws oserved in ll mle lirglutide-treted groups with incidences of 2%, 8%, 6%, nd 14% nd in femles t 0.25 nd 0.75 mg/kg/dy with incidences of 0%, 0%, 4%, nd 6% in 0 (control), 0.075, 0.25, nd 0.75 mg/kg/dy groups, respectively. Thyroid C-cell crcinoms re rre findings during crcinogenicity testing in rts. Studies in mice demonstrted tht lirglutide-induced C-cell prolifertion ws dependent on the GLP-1 receptor nd tht lirglutide did not cuse ctivtion of the RErrnged during Trnsfection (RET) protooncogene in thyroid C-cells. Humn relevnce of thyroid C-cell tumors in mice nd rts is unknown nd hs not een determined y clinicl studies or nonclinicl studies [see Boxed Wrning nd Wrnings nd Precutions (5.1)]. Lirglutide ws negtive with nd without metolic ctivtion in the Ames test for mutgenicity nd in humn peripherl lood lymphocyte chromosome errtion test for clstogenicity. Lirglutide ws negtive in repet-dose in vivo micronucleus tests in rts. In rt fertility studies using sucutneous doses of 0.1, 0.25 nd 1.0 mg/kg/dy lirglutide, mles were treted for 4 weeks prior to nd throughout mting nd femles were treted 2 weeks prior to nd throughout mting until gesttion dy 17. No direct dverse effects on mle fertility ws oserved t doses up to 1.0 mg/kg/dy, high dose yielding n estimted systemic exposure 11- times the humn exposure t the MRHD, sed on plsm AUC. In femle rts, n increse in erly emryonic deths occurred t 1.0 mg/kg/dy. Reduced ody weight gin nd food consumption were oserved in femles t the 1.0 mg/kg/dy dose. 14 CLINICAL STUDIES 14.1 Glycemic Control Trils in Adults with Type 2 Dietes Mellitus In glycemic control trils, VICTOZA hs een studied s monotherpy nd in comintion with one or two orl nti-dietic medictions or sl insulin. VICTOZA ws lso studied in crdiovsculr outcomes tril (LEADER tril). In ech of the plceo controlled trils, tretment with VICTOZA produced cliniclly nd sttisticlly significnt improvements in hemogloin A 1c nd fsting plsm glucose (FPG) compred to plceo. All VICTOZA -treted ptients strted t 0.6 mg/dy. The dose ws incresed in weekly intervls y 0.6 mg to rech 1.2 mg or 1.8 mg for ptients rndomized to these higher doses. VICTOZA 0.6 mg is not effective for glycemic control nd is intended only s strting dose to reduce gstrointestinl intolernce [see Dosge nd Administrtion (2)]. Monotherpy In this 52-week tril, 746 ptients were rndomized to VICTOZA 1.2 mg, VICTOZA 1.8 mg, or glimepiride 8 mg. Ptients who were rndomized to glimepiride were initilly treted with 2 mg dily for two weeks, incresing to 4 mg dily for nother two weeks, nd finlly incresing to 8 mg dily. Tretment with VICTOZA 1.8 mg nd 1.2 mg resulted in sttisticlly significnt reduction in HA 1c compred to glimepiride (Tle 3). The percentge of ptients who discontinued due to ineffective therpy ws 3.6% in the VICTOZA 1.8 mg tretment group, 6.0% in the VICTOZA 1.2 mg tretment group, nd 10.1% in the glimepiride-tretment group. The men ge of prticipnts ws 53 yers, nd the men durtion of dietes ws 5 yers. Prticipnts were 49.7% mle, 77.5% White, 12.6% Blck or Africn Americn nd 35.0% of Hispnic ethnicity. The men BMI ws 33.1 kg/m 2. Tle 3 Results of 52-week monotherpy tril VICTOZA 1.8 mg VICTOZA 1.2 mg 8 mg Intent to Tret Popultion (N) HA 1c (%) (Men) Bseline Chnge from seline (djusted men) Difference from glimepiride rm (djusted men) -0.6** -0.3* (-0.8, -0.4) (-0.5, -0.1) Percentge of ptients chieving A 1c <7% Fsting Plsm Glucose (mg/dl) (Men) Bseline Chnge from seline (djusted men) Difference from glimepiride rm (djusted men) -20** (-29, -12) -10* (-19, -1) Body Weight (kg) (Men) Bseline Chnge from seline (djusted men) Difference from glimepiride rm (djusted men) Intent to tret popultion using lst oservtion on study Lest squres men djusted for seline vlue *p vlue <0.05 **p vlue < ** (-4.3, -2.9) -3.2** (-3.9, -2.5) VICTOZA (lirglutide) injection, for sucutneous use 6 Men HA1c (%) VICTOZA 1.2 mg VICTOZA 1.8 mg LOCF Time (weeks) *p-vlue = for VICTOZA 1.2 mg compred to glimepiride p-vlue < for VICTOZA 1.8 mg compred to glimepiride P vlues derived from chnge from seline ANCOVA model. Figure 3 Men HA 1c for ptients who completed the 52-week tril nd for the Lst Oservtion Crried Forwrd (LOCF, intent-to-tret) dt t Week 52 (Monotherpy) Comintion Therpy Add on to Metformin In this 26-week tril, 1091 ptients were rndomized to VICTOZA 0.6 mg, VICTOZA 1.2 mg, VICTOZA 1.8 mg, plceo, or glimepiride 4 mg (one-hlf of the mximl pproved dose in the United Sttes), ll s dd-on to metformin. Rndomiztion occurred fter 6-week run-in period consisting of 3-week initil forced metformin titrtion period followed y mintennce period of nother 3 weeks. During the titrtion period, doses of metformin were incresed up to 2000 mg/dy. Tretment with VICTOZA 1.2 mg nd 1.8 mg s dd-on to metformin resulted in significnt men HA 1c reduction reltive to plceo dd-on to metformin nd resulted in similr men HA 1c reduction reltive to glimepiride 4 mg dd-on to metformin (Tle 4). The percentge of ptients who discontinued due to ineffective therpy ws 5.4% in the VICTOZA 1.8 mg + metformin tretment group, 3.3% in the VICTOZA 1.2 mg + metformin tretment group, 23.8% in the plceo + metformin tretment group, nd 3.7% in the glimepiride + metformin treted group. The men ge of prticipnts ws 57 yers, nd the men durtion of dietes ws 7 yers. Prticipnts were 58.2% mle, 87.1% White nd 2.4% Blck or Africn Americn. The men BMI ws 31.0 kg/m 2. Tle 4 Results of 26-week tril of VICTOZA s dd on to metformin VICTOZA 1.8 mg + Metformin VICTOZA 1.2 mg + Metformin Plceo + Metformin * 4 mg + Metformin Intent to Tret Popultion (N) HA 1c (%) (Men) Bseline Chnge from seline (djusted men) Difference from plceo + metformin rm (djusted men) -1.1** -1.1** (-1.3, -0.9) (-1.3, -0.9) Difference from glimepiride + metformin rm (djusted men) 0.0 (-0.2, 0.2) 0.0 (-0.2, 0.2) Percentge of ptients chieving A 1c <7% Fsting Plsm Glucose (mg/dl) (Men) Bseline Chnge from seline (djusted men) Difference from plceo + metformin rm (djusted men) -38** -37** (-48, -27) (-47, -26) Difference from glimepiride + metformin rm (djusted men) Body Weight (kg) (Men) -7 (-16, 2) -6 (-15, 3) Bseline Chnge from seline (djusted men) Difference from plceo + metformin rm (djusted men) Difference from glimepiride + metformin rm (djusted men) -1.3* (-2.2, -0.4) -3.8** (-4.5, -3.0) -1.1* (-2.0, -0.2) -3.5** (-4.3, -2.8) Intent to tret popultion using lst oservtion on study Lest squres men djusted for seline vlue For glimepiride, one-hlf of the mximl pproved United Sttes dose. *p vlue <0.05 **p vlue < VICTOZA Compred to Sitgliptin, Both s Add-on to Metformin In this 26 week, open-lel tril, 665 ptients on ckground of metformin 1500 mg per dy were rndomized to VICTOZA 1.2 mg once-dily, VICTOZA 1.8 mg once-dily or sitgliptin 100 mg once-dily, ll dosed ccording to pproved leling. Ptients were to continue their current tretment on metformin t stle, pre-tril dose level nd dosing frequency.