EDITION
`
`
`
`PERKINS COiE
`
`MAR 16 2011
`
`LAW LIBRARY
`
` PDR’
`
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`
`65
`
`201 |
`PAYSICIANS'
`DESK
`preeee
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`CEO: Edward Fotsch, MD
`President: David Tanzer
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`Copyright © 2010 PDR Network, LLC. Published by PDR Network, LLC at Montvale, NJ 07645-1725.All rights reserved. Noneof the contentof this Publication may be
`
`
`
`MPI EXHIBIT 1039 PAGE 1
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1039, p. 1 of 12
`
`

`

`
`Days of dosing, median (range)
`10 (4-15)
`10 (2-116)
`
`
`No.bolus injections, median (range)
`38 (36-42)
`15 (0-7)
`
`No. of additional bolus injections, median (range)
`0 (0-3)
`0 (0-4)
`Meantotal dose, mg 292.2 237.5
`
`
`
`
`
`“Includes dosing during the follow-up period after the 10-day study period,
`
`
`Efficacy by Dose Group, for Patients Receiving Doses Ranging from <61 to >90 micrograms/kg NovoSeven,
`Compassionate Use Programs and HTRS Registry
`NovoSeven Dose {micrograms/kg}
`Outcome*
`Unknown
`<61
`61-69
`70-80
`81-89
`
`Effective N (%)
`1 (43)
`3 (75)
`5 (63)
`10 (63)
`12 57)
`67
`
`
`Partial N (%}
`1(33)
`0 (0)
`0 (0)
`3 (19)
`3 (14)
`20
`
`Ineffective N (%.
`0 (0)
`1 (25)
`3 (38)
`2 (13)
`2 (10)
`17
`
`Unknown N (%)
`
`1 (33)
`
`0)
`
`0 (0)
`
`1 (6)
`
`4 (19)
`
`8
`
`
` Visitp
`
`2668/NOVO NORDISK ¢ NOVOSEVEN RT
`« For the latest PDR product information
`——
`Study 4: Dosing by Treatment Group
`‘WARNINGS AND PRECAUTIO
`© Thyroid C-cell tumors in avimals: H
`
`Continuous Infusion
`known. Counsel patients regarding thea rely
`Bolus (njection
`
`50 micrograms/kg/h
`90 micrograms/kg
`(n = 12)
`(n = 12)
`
`* Pancreatitis:
`In clinical trials, there we
`pancreatitis among Victoza-trented patianie
`
`comparator-treated patients, If Pancreatitie
`
`Vietoza and other potentially suspect diy.
`continued. Victoxa should not bu Testurter :
`
`is. confirmed. Use with caution in. patients «tM
`With’
`of pancreatitis (5.2),
`« Serious hypoglycemia: Can octeur when Vi
`ak
`
`with an insulin secretagogue (e.g, 4 eulfonay
`sider lowering the dose ofthe insulin Sarat
`i:
`duee the risk of hypoglycemia (5.3),
`
`* Macrovascular outcomes: There have beep.
`establishing contlusive evidence of MAcrovagey
`ls
`
`duction with Vietout or any other antidiabetieds
`
`ADVERSE REACTIONS“!
`
`® The most common adversereactions, reported jy,
`
`patients treated with Victoza and more eq
`nee
`
`patients treated: with placebo, are: headache, ny
`
`arrhes and anti-liraghitide antibody formation 6
`
`+ Immunogenicity-related events, including urticg
`
`more common among Victoxa-treated patients (0,
`
`among comparator-treated pationts (0.4%) jn nie
`’
`als (6),
`
`*
`To report SUSPECTED ADVERSE REACTIONS,
`Contact
`
`Novo Nordisk Inc, at 1-877-484-2869 or FDA at 1.8
`O0-FDAL
`1088 or www.fda.gov/medwatch.,
`DRUG INTERACTIONS
`
`* Vietoza delays gastric emptying. May impact:abisorgiigy
`af concomitantly administered oral medications, Uae
`tion (7),
`‘.
`
`———-USE IN SPECIFIC POPULATIONS——__
`* There are no data in patients below 18 yearsaf igs(Aa)
`* Use with caution in patients with renal or hopativimp
`ment. Limited data (86, 8.7),
`v
`See 17 for PATIENT COUNSELING INFORMATION
`and Medication Guide
`m
`Revised: 04/2010
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING:RISK OF THYROID C-CELL TUMORS
`1
`INDICATIONS AND USAGE
`1.1.
`Important Limitations of Use
`DOSAGE AND ADMINISTRATION
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1 Risk of Thyroid C-cell Tumors
`5.2
`Pancreatitis
`5.3.
`Use with Medications Known to Cause Hyporly:
`cemia
`5.4 Macrovascular Outcomes
`6 ADVERSE REACTIONS
`6.1
`Clinica} Trials Experience
`7 DRUG INTERACTIONS
`7.1 Oral Medications
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3 Nursing Mothers
`84
`Pediatric Use
`84 Geriatric Use
`8.6
`Renal Impairment
`8,7 Hepatic Impairment
`8.8
` Gastroparesis
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12,1 Mechanism of Action
`12,2 Pharmacodynamics
`12.3 Pharmacokinctiecs
`13 NONGLINICAL TOXICOLOGY
`
`
`
`
`21
`
`45
`
`tlle 112"
`
`16
`8
`4
`38
`No.of Bleeding Episodes'
`* Outcome assessed at end of treatment, last observation carried forward.
`7 N (@) do not add up to 100 due to rounding
`= One patient
`in the HTRS registry was excluded from efficacy analysis since NovoSeyen was used to maintain
`hemostasis after bleeding had beencontrolled,
`
`solution for subcutaneous use
`Initial U.S. Approval: 2010
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`See full prescribing information for complete boxed
`warning.
`* Liraglutide causes thyroid C-cell tumors at clinically
`relevant exposures in rodents.
`It
`is unknown
`whether Victoza causes thyroid C-call tumors, includ-
`ing medullary thyroid carcinoma (MTC), in humans,
`as human relevance could not be determined by clin-
`ical or nonclinical studies (5.1).
`* Victoza is contraindicated in patients with a personal
`or family history of MTC or in patients with Multiple
`Endocrine Neoplasia syndrome type 2 (MEN 2) (5.1).
`
`INDICATIONS AND USAGE—————
`Victoza is a glucagon-like peptide-1 (GLP-1) receptor ago-
`nist indicated az an adjunct, to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus (1).
`Important Limitations of Use (1.1);
`® Not recommended as first-line therapy for patients inad-
`equately controlied on diet and exercise (5.1),
`* Has not been studied sufficiently in patients with a his-
`tory of pancreatitis. Use caution (6,2),
`* Not for treatment of type 1 diabetes mellitus or diabetic
`ketoacidosis.
`:
`
`
`© Has not been studied in combination with insulin,
`DOSAGE AND ADMINISTRATION:
`* Adminiater once daily at any timeof day, independently of
`meals (2).
`e Inject subcutaneously in the abdomen, thigh or upper
`arm (2).
`* The injection site and timing can be changed without dose
`adjustment (2).
`* Initiate at 0.6mg per dayfor one week, This dose is in-
`
`Otmeob
`
`»
`
`/
`
`y
`:
`4
`‘
`
`1
`i
`Y
`
`a
`
`:
`
`i
`
`I
`
`lt
`|
`Is
`i:
`L
`
`7
`rf
`au
`|
`
`;
`iy
`
`!
`|
`
`5
`
`The diluent for reconstitution of NovoSeven RT ia a 10
`mmo) solution of L-histidine in water for injection and is
`supplied asa clepr colorless solution, and referred to aa the
`histidine diluent, The vials are madeof glass closed with a
`latex-free, chlorobutyl rubberdiac, and covered with an alu-
`minum cap: ‘The closed yials are equipped with a tamper
`evident snap-aff eap which is made of polypropylene.
`Prior to reconstituiivn, keep refrigerated or store between
`2-25°C/36-77°F. Do not freea:. Store protected from light. Do
`Hot Wee past the expiration date.
`After reconstitution. NoveSeven RT may be stared either at
`room temperature or refrigerated for up to 3 hours. Do not
`fresze reconstituted NovoSeven RT or store it im syringes.
`17
`=PATTENT COUNSELING INFORMATION
`Patients recetving NovoSeven RT should be informed of the
`benefits and risks associated with treatment. Patients
`should be warned about the early signs of hyperaensitivity
`reactions, including hives, urticaria, tightness of the chest,
`wheezing, hypotension, and anaphylaxis. Patienty should
`also be warned about the:signs of thrombosis, including new
`onzet swelling and-pnin in the limbs or abdomen, new onset
`chest pain, shortness of breath, loss of sensation or motor
`power, or altered consciousness or speech. Patients should
`be told to immediately seok medical help if any of the above
`signs or symptoms occur.
`Date of issue: August 6, 2010
`Version: 4
`License Number: 1261
`Novo Nordisk® is a registered trademark of Novo Nordisk
`A/S.
`NovoSevea® is a registered trademark of Novo Nordisk
`Health Care AG.
`© 1998-2010 Novo Nordisk A/S
`For information contact:
`Novo Nordisk Ine.
`100 College Road West
`Princeton, NJ 08540, USA
`1-877-NOVO-777
`
`
`
`MPI EXHIBIT 1039 PAGE 2
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1039, p. 2 of 12
`
`

`

` eeboandactivecontral,,respectively.
`‘tient, pancreatitis, with necrosis, was observedand led to MONS Were [ested WILM VICTOZA 1.5 Mg, PIRCebe, OFMs
`
`Vomiting /
`Constipation.
`
`
`
`Urinary Tract Infection
`
`Gmg per day for dne week. The 0.6 mg dose is a starting
`ties intended toweduesgastrointestinal symptoms during
`intial titration, ands noteffective for glycemic control. AF
`wrone weekot 0.6 mg per day, the doge should be increased
`wlimg. Tithe 1.2mgdese does not result in acceptable
`syremic control, thedosecan be increased to 1.8 mg,
`Vien initiating Victozn, considerreducing the dese of con-
`onitantly administeredinsulinsecretagogues (such as sul-
`tovlareas) to reduce the risk of hypoghyeamia fee Warn-
`nerond Precautions (0:2) and Arverse Reactions (6)].
`Vietezxa soltution should be inspected prior to each injection,
`int the solution shouldbeused only if it is clear, colorless,
`ud contains mo particles,
`) DOSAGE FORMS AND STRENGTHS
`idution for subeutancuus Injection, prefilled, multi-dose
`ear that deliversdoses of 0.6:mg, 12 mg, or 18mg (6 mg/’
`al, 3 mb).
`} CONTRAINDICATIONS
`
`Vitoriscontraindicated in patients with a personal or
`‘uly history ofmedullarythyroid carcinoma (MTC) or in
`pitiente with Multiple Endocrine Neoplasiasyndrome. type’
`DIMEN2)
`} WARNINGS AND PRECAUTIONS
`#1]
`Risk of Thyroid C-cellTumors:
`
`liregiutide ea
`dosé-dependentand treatment-duration-
`daendent thyroidO-cell tumors (adenomas:and/or carcino-
`ri) at clinically relevant exposuresinbath genders of rata
`und niew (SeeNontlinieal‘Toxicology (13.1)},Madignant, thy-
`nid C-cell carcinomasware detectedin rats andmice. Asta-
`iittully Bignifitrnt ingrease m cancer was Observed in rata
`reviving liraglotide at B-times clinical exposure conipared
`woattalé, Tt is unknown whetherVietdzs will eausethy-
`wad Celltumors, including medullary’ihiyroidcarcinoma
`ANC), inctamans, as the humin relevance of liraglutide-
`
`6-month trial. Follow-up serum calcitonin was 22.8 ng/L
`more than 2,5 years after the last dose of Vietoza. The larg-
`estincrease in serum calcitonin in a comparator-treatedpa-
`fientwaz seen with glimepiride in a patient whose serum
`calcitonin increased from19.3 ng/L at baseline to 44.8np/L
`at Week 65 and 38.1ng/L at-Weck 104. Among patients who
`began with serum calaitonin <20ng/L, calcitonin elevations
`to >20 ng/L. ocourred! in 0.7% of Victoza-trented patients;
`0.8% of placebo-treated patients, and 0.5% of active-
`cormparator-treated patients, with an incidence of 1.1%
`among patientstreated with 1.8 mg/dayof Victozs. Theclin-
`ical significance ofthesefindings is unknown.
`Counsel patients regarding the risk for MTC and the aymp-
`toms of thyroid tumors (e.g. a muss in the neck, dysphagia,
`dyspnes-or persistent hoarseness), It is amknown whether
`monitoring with servm calcitonin orthyroid ultrasound will
`mitigate the potential risk of MTC, and such monitoring
`mayincrease theriskofunnecessary procedures, due to low
`testspecificity forserum calcitonin“and o high background
`incidence ofthyraid disease, Patients with thyroid nodules
`noted onphysicalexamination orneckimagingobtainedfor
`other reasons should bereferred to.an. endocrinologist tor
`furtherevaluation.Although routine monitoring ofserum
`edleitoninig of tincertainvalue inpatients treated with
`Victozs, if serum calcitonin izmeasured and found to be el-
`sented thepatientshould be referred to anendocrinologist
`for further evaluation,
`5.2.
`Pancreatitia
`Tnclinical trialsof Vietoza, therewere7cases ofpancreati-
`tis) among Victoza-treated patients and 7 case: aming
`comparator-treatedpatients(2.2 ve.0.6 cases por1000
`patient-years), Five caseswithVictozaworereported as
`acute pancreatitis indtwo cases with Victozaworereported
`aschronic pancreatitis, In onecaseinaVietoan-treated pa-
`
`treated patients. The most common ‘adverse reaction4 lead-
`ing to withdrawal for Victoza-treatedpatients were nausea
`(2.8% yersus 0% for comparator)and vomiting (1.5% versus
`0.1% for comparator). Withdrawal due to gastrointestinal
`adverse events mainly occurred during’ thefirst 2-3montha
`af the trials.
`Tables Land 2 summarize the adverse avents' reportedin.
`=AofVieloza-treated patients inthe five controlled trials
`of26 weeks duration or longer,
`Table 1 Adverseevents reported in =5% of
`Victoza-treated patients or =5%of glimepiride-treated
`patients:52-week monotherapytrial
`All Victoza
`N = 497
`
`Adverse Event Term
`
`
`
`
`
`Visit PDR,net to register for Product Safety Alertsandto downloadmobilePDR" - free'to U.S. prescribers
`
`
`
`MPI EXHIBIT 1039 PAGE 3
`
`MPI EXHIBIT 1039 PAGE 3
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1039, p. 3 of 12
`
`

`

`2670/NOVO NORDISK ¢ VICTOZA
`
`]
`
`|
`
`|
`
`
`
`
`
`
` aa
`_. For the latest PDR product information, visit PDR.net
`
`
`
`Dizziness
`Table 2 Adverse events reported in =5%of Victoza-treated patients and occurring more frequently withVictoza
`
`compared to placebo: 26-week combination therapytrials
`Sinusitis
`Add-on to MetforminTrial
`
`
`Nasopharyngitis
`Placebo +
` All Victoza +
`
`Glimepiride +
`
`Metformin
`Metformin
`Metformin
`Back Pain
`
`N = 242
`
`N=121
`
`
`N = 724
`
`
`
`Hypertension
`Adverse Event Term
`
`
`
`
`{See table 2 at right]
`
`Gastrointestinal adverse events
`
`Diarrhea
`In thefiveclinical trials of 26 weeks duration or longer, gas-
`
`
`trointestinal adverse events were reported in 41% of
`Headache
`
`Victoza-treated patients and were dose-related, Gastroin-
`
`testinal adverse events occurred in 17%of comparator-
`Vomiting
`
`treated patients. Events that occurred more commonly
`among Victoza-treated patienta inchided nauses, vomiting,
`Add-on to Glimepiride Trial
`
`
`diarrhea, dyspepsia and constipation. In clinical trials af 26
`
`
`weeks duration or longer, the percentageof patients who re-
`Rosiglitazone =
`All Victoza +
`Placebo +
`
`ported nausea declined over time. Approximately 13% of
`Glimepinde
`Glimepiride
`Glimepiride
`
`
`Victoza-treated patients and 2% of comparator-treated pa-
`N 5231ce
`N = 695
`N=114
`
`
`tients reported nausva during the first 2 weeks of treat-
`ment.
`
` Adverse Event Term
`(%)
`(%)
`Immunogenicity
`
`
`Consistent with the potentially immunogenic properties of
`Nausea
`a5)
`
`protein. and peptide pharmaceuticals, patients treated with
`
`Victoza may develop anti-liraglutide antibodies, Approxi-
`
`mately 50-70% ofVictoza-treated patients in thefiveclinical
`
`
`trials of 26 weeks duration or longer were tested. for the
`presenceof anti-liraglutide antibodies at the end of treat-
`
`ment. Lowtiters (concentrations not requiring dilution of
`
`serum) of anti-liraglutide antibodies were detected in 8.6%
`of these Victoza-treated patients. Sampling was not per-
`formed uniformly across all patients in the clinical trials,
`and this may have resulted in an underestimate of the ac-
`tual percentage of patients who developed antibodies.
`Cross-réacting anti-liraglutide antibodies
`to native
`glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the
`Victora-treated patients in the 52-veek monotherapy tnal
`and in 4.8%of the Victoza-treated patients in the 26-week
`add-on combination therapytrials, These cross-reacting an-
`tibodies were not tested for neutralizing effect against na-
`tive GLP-1, and thus the potential for clinically significant
`neutralization of native GLP-1 was not assessed, Antibodies
`that had a neutralizing effect on liraghutide in an in yitra
`assay occurred in 2.3%of the Victoza-treated patients in the
`52-week monotherapytria] and in 1,0% of the Victoza-
`treated patients in the 26-weck add-on combination therapy
`trials,
`Among Victoza-treated patients who developed anti-
`liraglutide antibodies, the most common tategory of adverse
`events was that of infections, which occurred among 4D% of
`these patients compared to 36%, 84% and 35%of antibody-
`negative Victoza-treated, placebo-treated and active-
`control-treated patients, respectively. The specific infections
`which occurred with greater frequency among Victoza-
`treated antibody-positive patients were primarily nonseri-
`ous upper respiratory tract infections, which occurred
`among 11% of Victoza-treated antibody-positive patients,
`and among 7%, 7% and 5% of antibody-negative Victoza-
`treated, placebo-treated and active-control-treated patients.
`respectively. Among Victoza-treated antibody-negative pa-
`tients, the most common categorv of adverse events was
`that of gastrointestinal events, which occurred in 43%, 18%
`and 19% of antibody-negative Victoza-treated, placebo-
`treated and active-control-treated patients, respectively.
`Antibody formation wasnot associated with reduced efficacy
`of Victoza when comparing mean HbA,, of all antibody-
`positive and all antibody-negative patients. However, the 3
`patients with the highest titers of anti-liraglutide antibod-
`ies had no reduction in HbA,, with Victozz treatment.
`In clinical
`trials of Victozu, events from a composite
`of adverse events potentially related to immunogenicity
`(e.g. urticaria, angioedema) occurred among 0.8% of
`Victoza-treated patients and among 0.4% of comparator-
`cinomas were <1 cm in greatest diameter and were diag-
`treated patients, Urticaria accounted for approximately
`nosed in surgical pathology specimens after thyroidectomy
`one-half of the events in this composite for Victoza-treated
`prompted by findings on protocol-specified screening with
`patients. Patients who developed anti-liraglutide antibodies
`serum calcitonin or thyroid ultrasound,
`were not more likely to develop events from the immunoge-
`Hypogiyeumia
`nicity events composite than were patients who did not de-
`In the clinicaltrials of at least 26 weeks duration, hypogly-
`velop anti-liraglutide antibodies.
`cemia requiring the assistance of another person for treat-
`injection stte reactions
`mont occurred in 7 Victoza-treated patients (2.6 cases per
`Injection site reactions (¢.g., injection site rash, erythema)
`1000 patient-years) and in no comparater-treated patients.
`were reported in approximately 2%of Victoza-treated pa-
`tients in thefive clinical trials of at least 26 weeks duration.
`Six of these 7 patients treated with Vietoza were also taking
`a sulfonylurea. One other pitient was taking Victoza in
`Less than 0,2% of Victoza-treated patients discontinued duc
`combination with metformin but had another likely expla-
`to injection site reactions.
`nation for the hypoglycemia(this event occurred during hos-
`Papillarythyroid carcinuma
`In clinical trials of Vietoza, there were 6 reported cases of
`pitalization and after insulin infusion) ‘Table 3). Two addi-
`tional cases of hypoglycemia requiring the assistance of
`papillarythyroid carcinoma in patients treated with Victoza
`another person for treatment have subsequently been re-
`and 1 case in a comparator-treated patient (1.9 vs, 0.6 cases
`| ported in patients who were not. taking a concomitant sul-
`per 1000 patient-years). Mostof these papillary thyroid car-
`IMPORTANT NOTICE: Updated drug information is sent bi-monthly via the PDR® UpdateInsert. For monthly email updates, register at PDR.net.
`
`
`
` Placebo + Metform+
`Constipation
`
`
`
`
`
`medication, six events among Victoza-treated, patlestt
`
`ee|
`
`
`
`Diarrhea
`
`Constipation
`Dyspepsia
`
`72
`
`18
`
`Dad
`
`Wi
`0.9
`5.3
`26
`|
`0.9
`|
`5.2
`Add-on to Metformin + Glimepiride
`
`Glargine +
`Placebo +
`Victoza 1,8 +
`Metformin
`Metformin
`Metformin +
`
`
`
`+ Glimepiride
`+ Glimepiride
`Glimepiride
`Nua
`ope
`N=114
`N = 230
`
`
`Adverse Event Term
`
` Nausea
`
`
`10.0
`
`Diarrhea
`
`
`Headache
`
`Dyspepsia
`
`6,5
`Vomiting
`Add-on to Metformin + Rosiglitazone
`All Victoza + Metformin
`+ Rosiglitazone
`N = 855
`
`
`Hopilites’
`N= 175
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
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`
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`
`
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`
`
`
`
`
`
`
`
`
`
`
`(G1
`Adverse Event Term
`
`
`34.6
`
`14.1
`
`Nausea
`
`Diarrhea
`
`Vomiting
`
`Decreased Appetite
`Anorexia
`|
`Headache
`
`12.4
`
`9,3
`9.0
`
`Fatigue
`
`fonylurea. Both patients were receiving Victoza, one a
`monotherapy and the other in combination with metform.
`Both patients had another likely explanation for the ayye
`glycemia (one receivedinsulin during a frequently-samplel
`intravenous glucose tolerance test, and the other had inte
`cranial hemorrhave and uncertain food intake).
`[Sce table 3 at top of next pagel
`In a:pooled analysis ofclinical trials, the incidence ratelpt
`1,000 patient-years) for malignant neoplasms (based
`investigator-reported events, medical history, pathology r=
`norts, and surgical reports from both blinded-and open-label
`study poriods) was 10,9 for Vietoza, 6.3 for placebs, and 72
`for active comparator. After excluding papillarythyroid a>
`cinoma events [see Adverse Reactions (6.1)), no particule
`cancer cell type predominated. Seven malignant ncophsem
`events were reported beyond 1 year of exposure to Hudy
`
`MPI EXHIBIT 1039 PAGE 4
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1039, p. 4 of 12
`
`

`

`
`
`
`acts as a GLP-1 receptor agonist. The peptide precursor of
`liraglutide, produced by a process that includes expression
`|
`| of recombinant DNA in Saccharomyces cerevisiae, has been
`engineered to be 97% homologous to native human GLP-1
`by substituting arginine for
`lysine at position 34.
`Liraglutide is made by attaching a C-16 fatty acid (palmitic
`acid) with a glutamic acid spacer on the remaining lysine
`residue at position 26 of the peptide precursor. The molecu-
`lar formula of liraglutide is C,,.Hog5N430;, and the molec-
`ular weight is 3751.2 Daltons. The structural formula (Fig-
`ure 1) is:
`
`
`
`maternal plasma concentrations.
`fzal weight and dose-dependently increased the incidence
`3.4
`Pediatric Use
`ditotal major fetal abnormalities at all doses, The incidence
`Safety and effectiveness of Victoza have not been estab-
`malformations exceeded concurrent and historical con-
`lished in pediatric patients, Victoza is not recommended for
`cs at 0.01 mg/kg/day (kidneys, scapula), = 0.01 mg/ke/
`use in pediatric patients,
`gy(eyes, forelimb), 0.025 mg/kg/day (brain,tail and sacral
`85
`Geriatric Use
`setebrae, major blood vessels and heart, umbilicus),
`In the Victoza clinical trials, a total of 797 (20%) of the pa-
`20,025 mg/kg/day (sternum) and at 0.05 mg/kg/day (pari-
`tients were 65 years of age and over and 113 (2,8%) were 75
`gal bones, major blood vessels). Irregular ossification
`years of age and over. No overall differences in safety or ef-
`sdor skeletal abnormalities occurred in the skull and jaw,
`fectiveness were observed between these patients and
`ratebrae and ribs, sternum,pelvis, tail, and scapula; and
`younger patients, but greater sensitivity of some older indi-
`dse-dependent minor skeletal variations were observed.
`
`viduals cannot be ruled out.
`\ceral abnormalities occurred in blood vessels, lung,liver,
`3.6
`Renal Impairment
`ad esophagus. Bilobed or bifurcated gallbladder was seen
`Thereis limited experience in patients with mild, moderate.
`inall treatment groups, but not in the control group,
`and severe renal impairment, including end-stage renal dis-
`In pregnant female rats given subcutaneous doses of 0.1,
`ease. Therefore, Victoza should be used with caution in this
`(25 and 1.0 mg/kg/day liraglutide from gestation day 6
`patient population, No dose adjustmentof Victoza is recom-
`tough weaning or termination of nursing onlactation day
`mended for patients with renal impairment {see Clinical
`ij, estimated systemic exposures were0,8-, 3-, and 11-times
`Pharmacology (12.3).
`human exposure at the MRHDof 1.8 mg/day, based on
`87
`Hepatic Impairment
`tama AUC.A slight delay in parturition was observed in
`There is limited experience in patients with mild, moderate
`te majority of treated rats. Group mean body weight of
`or severe hepatic impairment. Therefore, Victoza should be
`etatal rats from liraglutide-treated dams was lower than
`used with caution in this patient population. No dose ad-
`tnatal rats from control group dams. Bloody scabs and
`justment of Victoza is recommended for patients with
`atated behavior occurred in male rats descended from
`hepatic impairment/see Clinical Pharmacology(12.3)).
`Vitaweal Birachleabroceldslebaaitidton. Each 1 mL of Victoza
`ins treated with 1 mg/kg/day liraglutide, Group mean
`88
`Gastroparesis
`bay weight from birth to postpartum day 14 trended lower
`solution contains 6 mg of liraglutide. Each pre-filled pen
`Victoza slows gastric emptying. Victoza has not been stud-
`nF, generation rats descended from liraglutide-treated
`contains a 3 mLsolution of Victoza equivalent to 18 mg
`ied in patients with pre-existing gastroparesis.
`i: compared to F, generation rats descended from con-
`liraglutide (free-base, anhydrous) andthefollowing inactive
`
`tls.
`but differences did not reach statistical significance
`ingredients: disodium phosphate dihydrate, 1.42 mg; prop-
`10
`OVERDOSAGE
`i any group,
`ylene glycol, 14 mg; phenol, 5.5 mg; and waterfor injection,
`In a clinical trial, one patient with type 2 diabetes experi-
`43 Nursing Mothers
`enced a single overdoseofVictoza 17,4 mg subcutaneous (10| 12
`CLINICAL PHARMACOLOGY
`his not known whether Victoza is excreted in human milk,
`times the maximum recommendeddose), Effects of the over-| 12.1
`Mechanism of Action
`Bxause maany drugs are excreted in human milk and be-
`dose included severe nausea and vomiting requiring hospi-| Liraglutide is an acylated human Glucagon-Like Peptide-1
`que of the potential
`for
`tumorigenicity. shown for
`talization. No hypoglycemia, was reported. The patient re-| (GLP-1) receptor agonist with 97% amino acid sequence ho-
`tglutide in animal studies, a decision should be made
`covered without complications, In the event of overdosage.| mology to endogenous human GLP-1(7-37), GLP-1(7-37)
`snether to discontinue nursing or to discontinue Victoza,
`appropriate supportive treatment should be initiated ac-| represents <20% of total circulating endogenous GLP-1.
`pking into account the importance of the drug to the
`cording to the patient’s clinical signs and symptoms.
`Like GLP-1(7-37), liraglutide activates the GLP-1 receptor,
`
`|
`
`Visit PDR.net to register for Product Safety Alerts and to download mobilePDR®- free to U.S. prescribers
`
`
`
`MPI EXHIBIT 1039 PAGE 5
`
`MPI EXHIBIT 1039 PAGE 5
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1039, p. 5 of 12
`
`

`

`dose ofliraglutide is approximately 1.2 Wh with an elimi- nation half-life of approximately 13 hours, making Victoza
`
`Table 4 Results of a 52-week monotherapytrial*
`
`Victoza 1.2 mgVictoza 1.8 mg | Glimepiride 8 mg
`
`
`251
`246
`|
`
`Intent-to-Treat Population (N)
`
`=I
`
`248
`
`—
`
`
`
`
`
`2672/NOVO NORDISK e VICTOZA
`
`For the latest PDR product information,visit PDR.net
`
`suitable for/once daily administration.
`Specific Populations
`Elderly—Age had no effect on the pharmacokinetic: of
`Victozabasedon apharmacokinetic atudy inhealthy elderly
`subjects (65:t0 83 years)and population pharmacokinetic
`analyses ofpatients 18 to 80 years ofage[sex Use tn Specie
`Populations (8.4)].
`Gender—Based-on the results of population pharmacoli-
`netic analyses, females have 34% lower weight-adjusted
`clearanceof Victoza compared to males.-Based on the expe
`sure response data, no dose adjustment is necessary based
`on. gender,
`Race and Ethnicity—Race andethnicityhud no effect on the
`pharmacokinetics ofVictoza based onthe resultsofpopule
`tion pharmacokinetic analyses thet included Caucasian,
`Black, Asinn und Hispanic/Non-Hispanic subjects.
`Body Weight—Body weight significantly affects the pharm
`eokineties ofVictoza based on results ofpopulation pharm
`eokineti¢ analyses) The exposure of liraglutide decrease
`with an increase in baseline body weight. However, the
`1.2 mg and 1.8 mg daily doses of Victozaprovided adequate
`systemic exposuresoverthe body weight range of40-160iat
`evaluated in the clinical trials, Liraglutide was not studied
`in patients with body weight >160 kg.
`Pediatric—Victoza has not been studied in pediatric pa
`tients [see Use in Specific Populations (8.4),
`Renal Impeirment—The single-dose pharmacokinetics of
`Victoza were evaluated in subjectswith yarying degrees of
`renal impairment. Subjects with mild (estimated creatinine
`clearance 50-80 mL/min) to severe (estimated creatinine
`clearance <30 mL/min) renal impairment and subjects will
`end-stage renal disease
`requiring dialysis were included in
`the trial, Compared to healthy subjects, liraglutide AUG im
`mild, moderate, and severe renal impairment and in end-
`stage renal diseasewas on average 35%, 19%, 29% and 30%
`lower, respectively [see Use in Specifie Populations (eal)
`Hepatic Impairment—The single-dose pharmacoldnetics af
`Victoza were evaluatedin subjects with varying degrees of
`hepatic impairment, Subjects with mild (Child Pugh sort.
`5-6) to severe (Child Pugh score > 9) hepatic impairment
`were included in the trial. Compared to healthy subjects
`litaghitide AUC in subjects with mild, moderato and sevet
`hepatic impairment was on average 11%, 14% and 425
`a membrane-boundcell-surface receptor coupledto adenylyl
`lower, respectively [see Use in Specific Populations (8.7L.
`eyclast by the stimulatery G-protein, Gs, in pancreatic beta
`Drug Interactions
`cells, Liraglutide increases intracellular cyelic AMP (cAMP)
`In vitro assessment of drug-drug interactions
`leading to insulinrelease in the presence of-elevated glucose
`Victoza has low potential for pharmacokinetic drug-drug io
`coricentrations. This insulinsecretion subsides as blood glu-
`teractions related to cytochrome P44() (CYP) andplasma
`cose concentrations decrease and approach euglycemia.
`protein binding.
`Liraglutidé also decreases glucagon secretion in a glucoge-
`In vivo assessmentofdrug-drug interactions
`dependent manner. The mechanism of blood glucose lower-
`The drug-drug interaction studies were performed at stanilp
`ing also involves a delay in gastric emptying
`state with Victoza 1.8 mg/day, Before administration of
`GLP-1(7-37) has « halflife of 1.5-2 minutes due to degrada-
`comitant treatment, subjects underwent a 0.6 mg wrestle
`tion by the ubiquitous endogenous enzymes, dipeptidy]
`dose increaseto reachthe maximum doseof1.8 me/day.A
`Figure 2 Mean Insulin Secretion Rate (ISR) versus Glucose
`peptidase IV (DPP-IV) and neutral endopeptidases (NEP),
`Cancantration Following Single-Dose Victoza 7.5 mica/kg (-0.7 mg)
`ministration ofthe interacting drugs was timed so thst Coa
`or Placebo In Patients with Type 2 Diabetes (N=10) During Graded
`Unlike native GLP-1, liraglutide is stable against metabolic
`of Vietoza (8:12h) would coincide with the absorption peti
`GlucoseInfusion
`of the co-administered drugs,
`degradation by both peptidases and has a plasma hall-life af
`13 hours after subcutaneous administration. The pharma-
`Digoxin
`12.3
`Pharmacokinetics
`cokinetic profile of liraglutide, which makes it suitable for
`A gingle dose of digoxin 1 mg wasadministered 7 hours af
`Absorption—Following subcutaneous administration, maxi-
`once-daily administration,is a resultof self-nssoviation that
`ter the dose of Victoza atsteady state. The conpomitatt
`mum concetitrations of liraglutide are achieved at 8-12
`delays shsorption, plasma protein binding and. stability
`administration with’ Victoza resulted in a reduction afait
`hours post dosing. The mean peak (C,,..) and total (AUC)
`against, metabolic. degradation by DPP-TV and NEP;
`goxinAUC by 16%; C,,... decreased by 31%. Digoxin medita
`exposures of liraglutide were 35 ng/mL and 960 ng-h/mL.,
`12:2
`Pharmacodynamics.
`time to maxima