`RESEARCH
`
`APPLICATION NUMBER: ‘
`22-341
`
`LABELING
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use Victoza
`safely and effectively. See full prmcribing information for Victoza.
`
`.......................................CONTRAINDICATIONS............................................
`Do not use in patients with a personal or family history of medullary thyroid
`carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 (4).
`
`Victoza” (liraglutide [rDNA origin] injection), solution for subcutaneous use
`Initial U.S. Approval: 2010
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`leefl/llpremrzfii/IgI'll/ori/mlin/Iflr complete éarea’war/1:71;.
`Liraglutide causes thyroid C-cell tumors at clinically relevant exposures
`in rodents. It is unknown whether Victoza causes thyroid C—cell
`tumors, including medullary thyroid carcinoma (MTC), in humans, as
`human relevance could not be determined by clinical or nonclinical
`studies (5.1).
`Victoza is contraindicated in patients with a personal or family history
`of MTC or in patients with Multiple Endocrine Ncoplasia syndrome
`type 2 (MEN 2) (5.1).
`
`
`
`.......................................INDICATIONS AND USAGE............-.--.n...........n......
`Victoza is a glucagon-Iike peptide-I (GLP-1) receptor agonist indicated as an
`adjunct to diet and exercise to improve glycemic control in adults with type 2
`diabetes mellitus (I).
`'
`
`Important Limitations of Use (1.1):
`0 Not recommended as first-line therapy for patients inadequately controlled
`on diet and exercise (5.l).
`- Has not been studied sufficiently in patients with a history of pancreatitis.
`Use caution (5.2).
`Not for treatment oftype I diabetes mellitus or diabetic ketoacidosis.
`Has not been studied in combination with insulin.
`
`..................................DOSAGE AND ADMINISTRATION""""""“""""""""'
`Administer once daily at any time of day, independently of meals (2).
`Inject subcutaneously in the abdomen, thigh or upper arm (2).
`The injection site and timing can be changed without dose adjustment (2).
`Initiate at 0.6 mg per day for one week. This dose is intended to reduce
`gastrointestinal symptoms during initial titration, and is not effective for
`glycemic control. After one week, increase the dose to 1.2 mg. If the 1.2 mg
`dose does not result in acceptable glycemic control, the dose can be
`increased to 1.8 mg (2).
`- When initiating Victoza, consider reducing the dose of concomitantly-
`administered insulin secretagogues to reduce the risk of hypoglycemia (2).
`
`...............................DOSAGE FORMS AND STRENGTHS------------------'-----------
`0 Solution for subcutaneous injection, pre-frlled, multi—dose pen that delivers
`doses of 0.6 mg, 1.2 mg, or 1.8 mg (6 mg/mL, 3 mL) (3).
`
`FULL PRESCRIBING INFORMATION: CONTENTS"
`BOXED \VARNING: RISK OF TI-IYROID C-CELL TUMORS
`
`1
`
`01th
`
`6
`
`7
`
`8
`
`INDICATIONS AND USAGE
`1.1
`Important Limitations of Use
`DOSAGE AND ADMINISTRATION
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1 Risk ofThyroid C-ceII Tumors
`5.2 Pancreatitis
`5.3 Use with Medications Known to Cause Hypoglycemia
`5.4 Macrovascular Outcomes
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`DRUG INTERACTIONS
`7.1 Oral Medications
`USE IN SPECIFIC POPULATIONS
`81 Pregnancy
`’
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`8.8 Gastroparesis
`
`...........................WARNINGS AND PRECAUTIONS-"m-m--------------’----
`Thyroid C—cell tumors in animals: Human relevance unknown. Counsel
`patients regarding the risk of medullary thyroid carcinoma and the
`symptoms of thyroid tumors (51).
`Pancreatitis: In clinical trials, there were more cases of pancreatitis among
`Victoza-treated patients than among comparator-treated patients. If
`pancreatitis is suspected, Victoza and other potentially suspect drugs
`should be discontinued. Victoza should not be restarted if pancreatitis is
`confirmed Use with caution in patients with a history of pancreatitis (5.2).
`Serious hypoglycemia: Can occur when Victoza is used with an insulin
`secretagogue (e.g. a sulfonylurea). Consider lowering the dose of the
`insulin secretagogue to reduce the risk of hypoglycemia (5.3).
`Macrovascular outcomes: There have been no studies establishing
`conclusive evidence of macrovascular risk reduction with Victoza or any
`other antidiabetic drug (5.4).
`
`...............................ADVERSE REACTIONS...........................................
`The most common adverse reactions, reported in 25% of patients treated
`with Victoza and more commonly than in patients treated with placebo,
`are: headache, nausea, diarrhea and anti-Iiraglutide antibody formation (6).
`lmmunogenicity—related events, including urticaria, were more common
`among Victoza-treated patients (0.8%) than among comparator-treated
`patients (0.4%) in clinical trials (6),
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
`Inc. at 1-877-484-2869 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`-———-—-———--——DRUG INTERACTIONS---——--——-——--—--—--—----
`Victoza delays gastric emptying. May impact absorption of concomitantly
`administered oral medications. Use caution (7).
`
`............................. USE IN SPECIFIC POPULATIONSu-un-nunuunuu-uu
`There are no data in patients below 18 years of age (8.4),
`Use with caution in patients with renal or hepatic impairment. Limited data
`(8.6, 8.7).
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-Approved
`Medication Guide.
`Revised: 1/2010
`
`.1011
`12
`
`13
`
`14
`
`16
`
`17
`
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`122 Pharmacodynamics
`12.3 Phannacokinetics
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, lmpainnent of Fertility
`CLINICAL STUDIES
`14. I Monotherapy
`14.2 COmbination Therapy
`HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied *
`16.2 Recommended Storage
`PATIENT COUNSELING INFORMATION
`17.1 Risk of Thyroid C—cell Tumors
`I 7.2 Pancreatitis
`17.3 Never Share a Victoza Pen Between Patients
`17.4
`Instructions
`17.5 Laboratory Tests
`176 FDA-Approved Medication Guide
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`FULL PRESCRIBING INFORMATION
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`
`Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at
`clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza causes
`thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance
`could not be ruled out by clinical or nonclinical studies. Victoza is contraindicated in patients with a
`personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2
`(MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound
`was performed during clinical trials, but this may have increased the number of unnecessary thyroid
`surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate
`human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of
`thyroid tumors [fee Cali/mflmf'cmiofls [49, #747721?ng alzdP/‘ecmztfo/zy [5. l/ a/zd/Vo/zcé'm'ca/
`
`[bride/03y {I} [j].
`
`.
`INDICATIONS AND USAGE
`1
`Victoza is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2
`diabetes mellitus.
`
`Important Limitations of Use
`1.1
`I Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe
`Victoza only to patients for whom the potential benefits are considered to outweigh the potential risk.
`Victoza is not recommended as first-line therapy for patients who have inadequate glycemic control on
`diet and exercise.
`
`I In clinical trials of Victoza, there were more cases of pancreatitis with Victoza than with comparators.
`Victoza has not been studied sufficiently in patients with a history of pancreatitis to determine whether
`these patients are at increased risk for’pancreatitis while using Victoza. Use with caution in patients
`with a history of pancreatitis.
`'
`
`I Victoza is not a substitute for insulin. Victoza should not be used in patients with type 1 diabetes
`mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.
`
`I The concurrent use of Victoza and insulin has not been studied.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`Victoza can be administered once daily at any time of day, independently of meals, and can be injected
`subcutaneously in the abdomen, thigh or upper arm. The injection site and timing can be changed
`without dose adjustment.
`-
`
`For all patients, Victoza should be initiated with a dose of 0.6 mg per day for one week. The 0.6 mg dose
`is a starting dose intended to reduce gastrointestinal symptoms during initial titration, and is not effective
`for glycemic control. After one week at 0.6 mg per day, the dose should be increased to 1.2 mg. If the
`1.2 mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg.
`
`When initiating Victoza, consider reducing the dose of concomitantly administered insulin secretagOgues
`(such as sulfonylureas) to reduce the risk of hypoglycemia [we Wary/figs aim/Precautz'om ($.57 and
`Adi/ewe Rage/[bay {07/
`
`
`
`Victoza solution should be inspected prior to each injection, and the solution should be used only if it is
`'clear, colorless, and contains no particles.
`
`3
`DOSAGE FORMS AND STRENGTHS
`Solution for subcutaneous injection, pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg, or
`1.8 mg (6 mg/mL, 3 mL).
`
`4
`
`CONTRAINDICATIONS
`
`Victoza is contraindicated in patients with a personal or family history of medullary thyroid carcinoma
`(MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`Risk of Thyroid C-cell Tumors
`5.1
`Liraglutide causes dose-dependent and treatment—duration-dependent thyroid C-cell tumors (adenomas
`and/or carcinomas) at clinically relevant exposures in both genders of rats and mice flee/lbzzc/i/zz‘ca/
`[mica/0g} {/3 1)]. Malignant thyroid C—cell carcinomas were detected in rats and mice. A statistically
`significant increase in cancer was observed in rats receiving liraglutide at 8—times clinical exposure
`compared to controls. It is unknown whether Victoza will cause thyroid C-cell tumors, including
`medullary thyroid carcinoma (MTC), in humans, as the human relevance'of liraglutide-induced rodent
`thyroid C-cell tumors could not be determined by clinical or nonclinical studies fleefloxed/Famzfig
`Cali/raz'lztzirba/io/zy (49/.
`
`In the clinical trials, there have been 4 repOrted cases of thyroid C-cell hyperplasia among Victoza—treated
`patients and 1 case in a comparator—treated patient (1.3 vs. 0.6 cases per 1000 patient-years). One
`additional case of thyroid C-cell hyperplasia in a Victoza—treated patient andll case of MTC in a
`comparator-treated patient have subsequently been reported. This comparator-treated patient with MTC
`had pre-treatment serum calcitonin concentrations >1000 ng/L suggesting pre-existing disease. All of
`these cases were diagnosed after thyroidectomy, which was prompted by abnormal results on routine,
`protocol-specified measurements of serum calcitonin. Four of the five liraglutide-treated patients had
`elevated calcitonin concentrations at baseline and throughout the trial. One liraglutide and one non—
`liraglutide-treated patient developed elevated calcitonin concentrations while on treatment.
`
`'
`
`Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. The
`serum calcitonin assay used in the Victoza clinical trials had a lower limit of quantification (LLOQ) of
`0.7 ng/L and the upper limit of the reference range was 5.0 ng/L for women and 8.4 ng/L for men. At
`Weeks 26 and 52 in the clinical trials, adjusted mean serum calcitonin concentrations were higher in
`Victoza-treated patients compared to placebo—treated patients but not compared to patients receiving
`active comparator. At these timepoints, the adjusted mean serum calcitonin values (~ 1.0 ng/L) werejust
`abOVe the LLOQ with between-group differences in adjusted mean serum calcitonin values of
`' approximately 0.1 ng/L or less. Among patients with pre-treatment serum calcitonin below the upper limit
`of the reference range, shifts to above the upper limit of the reference range which persisted in subsequent
`measurements occurred most frequently among patients treated with Victoza 1.8 mg/day.
`In trials with
`on-treatment serum calcitonin measurements out to 5-6 months, 1.9% of patients treated with Victoza 1.8
`mg/day developed new and persistent calcitonin elevations above the upper limit of the reference range.
`compared to 0.8-1.1% of patients treated with control medication or the 0.6 and 1.2 mg doses of Victoza.
`In trials with on~treatment serum calcitonin measurements out to 12 months, 1.3% of patients treated with
`Victoza 1.8 mg/day had new and persistent elevations of calcitonin from below or within the reference
`range to above the upper limit of the reference range, compared to 0.6%, 0% and 1.0% of patients treated
`
`
`
`with Victoza 1.2 mg, placebo and active control, respectively. Otherwise, Victoza did not produce
`consistent dose-dependent or time-dependent increases in serum calcitonin.
`
`Patients with MTC usually have calcitonin values >50 ng/L. In Victoza clinical trials, among patients
`with pre-treatment serum calcitonin <50 ng/L, one Victoza-treated patient and no comparator-treated
`patients developed serum calcitonin >50 ng/L. The Victoza-treated patient who developed serum
`calcitonin >50 ng/L had an elevated pre-treatment serum calcitonin of 10.7 ng/L that increased to 30.7
`ng/L at Week 12 and 53.5 ng/L at the end of the 6—month trial. Follow—up serum calcitonin was 22.3 ng/L
`more than 2.5 years after the last dose of Victoza. The largest increase in serum calcitonin in a
`comparator-treated patient was seen with glimepiride in a patient whose serum calcitonin increased fiom
`19.3 ng/L at baseline to 44.8 ng/L at Week 65 and 38.1 ng/L at Week 104. Among patients who began
`with serum calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of Victoza-treated
`patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients, with an
`incidence of 1.1% among patients treated with 1.8 mg/day of Victoza. The clinical significance of these
`findings is unknown.
`
`Counsel patients regarding the risk for MTC and the symptoms of thyroid tumors (e.g. a mass in the neck,
`dysphagia, dyspnea or persistent hoarseness). It is unknown whether monitoring with serum calcitonin or
`thyroid ultrasound will mitigate the potential risk of MTC, and such monitoring may increase the risk of
`unnecessary procedures, due to low test specificity for serum calcitonin and a_ high background incidence
`of thyroid disease. Patients with thyroid nodules noted on physical examination or neck imaging obtained
`for other reasons should be referred to an endocrinologist for further evaluation. Although routine
`monitoring of serum calcitonin is of uncertain value in patients treated with Victoza, if serum calcitonin is
`measured and found to be elevated, the patient should be referred to an endocrinologist for further
`evaluation.
`
`5.2
`
`Pancreatitis
`
`In clinical trials of Victoza, there were 7 cases of pancreatitis among Victoza-treated patientsand 1 case
`among comparator-treated patients (2.2 vs. 0.6 cases per 1000 patient-years). Five cases with Victoza
`were reported as acute pancreatitis and two cases with Victoza were reported as chronic pancreatitis. In
`one case in a Victoza-treated patient, pancreatitis, with necrosis, was observed and led to death; however
`clinical causality could not be established. One additional case of pancreatitis has subsequently been
`reported in a Victoza-treated patient. Some patients had other risk factors for pancreatitis, such as a
`history of cholelithiasis or alcohol abuse. There are no conclusive data establishing a risk of pancreatitis
`with Victoza treatment. Alter initiation of Victoza, and after dose increases, observe patients carefully
`for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating
`to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, Victoza
`and other potentially suspect medications should be discontinued promptly, confirmatory tests should be
`performed and appropriate management should be initiated. If pancreatitis is confirmed, Victoza should
`not be restarted. Use with caution in patients witha history of pancreatitis.
`
`Use with Medications Known to Cause Hypoglycemia
`5.3
`Patients receiving Victoza in combination with an insulin secretagogue (e.g., sulfonylurea) may have an
`increased risk of hypoglycemia. In the clinical trials of at least 26 weeks duration, hypoglycemia
`requiring the assistance of another person for treatment occurred in 7 Victoza-treated patients and in no
`comparator-treated patients. Six of these 7 patients treated with Victoza were also taking a sulfonylurea.
`The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea or other insulin
`secretagogues flee Advance Xena/2'0”: {a 17/
`
`
`
`5.4 Macrovascular Outcomes
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with
`Victoza or any other antidiabetic drug.
`
`6
`
`ADVERSE REACTIONS
`
`Clinical Trials Experience
`6.1
`Because clinical trials are conducted under widely. varying conditions, adverse reaction rates observed in
`the clinical trials of a drug cannot be directly compared to rates in the clinical-trials of another drug and
`may not reflect the rates observed in practice.
`
`The safety of Victoza was evaluated in a 52-week monotherapy trial and in four 26-week, add—on
`combination therapy trials.
`In the monotherapy trial, patients were treated with Victoza 1.2 mg daily,
`Victoza 1.8 mg daily, or glimepiride 8 mg daily. In the add-on to metformin trial, patients were treated
`with Victoza 0.6 mg, Victoza 1.2 mg, Victoza 1.8 mg, placebo, or glimepiride 4 mg. In the add-on to
`glimepiride trial, patients were treated with Victoza 0.6 mg, Victoza 1.2 mg, Victoza 1.8 mg, placebo, or
`rosiglitazone 4 mg. In the add-on to metformin +_ glimepiride trial, patients were treated with Victoza 1.8
`mg, placebo, or insulin glargine. In the add—on to metformin + rosiglitazone trial, patients were treated
`with Victoza 1.2 mg, Victoza 1.8 mg or placebo flee C/z'zzz'ca/J'tz/dl'ey [/49].
`
`PfiMt/rmmls’
`
`The incidence of withdrawal due to adverse events was 7.8% for Victoza—treated patients and 3.4% for
`comparator-treated patients in the five controlled trials of 26 weeks duration or longer. This difference
`was driven by withdrawals due to gastrointestinal adverse reactions, which occurred in 5.0% of Victoza-
`treated patients and 0.5% of comparator-treated patients. The most common adverse reactions leading to
`withdrawal for Victoza-treated patients were nausea (2. 8% versus 0% for comparator) and vomiting
`(1.5% versus 0.1% for comparator). Withdrawal due to gastrointestinal adverse events mainly occurred
`during the first 2-3 months of the trials.
`
`Tables 1 and 2 summarize the adverse events reported in 25% of Victoza—treated patients in the five
`controlled trials of 26 weeks duration or longer.
`
`Table 1 Adverse events reported in 2 5% of Victoza-treated patients or 25% of glimepiride-treated
`atients: 52-week monotheran trial
`
`
`All Victoza
`N= 497
`
`Glimepin'de
`N= 248
`
`
`
`___—I_
`85
`
`
`
`
`
`—-—_
`—_—n-
`-—m-
`
`
`"Ii——
`_m-
`_-
`
`
`_-a_—
`—_
`
`
`——
`-_—
`_—
`
`_—
`
`
`
`Metformin
`N=724
`
`Metformin
`N=121
`
`Placebo+
`
`Table 2 Adverse events reported in 2 5% of Victoza-treated patients and occurring more frequently
`with Victoza com ared to .lacebo: 26-week combination thera trials
`
`
`
`Add-on to Metformin Trial
`
`
`
`— All Victoza+
`Glimepiride+
`Metformin
`N=242
`
`
`
`
`“-59-”-
`-_——.E-
`
`
`Add-on to Glime n iride Trial
`
`All Victoza +
`Placebo +
`Rosiglitazone +
`
`Glimepiride
`Glimepiride
`Glimepiride
`
`N=114
`N=23l
`
`
`
`
`Add—on to Metformin + Glimeiride
`
`
`Victoza 1.8+
`Placebo +
`
`
`Metformin +
`Metformin +
`Metformin +
`
`
`
`
`
`Glimepiride
`Glimepiride
`Glimepiride
`
`
`
`
`N = 230
`
`Placebo +
`All Victoza +
`
`
`
`Metformin +
`Metformin +
`
`
`
`Rosiglitazone
`Rosiglitazone
`
`
`
`
`
`
`Gay/lw‘zz/ey/z'fla/adveme eye/218'
`
`In the five clinical trials of 26 weeks duration or longer, gastrointestinal adverse events were reported in
`41% of Victoza—treated patients and were dose-related. Gastrointestinal adverse events occurred in 17%
`of comparator-treated patients. Events that occurred more commonly among Victoza-treated patients
`included nausea, vomiting, diarrhea, dyspepsia and constipation. In clinical trials of 26 weeks duration or
`longer, the percentage of patients who reported nausea declined over time. Approximately 13% of
`Victoza-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of
`treatment.
`
`
`
`[lizmzz/zoge/zz'czb/
`Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients
`treated with Victoza may develop anti-liraglutide antibodies. Approximately 50-70% of Victoza-treated
`patients in the five clinical trials of 26 weeks duration or longer were tested for the presence of anti-
`liraglutide antibodies at the end of treatment Low titers (concentrations not requiring dilution of serum)
`of anti-liraglutide antibodies were detected1n 8.6% of these Victoza—treated patients. Sampling was not
`performed uniformly across all patients in the clinical trials, and this may have resulted in an
`underestimate of the actual percentage of patients who developed antibodies. Cross-reacting anti-
`liraglutide antibodies to native glucagon-like peptide-l (GLP-l) occurred in 6.9% of the Victoza—treated
`patients in the 52-week monotherapy trial and in 4.8% of the Victoza-treated patients in the 26—week add-
`on combination therapy trials. Thesecross-reacting antibodies were not tested for neutralizing effect
`against native GLP-l , and thus the potential for clinically significant neutralization of native GLP—I was
`not assessed. Antibodies that had a neutralizing effect on liraglutide in an I}; Vitra assay occurred in 2.3%
`of the Victoza-treated patients in the 52-week monotherapy trial and in 1.0% of the Victoza-treated
`patients in the 26—week add-on combination therapy trials.
`
`Among Victoza-treated patients who developed anti-liraglutide antibodies, the most common category of
`adverse events was that of infections, which occurred among 40% of these patients compared to 36%,
`34% 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 nonserious 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 patients, the most common category of adverse events was that of
`gastrointestinal events, which occurred1n 43%, 18% and 19% of antibody-negative Victoza-treated,
`placebo-treated and active—control-treated patients, respectively Antibody formation was not associated
`with reduced efficacy of Victoza when comparing mean I-IbA1c of all antibody-positive and all antibody-
`negative patients. However, the 3 patients with the highest titers of anti-liraglutide antibodies had no
`reduction in HbAIc with Victoza treatment.
`
`In clinical trials of Victoza, 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-treated patients. Urticaria accounted for approximately one—half of the events in this
`composite for Victbza-treated patients. Patients who developed anti-liraglutide antibodies were not more
`likely to develop events from the immunogenicity events composite than were patients who did not
`develop anti-liraglutide antibodies.
`
`[/y'ecz‘z'o/z .rz'fe mac/[012:
`Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of Victoza-
`treated patients in the five clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza-treated
`patients discontinued due to injection site reactions.
`
`Papfl/a/y t/g/rw’z/azmzizama
`In clinical trials of Victoza, there were 6 reported cases of papillary thyroid carcinoma in patients treated
`with Victoza and 1 case in a comparator-treated patient (1.9 vs. 0.6 cases per 1000 patient—years). Most
`of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical
`pathology specimens afier thyroidectomy prompted by findings on protocol-specified screening with
`serum calcitonin or thyroid ultrasound.
`
`
`
`Hypogé/cemitz
`
`In the clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another
`person for treatment occurred in 7 Victoza-treated patients (2.6 cases per 1000 patient-years) and in no
`comparator-treated patients. Six of these 7 patients treated with Victoza were also taking a sulfonylurea.
`One other patient was taking Victoza in combination with metformin but had another likely explanation
`for the hypoglycemia (this event occurred during hospitalization and after insulin infusion) (Table 3).
`Two additional cases of hypoglycemia requiring the assistance of another person for treatment have
`subsequently been reported in patients who were not taking a concomitant sulfonylurea. Both patients
`were receiving Victoza, one as monotherapy and the other in. combination with metformin. Both patients
`had another likely explanation for the hypoglycemia (one received insulin during a frequently-sampled
`intravenous glucose tolerance test, and the other had intracranial hemorrhage and uncertain food intake).
`
`Table 3 Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in the 52-Week Monotherapy Trial
`and in the 26-Week Combination Therapy Trials
`_———
`
`
`
`
`
`—____—
`Patient able to self-treat __—
`__—
`
`
`Add-on to Metformin
`Victoza +
`Glimepiride +
`Placebo +
`
`
`Metformin
`Metformin
`Metformin
`»
`(N = 121)
`(N =- 242)
`(N = 724)
`
`
`Patient not able to self-treat
`0.1 (0.001) ____
`Patient able to self—treat
`3.6 (0.05)
`.
`22.3 (0.87)
`2.5 (0.06)
`
`
`Add-on to Glimepiride
`Victoza +
`Rosiglitazone +
`Placebo +
`
`
`
`Glimepiride
`Glimepiride
`Glimepiride
`(N=695)
`(N=231)
`(N= 114)
`
`
`
`0.1(0003) -—-
`00010110110101.1000$010.00...
`
`
`
`7.5 (0.38)
`4.3 (0.12)
`2.6 (0.17)
`Patient able to self-treat
`0.9 (0.05)
`0.9 (0.02) _-
`Not classified
`
`Victoza +
`Placebo +
`Add-on to Metformin +
`
`
`
`Rosiglitazone
`Metformin +
`Metformin +
`Rosiglitazone
`Rosiglitazone
`
`
`(N = 355)
`(N = 175)
`
`
`Patient not able to self-treat “
`
`
`Patient able to self-treat
`7.9 (0.49) _ 4.6 (0.15)
`
`
`Not classified
`0.6 (0.01) — 1.1 (0.03)
`
`
`
`Add—on to Metformin +
`Victoza +
`Insulin glargine +
`Placebo +
`
`
`Glimepiride
`Metformin +
`Metformin +
`Metformin +
`
`Glimepiride
`Glimepiride
`Glimepiride -
`
`
`(N = 230)
`(N = 232)
`(N = 114)
`
`
`__—_-_
`
`
`
`
`_—-—-_
`
`
`
`In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for malignant neoplasms
`' (based on investigator-reported events, medical history, pathology reports, and surgical reports from both
`blinded and open—label study periods) was 10.9 for Victoza, 6.3 for placebo, and 7.2 for active
`comparator. After excluding papillary thyroid carcinoma events fieeddverygjl’eac/iow (61)], no
`particular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year
`of exposure to study medication, six events among Victoza-treated patients (4 colon, l prostate and l
`nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not
`been established.
`
`Laboratory Tests
`In the five clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations
`(elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of Victoza—
`treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This
`finding was not accompanied by abnormalities in other liver tests. The significance ofthis isolated
`finding is unknown.
`
`DRUG INTERACTIONS
`7
`Oral Medications
`7.]
`Victoza causes a delay of gastric emptying, and thereby has the potential to impact the absorption of
`concomitantly administered oral medications. In clinical pharmacology trials, Victoza did not affect the
`absorption of the tested orally administered medications to any clinically relevant degree. Nonetheless,
`caution should be exercised when oral medications are concomitantly administered with Victoza.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Pregnancy Category C.
`There are no adequate and well-controlled studies of Victoza in pregnant women. Victoza should be used
`during pregnancy only if the potential benefit justifies the potential risk to the fetus. Liraglutide has been
`shown to be teratogenic in rats at or above 0.8 times the human systemic exposures resulting from the
`maximum recommended human dose (MRHD) of 1.8 mg/day based on plasma area under the time-
`concentration curve (AUC). Liraglutide has been shown to cause reduced growth and increased total
`major abnormalities in rabbits at systemic exposures below human exposure at the MRHD based on
`plasma AUC.
`
`Female rats given subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day liraglutide beginning 2 weeks
`before mating through gestation day 17 had estimated systemic exposures 0.8-, 3-, and 11-times the
`human exposure at the MRI-ID based on plasma AUC comparison. The number of early embryonic
`deaths in the 1 mg/kg/day group increased slightly. Fetal abnormalities and variations in kidneys and
`blood vessels, irregular ossification of the skull, and a more complete state of ossification occurred at all
`doses. Mottled liver and minimally kinked ribs occurred at the highest dose. The incidence of fetal
`malformations in liraglutide—treated groups exceeding concurrent and historical controls were misshapen
`oropharynx and/or narrowed opening into larynx at 0.1 mg/kg/day and umbilical hernia at 0.1 and 0.25
`mg/kg/day.
`
`Pregnant rabbits given subcutaneous doses of 0.01, 0.025 and 0.05 mg/kg/day liraglutide from gestation
`day 6 through day 18 inclusive, had estimated systemic exposures less than the human exposure at the
`MRHD of 1.8 mg/day at all doses, based on plasma AUC. Liraglutide decreased fetal weight and dose-
`dependently increased the incidence of total major fetal abnormalities at all doses. The incidence of
`
`
`
`malformations exceeded concurrent and historical controls at 0.01 mg/kg/day (kidneys, scapula), Z 0.01
`mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral vertebrae, major blood vessels and
`heart, umbilicus), 2 0.025 mg/kg/day (sternum) and at 0.05 mg/kg/day (parietal bones, major blood
`vessels). Irregular ossification and/or skeletal abnormalities occurred in the skull and jaw, vertebrae and
`- ribs, sternum, pelvis, tail, and scapula; and dose-dependent minor skeletal variations were observed.
`Visceral abnormalities occurred in blood vessels, lung, liver, and esophagus. Bilobed or bifurcated
`gallbladder was seen in all treatment groups, but not in the control group.
`
`In pregnant female rats given subcutaneous doses of 0. l, 0.25 and 1.0 mg/kg/day liraglutide from
`gestation day 6 through weaning or termination of nursing on lactation day 24, estimated systemic
`exposures were 0. 8-, 3-, and Il-times human exposure at the MRHD of 1.8 mg/day, based on plasma
`AUC. A slight delay1n parturition was observedin the majority of treated rats. Group mean body weight
`of neonatal rats from liraglutide-treated dams was lower than neonatal rats from control group dams.
`Bloody scabs and agitated behavior occurred in male rats descended from dams treated with 1 mg/kg/day
`liraglutide. Group mean body weight from birth to postpartum day 14 trended lower in F2 generation rats
`descended from liraglutide-treated rats compared to F2 generation rats descended from controls, but
`differences did not reach statistical significance for any group.
`
`Nursing Mothers
`8.3
`It is not known whether Victoza is excreted in human milk. Because many drugs are excreted in human
`milk and because of the potential for tumorigenicity shown for liraglutide in animal studies, a decision
`shoul