`
`
`
`
`
`
`
` ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE FORMS AND STRENGTHS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙-∙∙∙∙∙∙∙∙∙∙∙∙∙∙
` Injection, pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg,
`
`
`
`
`•
` 1.8 mg, 2.4 mg or 3 mg (6 mg/mL, 3 mL) (3).
`
`
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙CONTRAINDICATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`• Personal or family history of medullary thyroid carcinoma or Multiple
`
`
`
`Endocrine Neoplasia syndrome type 2 (4, 5.1).
`
`• Hypersensitivity to liraglutide or any product components (4, 5.7).
`
`
`
`• Pregnancy (4, 8.1).
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙WARNINGS AND PRECAUTIONS∙∙∙∙∙∙∙∙∙-∙∙∙∙∙∙∙∙--∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`• Thyroid C-cell Tumors: See Boxed Warning (5.1).
`
`
`
`• Acute Pancreatitis: Discontinue promptly if pancreatitis is suspected. Do
`
`
`
`
`
`not restart if pancreatitis is confirmed (5.2).
`
`
`
`• Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected,
`
`
`
`
`
`gallbladder studies are indicated (5.3).
`
`
`• Serious Hypoglycemia: Can occur when Saxenda is used with an insulin
`
`
`
`
`secretagogue (e.g. a sulfonylurea). Consider lowering the dose of anti-
`
`
`diabetic drugs to reduce the risk of hypoglycemia (2, 5.4).
`
`
`• Heart Rate Increase: Monitor heart rate at regular intervals (5.5).
`
`
`
`• Renal Impairment: Has been reported postmarketing, usually in association
`
`
`
`
`
`
`with nausea, vomiting, diarrhea, or dehydration which may sometimes
`
`
`require hemodialysis. Use caution when initiating or escalating doses of
`
`
`Saxenda in patients with renal impairment (5.6).
`
`
`
`• Hypersensitivity Reactions: Postmarketing reports of serious
`
`
`
`hypersensitivity reactions (e.g., anaphylactic reactions and angioedema).
`
`Discontinue Saxenda and other suspect medications and promptly seek
`
`
`
`
`
`medical advice (5.7).
`
`• Suicidal Behavior and Ideation: Monitor for depression or suicidal thoughts.
`
`
`Discontinue Saxenda if symptoms develop (5.8).
`
`
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ADVERSE REACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙-∙∙∙∙∙∙∙∙∙∙∙
`
`
`• Most common adverse reactions, reported in greater than or equal to 5%
`
`
`
`
`
`are: nausea, hypoglycemia, diarrhea, constipation, vomiting, headache,
`
`
`
`decreased appetite, dyspepsia, fatigue, dizziness, abdominal pain, and
`
`
`
`
`increased lipase (6.1).
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
`
`Inc. at 1-844-363-4448 or FDA at 1-800-FDA-1088
`
`
`
`or www.fda.gov/medwatch.
`
`
`------------------------------DRUG INTERACTIONS----------------------------------
`• Saxenda delays gastric emptying. May impact absorption of concomitantly
`
`
`
`
`administered oral medications. Use with caution (7).
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙USE IN SPECIFIC POPULATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙-∙∙∙-∙∙∙∙
`
`• Pediatric Use: Safety and effectiveness not established and use not
`
`
`
`recommended (8.4).
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`
`
`
`Medication Guide.
`
`
`
`Revised: 5/2017
`
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
` SAXENDA® safely and effectively. See full prescribing information
`
`
` for SAXENDA.
`
`
`
`SAXENDA (liraglutide) injection, 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 both genders of rats and mice. It is unknown
` whether Saxenda causes thyroid C-cell tumors, including
`
`
`
`
` medullary thyroid carcinoma (MTC), in humans, as the human
` relevance of liraglutide-induced rodent thyroid C-cell tumors
`
`
`
`
`
` has not been determined (5.1).
`
`
`
`
`
`
`Saxenda is contraindicated in patients with a personal or family
`
`
`
`history of MTC or in patients with Multiple Endocrine
`
`
`
`
`Neoplasia syndrome type 2 (MEN 2). Counsel patients
`
`
`regarding the potential risk of MTC and the symptoms of
`
`
`
` thyroid tumors (4, 5.1, 13.1).
`
`
`
` ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙RECENT MAJOR CHANGES∙∙∙∙∙-∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
` Boxed Warning……………………………………………………..9/2016
` Warnings and Precautions, Risk of Thyroid C-cell Tumors (5.1)....9/2016
`
`
`
`
` Warnings and Precautions, Pancreatitis (5.2)……………………...5/2017
`
`
`
`
` Warnings and Precautions, Acute Gallbladder Disease (5.3)……...5/2017
`
`
`
` Warnings and Precautions, Suicidal Behavior and Ideation (5.8)…5/2017
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`
`Saxenda is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated
`
`
`
`as an adjunct to a reduced-calorie diet and increased physical activity for
`
`
`
`
`
`
`chronic weight management in adult patients with an initial body mass
`
`
`
`
`
`index (BMI) of
`
`30 kg/m2 or greater (obese) (1) or
`
`•
`
`
`27 kg/m2 or greater (overweight) in the presence of at least
`
`
`
`•
` one weight-related comorbid condition (e.g. hypertension,
`
`
`
`
` type 2 diabetes mellitus, or dyslipidemia) (1).
`
`
`
` Limitations of Use:
`
`
`
`
`
`
`
`
` • Saxenda is not indicated for the treatment of type 2 diabetes (1).
`
` • Saxenda should not be used in combination with any other GLP-1
`
`
`
`
`
`
` receptor agonist (1).
`
`
`
`
`
` • Saxenda should not be used with insulin (1, 5.4).
`
`
`
` • The effects of Saxenda on cardiovascular morbidity and mortality
`
`
`
`
` have not been established (1).
`
`
` • The safety and efficacy of coadministration with other products for
`
`
`
`
` weight loss have not been established (1).
` • Saxenda has not been studied in patients with a history of
`
`
`
`
`
` pancreatitis (1, 5.2).
`
`
` ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE AND ADMINISTRATION∙∙∙∙-∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
` • Recommended dose of Saxenda is 3 mg daily. Administer at any
`
`
`
`
`
` time of day, without regard to the timing of meals (2).
`
`
`
`
`
` Initiate at 0.6 mg per day for one week. In weekly intervals,
`
`
` increase the dose until a dose of 3 mg is reached (2).
`
`
`
`
` Inject subcutaneously in the abdomen, thigh or upper arm (2).
`
`
`•
`
`• The injection site and timing can be changed without dose
`
`
` adjustment (2).
`
`
`
`
`
`
`
`
`
`
`•
`
`
`
`
`
`
`
`
`
`Reference ID: 4089789
`
`
`
`
` 10
`
` 11
`
` 12
`
`
`
`
` OVERDOSAGE
`
` DESCRIPTION
` CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`CLINICAL STUDIES
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 How Supplied
`
`
`16.2 Recommended Storage
`
`
`PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`
`listed.
`
`13
`
`
`14
`
`16
`
`
`17
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
` BOXED WARNING: RISK OF THYROID C-CELL TUMORS
`
`1
`
`2
`
`3
`
`4
`
`5
`
`
`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`5.1 Risk of Thyroid C-cell Tumors
`
`
`
`5.2 Acute Pancreatitis
`
`
`
`
`5.3 Acute Gallbladder Disease
`
`
`
`5.4 Risk for Hypoglycemia with Concomitant Use of
`
`
`
`Anti-Diabetic Therapy
`
`
`5.5 Heart Rate Increase
`
`
`
`5.6 Renal Impairment
`
`
`
`5.7 Hypersensitivity Reactions
`
`
`
`
`5.8 Suicidal Behavior and Ideation
`
`
`6
`ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
`
`DRUG INTERACTIONS
`
`
`7.1 Oral Medications
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`
`8.2 Lactation
`
`
`
`8.4 Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Renal Impairment
`
`
`8.7 Hepatic Impairment
`
`
`8.8 Gastroparesis
`
`
`
`
`7
`
`
`8
`
`
`
`
`Reference ID: 4089789
`
`
`
`
`
` 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 Saxenda
`
` causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the
`
` human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined
`[see Warnings and Precautions (5.1) and Nonclinical Toxicology (13.1)].
`
`
`
`
`• Saxenda is contraindicated in patients with a personal or family history of MTC and in patients
`
`with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the
`
`
`
`potential risk of MTC with use of Saxenda and inform them of symptoms of thyroid tumors
`
`
`(e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of
`
`serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC
`
` in patients treated with Saxenda [see Contraindications (4), Warnings and Precautions (5.1)].
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`
`
`Saxenda is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight
`
`
`
`management in adult patients with an initial body mass index (BMI) of
`
`
`• 30 kg/m2 or greater (obese), or
`
`
`
`• 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g.,
`
`
`
`hypertension, type 2 diabetes mellitus, or dyslipidemia)
`
`
`
`
`
`
`
`Limitations of Use
`
` Saxenda is not indicated for the treatment of type 2 diabetes mellitus.
`
`
`
`
`
` Saxenda and Victoza® both contain the same active ingredient, liraglutide, and therefore should not be used
`
`
`
`
`
` together. Saxenda should not be used in combination with any other GLP-1 receptor agonist.
`
` Saxenda has not been studied in patients taking insulin. Saxenda and insulin should not be used together [see
`
`
`
` Warnings and Precautions (5.4)].
`
`
`
`
`
`
` The effects of Saxenda on cardiovascular morbidity and mortality have not been established.
`
`
`
`
`
`
`
` The safety and effectiveness of Saxenda in combination with other products intended for weight loss,
`
` including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established.
`
`
`
`
`
`
` Saxenda has not been studied in patients with a history of pancreatitis [see Warnings and Precautions (5.2)].
`
`
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`The recommended dosage of Saxenda is 3 mg daily. The dose escalation schedule in Table 1 should be used to
`
`
`
`
`
`
`
`reduce the likelihood of gastrointestinal symptoms. If patients do not tolerate an increased dose during dose
`
`
`escalation, consider delaying dose escalation for approximately one additional week. Saxenda should be
`
`
`
`discontinued, however, if a patient cannot tolerate the 3 mg dose, as efficacy has not been established at lower
`
`
`
`
`
`doses (0.6, 1.2, 1.8, and 2.4 mg).
`
`
`
`
`
`Table 1.
`
`
`
`
`
`
`
`
`Dose Escalation Schedule
`
`
`
` Week
`
`
`
` Daily Dose
`
`Reference ID: 4089789
`
`
`
`
` 1
`
` 2
`
` 3
`
` 4
` 5 and onward
`
`
`
`
` 0.6 mg
`
` 1.2 mg
`
` 1.8 mg
`
` 2.4 mg
`
` 3 mg
`
`
`
`
`
`
`
`Saxenda should be taken once daily at any time of day, without regard to the timing of meals. Saxenda can be
`
`
`
`
`injected subcutaneously in the abdomen, thigh, or upper arm. The injection site and timing can be changed
`
`
`
`
`without dose adjustment. Saxenda must not be administered intravenously or intramuscularly.
`
`
`
`
`When initiating Saxenda in patients taking insulin secretagogues (such as sulfonylureas), consider reducing the
`
`
`
`
`
`dose of the insulin secretagogue (for example, by one-half) to reduce the risk for hypoglycemia, and monitor
`
`
`blood glucose. Saxenda and insulin should not be used together [see Warnings and Precautions (5.4) and
`
`
`
`
`Adverse Reactions (6.1)]. Conversely, if discontinuing Saxenda in patients with type 2 diabetes, monitor for an
`
`increase in blood glucose.
`
`
`
`
`
`
`
`
`Evaluate the change in body weight 16 weeks after initiating Saxenda and discontinue Saxenda if the patient has
`
`
`
`not lost at least 4% of baseline body weight, since it is unlikely that the patient will achieve and sustain
`
`clinically meaningful weight loss with continued treatment.
`
`
`
`
`If a dose is missed, the once-daily regimen should be resumed as prescribed with the next scheduled dose. An
`
`
`
`extra dose or increase in dose should not be taken to make up for the missed dose. If more than 3 days have
`
`
`
`
`elapsed since the last Saxenda dose, patients should reinitiate Saxenda at 0.6 mg daily and follow the dose
`
`
`
`
`escalation schedule in Table 1, which may reduce the occurrence of gastrointestinal symptoms associated with
`
`reinitiation of treatment.
`
`
`
`Prior to initiation of Saxenda, patients should be trained by their healthcare professional on proper injection
`
`
`technique. Training reduces the risk of administration errors such as needle sticks and incomplete dosing. Refer
`
`
`
`
`
`to the accompanying Instructions for Use for complete administration instructions with illustrations.
`
`
`
`Saxenda solution should be inspected prior to each injection, and the solution should be used only if it is clear,
`
`colorless, and contains no particles.
`
`
`
`
`
`BMI is calculated by dividing weight in (kilograms) by height (in meters) squared. A chart for determining BMI
`
`based on height and weight is provided in Table 2.
`
`
`Reference ID: 4089789
`
`
`
`
`
`
`
` Table 2.
`
`
`
` BMI Conversion Chart
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`Solution for subcutaneous injection, pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4
`
`
`mg, or 3 mg (6 mg/mL, 3 mL).
`
`
`
`CONTRAINDICATIONS
`4
`
`
`Saxenda is contraindicated in:
`
`• Patients with a personal or family history of medullary thyroid carcinoma (MTC) or patients with
`
`
`
`
`Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)]
`
`
`
`
`• Patients with a prior serious hypersensitivity reaction to liraglutide or to any of the product components
`
`
`
`
`
`
`
`[see Warnings and Precautions (5.7)]
`
`
`• Pregnancy [see Use in Specific Populations (8.1)]
`
`
`
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`
`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 [see Nonclinical
`
`
`
`
`Toxicology (13.1)]. Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether
`
`
`
`Saxenda 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 has not been determined.
`
`
`
`
`
`
`Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in
`
`
`these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in
`
`humans.
`
`
`Saxenda is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2.
`
`Counsel patients regarding the potential risk for MTC with the use of Saxenda and inform them of symptoms of
`
`
`
`
`
`thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness).
`
`
`
`
`
`Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of
`
`
`
`
`
`
`
`
`MTC in patients treated with Saxenda. Such monitoring may increase the risk of unnecessary procedures, due
`
`
`
`
`
`
`Reference ID: 4089789
`
`
`
`
`
` to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly
`
`
`
`
`
`
` elevated serum calcitonin may indicate MTC, and patients with MTC usually have calcitonin values greater
` than 50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated.
`
`
` Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.
`
`
`
`
`
`Acute Pancreatitis
`5.2
`
`
`Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or
`
`
`necrotizing pancreatitis, has been observed in patients treated with liraglutide. After initiation of Saxenda,
`
`
`
`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, Saxenda should promptly be discontinued and appropriate management should be initiated. If
`
`
`
`
`pancreatitis is confirmed, Saxenda should not be restarted.
`
`
`
`
`
`
`
`In Saxenda clinical trials, acute pancreatitis was confirmed by adjudication in 9 (0.3%) of 3291 Saxenda-treated
`
`
`
`
`
`patients and 2 (0.1%) of 1843 placebo-treated patients. In addition, there were 2 cases of acute pancreatitis in
`
`
`
`
`
`
`
`Saxenda-treated patients who prematurely withdrew from these clinical trials, occurring 74 and 124 days after
`
`
`
`
`
`the last dose. There were 2 additional cases in Saxenda-treated patients, 1 during an off-treatment follow-up
`
`
`period within 2 weeks of discontinuing Saxenda, and 1 that occurred in a patient who completed treatment and
`
`was off-treatment for 106 days.
`
`
`It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using
`
`
`Saxenda, since these patients were excluded from clinical trials.
`
`
`
`Acute Gallbladder Disease
`5.3
`
`
`
`
`
`In Saxenda clinical trials, 2.2% of Saxenda-treated patients reported adverse events of cholelithiasis versus
`
`
`
`0.8% of placebo-treated patients. The incidence of cholecystitis was 0.8% in Saxenda-treated patients versus
`
`
`
`
`0.4% in placebo-treated patients. The majority of Saxenda-treated patients with adverse events of cholelithiasis
`
`
`
`
`
`and cholecystitis required cholecystectomy. Substantial or rapid weight loss can increase the risk of
`
`
`
`
`cholelithiasis; however, the incidence of acute gallbladder disease was greater in Saxenda-treated patients than
`
`
`
`
`
`
`
`in placebo-treated patients even after accounting for the degree of weight loss. If cholelithiasis is suspected,
`
`
`
`
`gallbladder studies and appropriate clinical follow-up are indicated.
`
`
`
`
`
`
`Risk for Hypoglycemia with Concomitant Use of Anti-Diabetic Therapy
`5.4
`
`The risk for serious hypoglycemia is increased when Saxenda is used in combination with insulin secretagogues
`
`
`(for example, sulfonylureas) in patients with type 2 diabetes mellitus. Therefore, patients may require a lower
`
`
`dose of sulfonylurea (or other concomitantly administered insulin secretagogues) in this setting [see Dosage
`
`
`
`and Administration (2) and Adverse Reactions (6.1)]. Saxenda should not be used in patients taking insulin.
`
`
`
`Saxenda can lower blood glucose [see Clinical Pharmacology (12.2)]. Monitor blood glucose parameters prior
`
`
`
`
`
`
`
`
`
`to starting Saxenda and during Saxenda treatment in patients with type 2 diabetes. If needed, adjust co
`
`
`
`administered anti-diabetic drugs based on glucose monitoring results and risk of hypoglycemia.
`
`
`Heart Rate Increase
`5.5
`
`
`
`
`
`
`Mean increases in resting heart rate of 2 to 3 beats per minute (bpm) were observed with routine clinical
`
`
`
`
`
`monitoring in Saxenda-treated patients compared to placebo in clinical trials. More patients treated with
`
`
`
`
`
`
`
`
`
`Saxenda, compared with placebo, had changes from baseline at two consecutive visits of more than 10 bpm
`
`
`
`
`(34% versus 19%, respectively) and 20 bpm (5% versus 2%, respectively). At least one resting heart rate
`
`
`
`
`
`exceeding 100 bpm was recorded for 6% of Saxenda-treated patients compared with 4% of placebo-treated
`
`
`
`
`patients, with this occurring at two consecutive study visits for 0.9% and 0.3%, respectively. Tachycardia was
`
`
`
`
`
`
`reported as an adverse reaction in 0.6% of Saxenda-treated patients and in 0.1% of placebo-treated patients.
`
`
`Reference ID: 4089789
`
`
`
`
`
` In a clinical pharmacology trial that monitored heart rate continuously for 24 hours, Saxenda treatment was
`
`
`
`
`
`
`
`
` associated with a heart rate that was 4 to 9 bpm higher than that observed with placebo.
`
`
`
`
`
`
`
`
`The clinical significance of the heart rate elevation with Saxenda treatment is unclear, especially for patients
`
`
`
`
`
`
`with cardiac and cerebrovascular disease as a result of limited exposure in these patients in clinical trials.
`
`
`
`
`Heart rate should be monitored at regular intervals consistent with usual clinical practice. Patients should inform
`
`
`
`
`health care providers of palpitations or feelings of a racing heartbeat while at rest during Saxenda treatment. For
`
`
`
`
`patients who experience a sustained increase in resting heart rate while taking Saxenda, Saxenda should be
`
`discontinued.
`
`
`
`
`Renal Impairment
`5.6
`
`
`
`In patients treated with GLP-1 receptor agonists, including Saxenda, there have been reports of acute renal
`
`failure and worsening of chronic renal failure, sometimes requiring hemodialysis [see Adverse Reactions (6.2)].
`
`
`
`
`
`
`
`
`
`Some of these events were reported in patients without known underlying renal disease. A majority of the
`
`
`
`
`
`reported events occurred in patients who had experienced nausea, vomiting, or diarrhea leading to volume
`
`
`depletion. Some of the reported events occurred in patients receiving one or more medications known to affect
`
`
`
`
`
`renal function or volume status. Altered renal function has been reversed in many of the reported cases with
`
`
`supportive treatment and discontinuation of potentially causative agents, including liraglutide. Use caution
`
`when initiating or escalating doses of Saxenda in patients with renal impairment [see Use in Specific
`
`
`
`Populations (8.6)].
`
`
`
`
`5.7 Hypersensitivity Reactions
`
`
`
`There have been reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in
`patients treated with liraglutide [see Adverse Reactions (6.1, 6.2)]. If a hypersensitivity reaction occurs, the
`
`
`
`
`
`
`
`
`patient should discontinue Saxenda and other suspect medications and promptly seek medical advice.
`
`
`
`
`
`Angioedema has also been reported with other GLP-1 receptor agonists. Use caution in a patient with a
`
`
`
`history of angioedema with another GLP-1 receptor agonist because it is unknown whether such patients
`
`
`will be predisposed to angioedema with Saxenda.
`
`
`
`
`
`Suicidal Behavior and Ideation
`5.8
`
`
`
`
`In Saxenda clinical trials, 9 (0.3%) of 3384 Saxenda-treated patients and 2 (0.1%) of the 1941 placebo-treated
`
`
`patients reported suicidal ideation; one of these Saxenda-treated patients attempted suicide. Patients treated with
`
`Saxenda should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior,
`
`and/or any unusual changes in mood or behavior. Discontinue Saxenda in patients who experience suicidal
`
`
`
`thoughts or behaviors. Avoid Saxenda in patients with a history of suicidal attempts or active suicidal ideation.
`
`
`
`ADVERSE REACTIONS
`6
`
`
`
`
`
`
`The following serious adverse reactions are described below or elsewhere in the prescribing information:
`
`
`• Risk of Thyroid C-Cell Tumors [see Warnings and Precautions (5.1)]
`
`
`
`
`
`• Acute Pancreatitis [see Warnings and Precautions (5.2)]
`
`
`
`
`
`• Acute Gallbladder Disease [see Warnings and Precautions (5.3)]
`
`
`
`
`• Risk for Hypoglycemia with Concomitant Use of Anti-Diabetic Therapy [see Warnings and Precautions
`
`
`
`
`(5.4)]
`
`
`
`• Heart Rate Increase [see Warnings and Precautions (5.5)]
`
`
`
`
`• Renal Impairment [see Warnings and Precautions (5.6)]
`
`
`
`
`
`• Hypersensitivity Reactions [see Warnings and Precautions (5.7)]
`
`
`
`
`
`• Suicidal Behavior and Ideation [see Warnings and Precautions (5.8)]
`
`
`
`
`
`
`6.1
`
`
`Clinical Trials Experience
`
`Reference ID: 4089789
`
`
`
`
`
` 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 studies of another drug and may not
` reflect the rates observed in practice.
`
`
`
`
`
`
`
`
`Saxenda was evaluated for safety in 5 double-blind, placebo controlled trials that included 3384 overweight or
`
`
`
`obese patients treated with Saxenda for a treatment period up to 56 weeks (3 trials), 52 weeks (1 trial), and 32
`
`
`
`weeks (1 trial). All patients received study drug in addition to diet and exercise counseling. In these trials,
`
`
`
`
`
`patients received Saxenda for a mean treatment duration of 46 weeks (median, 56 weeks). Baseline
`
`
`
`characteristics included a mean age of 47 years, 71% women, 85% white, 39% with hypertension, 15% with
`type 2 diabetes, 34% with dyslipidemia, 29% with a BMI greater than 40 kg/m2, and 9% with cardiovascular
`
`
`
`
`
`
`
`
`
`
`
`disease. In one of the 56-week trials, a subset of patients (with abnormal glucose measurements at
`
`
`randomization) [see Clinical Studies (14)] were enrolled for a placebo-controlled 160-week period instead,
`
`
`
`
`
`
`
`
`followed by a 12-week off-treatment follow-up. For those participating in this 160-week period, patients
`
`
`
`
`
`
`
`received Saxenda for a mean treatment duration of 110 weeks (median, 159 weeks). For all trials, dosing was
`
`initiated and increased weekly to reach the 3 mg dose.
`
`
`
`
`
`
`In clinical trials, 9.8% of patients treated with Saxenda and 4.3% of patients treated with placebo prematurely
`
`
`
`discontinued treatment as a result of adverse reactions. The most common adverse reactions leading to
`
`
`
`
`
`discontinuation were nausea (2.9% versus 0.2% for Saxenda and placebo, respectively), vomiting (1.7% versus
`
`
`
`
`
`less than 0.1%), and diarrhea (1.4% versus 0%).
`
`Adverse reactions reported in greater than or equal to 2% of Saxenda-treated patients and more frequently than
`
`
`in placebo-treated patients are shown in Table 3.
`
`
`
`
`Table 3.
`
`
`Adverse Reactions Reported in Greater Than or Equal to 2% of Saxenda-treated Patients
`
`
`
`and More Frequently than with Placebo*
`
`
`
`
`
`
` Placebo
`
` N = 1941
`
` %
`
`
` 13.8
`
` 9.9
`
` 8.5
`
` 3.9
`
` 2.7
`
` 3.1
`
` 2.7
`
` 1.7
`
` 3.0
`
` 0.2
`
` 2.5
`
` 1.0
`
`
` 12.7
`
` 2.3
`
`
` 12.6
`
` 5.0
`
`
`
` Saxenda
`
` N = 3384
` %
`
`
`
` 39.3
`
` 20.9
`
` 19.4
`
` 15.7
`
` 9.6
`
` 5.4
`
` 5.1
`
` 4.7
`
` 4.5
`
` 4.5
`
` 4.0
`
` 2.3
`
`
` 23.0
`
` 10.0
`
`
` 13.6
`
` 6.9
`
`
`
`
` 4.6
`
`
`
` 7.5
`
`
`
`
`
`
` Gastrointestinal Disorders
`
`
` Nausea
`
` Diarrhea
`
`
` Constipation
`
`
`
` Vomiting
`
` Dyspepsia
`
`
` Abdominal Pain
`
`
` Upper Abdominal Pain
`
`
`
`
` Gastroesophageal Reflux Disease
`
`
` Abdominal Distension
`
`
` Eructation
`
`
` Flatulence
`
`
` Dry Mouth
` Metabolism and Nutrition Disorders
`
` Hypoglycemia in T2DM1
`
`
` Decreased Appetite
`
`
` Nervous System Disorders
`
` Headache
`
`
` Dizziness
`
` General Disorders and Administration Site
` Conditions
`
`
`
` Fatigue
`
`
`
`
`
`
`
`
`
`Reference ID: 4089789
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2.5
`
` 0.2
`
` Injection Site Erythema
`
` 2.5
`
` 0.6
`
` Injection Site Reaction
`
`
`
`
` 2.1
`
` 0.8
`
` Asthenia
`
`
`Infections and Infestations
`
` 4.7
`
` 3.2
`
`
` Gastroenteritis
`
` 4.3
`
` 3.1
`
` Urinary Tract Infection
`
`
` 2.8
`
` 1.6
`
` Viral Gastroenteritis
`
`
`
` Investigations
`
` 5.3
`
` 2.2
`
` Increased Lipase
`
`
`
`
` Psychiatric Disorders
`
`
` 2.4
`
` 1.7
`
`
` Insomnia
`
` 2.0
`
` 1.6
`
`
` Anxiety
`
` 1 Documented symptomatic (defined as documented symptoms of hypoglycemia in combination with a plasma glucose less than or
`
`
` equal to 70 mg/dL) in patients with type 2 diabetes (Study 2). See text below for further information regarding hypoglycemia in
`
`
`
` patients with and without type 2 diabetes. T2DM = type 2 diabetes mellitus
`
`
`
`
`
` * Adverse reactions for trials with treatment period up to 56 weeks
`
`
`
`
` Hypoglycemia
`
`
`
`
`
`
` Saxenda can lower blood glucose. In a clinical trial involving patients with type 2 diabetes mellitus and
`
` overweight or obesity, severe hypoglycemia (defined as requiring the assistance of another person) occurred in
`
`
`
`
` 3 (0.7%) of 422 Saxenda-treated patients and in none of the 212 placebo-treated patients. Each of these 3
`
`
`
`
`
` Saxenda-treated patients was also taking a sulfonylurea. In the same trial, among patients taking a sulfonylurea,
`
`
`
`
`
`
`
`
` documented symptomatic hypoglycemia (defined as documented symptoms of hypoglycemia in combination
`
`
`
` with a plasma glucose less than or equal to 70 mg/dL) occurred in 48 (43.6%) of 110 Saxenda-treated patients
`
`
`
`
` and 15 (27.3%) of 55 placebo-treated patients. The doses of sulfonylureas were reduced by 50% at the
`
`
`
`
`
`
`
` beginning of the trial per protocol. The frequency of hypoglycemia may be higher if the dose of sulfonylurea is
`
`
`
`
` not reduced. Among patients not taking a sulfonylurea, documented symptomatic hypoglycemia occurred in 49
`
`
`
`
`
` (15.7%) of 312 Saxenda-treated patients and 12 (7.6%) of 157 placebo-treated patients.
`
`
`
`
`
` In Saxenda clinical trials involving patients without type 2 diabetes mellitus, there was no systematic capturing
`
`
`
`
`
` or reporting of hypoglycemia, as patients were not provided with blood glucose meters or hypoglycemia diaries.
` Spontaneously reported symptomatic episodes of unconfirmed hypoglycemia were reported by 46 (1.6%) of
`
`
`
`
`
` 2962 Saxenda-treated patients and 19 (1.1%) of 1729 placebo-treated patients. Fasting plasma glucose values
` obtained at routine clinic visits less than or equal to 70 mg/dL, irrespective of hypoglycemic symptoms, were
`
`
`
`
`
`
` reported as “hypoglycemia” in 92 (3.1%) Saxenda-treated patients and 13 (0.8%) placebo-treated patients.
`
`
`
`
`
`
`Gastrointestinal Adverse Reactions
`
`
`
`
`
`
`
`In the clinical trials, approximately 68% of Saxenda-treated patients and 39% of placebo-treated patients
`reported gastrointestinal disorders; the most frequently reported was nausea (39% and 14% of patients treated
`
`
`
`with Saxenda and placebo, respectively). The percentage of patients reporting nausea declined as treatment
`
`
`
`continued. Other common adverse reactions that occurred at a higher incidence among Saxenda-treated patients
`
`included diarrhea, constipation, vomiting, dyspepsia, abdominal pain, dry mouth, gastritis, gastroesophageal
`
`
`
`reflux disease, flatulence, eructation and abdominal distension. Most episodes of gastrointestinal events were
`
`
`
`
`mild or moderate and did not lead to discontinuation of therapy (6.2% with Saxenda versus 0.8% with placebo
`
`
`
`
`discontinued treatment as a result of gastrointestinal adverse reactions). There have been reports of
`
`gastrointestinal adverse reactions, such as nausea, vomiting, and diarrhea, associated with volume depletion and
`
`renal impairment [see Warnings and Precautions (5.6)].
`
`
`
`
`Asthenia, Fatigue, Malaise, Dysgeusia and Dizziness
`
`Events of asthenia, fatigue, malaise, dysgeusia and dizziness were mainly reported within the first 12 weeks of
`
`
`
`
`treatment with Saxenda and were often co-reported with gastrointestinal events such as nausea, vomiting, and
`
`diarrhea.
`
`
`
`
`
`
`
`Reference ID: 4089789
`
`
`
`
`
`
`
`
`
`
`
`Immunogenicity
` Patients treated with Saxenda may develop anti-liraglutide antibodies. Anti-liraglutide antibodies were detected
`
`
`
`
`
`
` in 42 (2.8%) of 1505 Saxenda-treated patients with a post-baseline assessment. Antibodies that had a
` neutralizing effect on liraglutide in an in vitro assay occurred in 18 (1.2%) of 1505 Saxenda-treated patients.
`
`
`
`
`
` Presence of antibodies may be associated with a higher incidence of injection site reactions and reports of low
`
` blood glucose. In clinical trials, these events were usually classified as mild and resolved while patients
`
`
`
`
` continued on treatment.
`
`
`
`
`
`The detection of antibody formation is highly d