Saxenda Drug Information

Important Administration Instructions • Prior to initiation of SAXENDA, train patients on proper injection technique. Refer to the accompanying Instructions for Use for complete administration instructions with illustrations. • Inspect SAXENDA visually prior to each injection. Only use if solution is clear, colorless, and contains no particles. • Administer SAXENDA in combination with a reduced-calorie diet and increased physical activity. • Inject SAXENDA subcutaneously once daily at any time of day, without regard to the timing of meals. • Inject SAXENDA subcutaneously in the abdomen, thigh, or upper arm.

No dosage adjustment is needed if changing the injection site and/or timing. • Rotate injection sites within the same region in order to reduce the risk of cutaneous amyloidosis. • If a dose is missed, resume the once-daily regimen as prescribed with the next scheduled dose. Do not administer an extra dose or increase the dose to make up for the missed dose. • If more than 3 days have elapsed since the last SAXENDA dosage, reinitiate SAXENDA at 0.6 mg daily and follow the dosage escalation schedule in Table 1, to reduce the risk of gastrointestinal adverse reactions associated with reinitiation of treatment.

Dosage in Adults and Pediatric Patients Aged 12 Years and Older • Initiate SAXENDA with a dose of 0.6 mg daily for one week. Table 1. Dosage Escalation Schedule Week Daily Dose and onward 3 mg Adult Patients • For adults, the recommended dosage of SAXENDA is 3 mg daily, lower dosages are for titration only. • Discontinue SAXENDA if the patient cannot tolerate the 3 mg dosage. • If patients do not tolerate an increased dose during dosage escalation, consider delaying dosage escalation for approximately one additional week. • 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. • In adult patients with type 2 diabetes, monitor blood glucose prior to starting SAXENDA and during SAXENDA treatment.

Pediatric Patients • For pediatric patients, the recommended maintenance dosage of SAXENDA is 3 mg daily. Pediatric patients who do not tolerate 3 mg daily may have their maintenance dose reduced to 2.4 mg daily. Discontinue SAXENDA if the patient cannot tolerate the 2.4 mg dose. • If pediatric patients do not tolerate an increased dose during dosage escalation, the dose may also be lowered to the previous level.

Dosage escalation for pediatric patients may take up to 8 weeks. • Evaluate the change in BMI after 12 weeks on the maintenance dose and discontinue SAXENDA if the patient has not had a reduction in BMI of at least 1% from baseline, since it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.

Clinical Trials Experience

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. All patients received study drug in addition to a reduced-calorie diet and increased physical activity counseling. In the adult trials, patients received SAXENDA for a mean treatment duration of 46 weeks (median, 56 weeks).

In one of the 56-week trials, a subset of patients (with abnormal glucose measurements at randomization) 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 adult 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. Adverse reactions reported in greater than or equal to 2% of SAXENDA-treated adult patients and more frequently than in placebo-treated patients are shown in Table 2. Table 2.

See text below for further information regarding hypoglycemia in patients with and without type 2 diabetes. T2DM = type 2 diabetes mellitus. Table 3.

Pediatric patients did not have type 2 diabetes mellitus. See text below for more detailed hypoglycemia information. Hypoglycemia Adult Patients with Type 2 Diabetes In a clinical trial in adult patients with type 2 diabetes mellitus and overweight (excess weight) or obesity, severe hypoglycemia (defined as requiring the assistance of another person) occurred in 3 (0.7%) of 422 SAXENDA-treated patients (all taking a sulfonylurea) and in none of the 212 placebo-treated patients.

The doses of sulfonylureas were reduced by 50% at the beginning of the trial per protocol. No meaningful difference in hypoglycemia, defined as blood glucose less than 54 mg/dL with or without symptoms, was reported between groups. Adult Patients without Type 2 Diabetes In SAXENDA clinical trials in adult patients without type 2 diabetes mellitus, there was no systematic capturing or reporting of hypoglycemia; patients were not provided with blood glucose meters or hypoglycemia diaries.

No severe hypoglycemic episodes, defined as requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions, occurred in the SAXENDA treatment group. 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. In a SAXENDA pediatric clinical trial, pancreatitis was not independently adjudicated.

Pancreatitis was reported in 1 (0.8%) SAXENDA-treated patient and resulted in treatment discontinuation. Gastrointestinal Adverse Reactions In the adult 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). Severe gastrointestinal adverse reactions were reported more frequently among patients receiving SAXENDA (4.8%) than placebo (1.4 %).

There have been reports of gastrointestinal adverse reactions, such as nausea, vomiting, and diarrhea, associated with volume depletion and renal impairment. 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). 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. In a pediatric clinical trial, 8% of patients treated with SAXENDA versus no patients who received placebo discontinued treatment as a result of gastrointestinal adverse reactions. Most adverse reactions leading to discontinuation were due to vomiting and nausea (4.8% and 3.2% of SAXENDA-treated patients, respectively).

Cardiovascular Safety Cardiovascular safety was assessed (LEADER, NCT01179048) in 9,340 patients with inadequately controlled type 2 diabetes and cardiovascular disease randomized to liraglutide 1.8 mg or placebo in addition to standard of care treatments for type 2 diabetes for a median duration of 3.5 years. The primary endpoint was the time from randomization to first occurrence of a major adverse cardiovascular event (MACE) defined as: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. No increased risk for MACE was observed with liraglutide 1.8 mg.

The total number of primary component MACE endpoints was 1,302. Liraglutide 1.8 mg (Victoza) is used in the treatment of type 2 diabetes mellitus in adults. The efficacy of liraglutide at doses below 3 mg daily has not been established for weight reduction.

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. Immunogenicity The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

For these reasons, the incidence of antibodies to SAXENDA cannot be directly compared with the incidence of antibodies of other products. Patients treated with SAXENDA may develop anti-liraglutide antibodies. Anti-liraglutide antibodies were detected in 42 (2.8%) of 1505 SAXENDA-treated adult 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.

Two patients (1.7%) remained positive throughout the follow-up period; 1 (0.9%) had antibodies cross reactive to native GLP-1. No patients had neutralizing antibodies. Allergic Reactions Urticaria was reported in 0.7% of SAXENDA-treated patients and 0.5% of placebo-treated patients.

Anaphylactic reactions, asthma, bronchial hyperreactivity, bronchospasm, oropharyngeal swelling, facial swelling, angioedema, pharyngeal edema, type IV hypersensitivity reactions have been reported in patients treated with liraglutide in clinical trials. Cases of anaphylactic reactions with additional symptoms such as hypotension, palpitations, dyspnea, and edema have been reported with marketed use of liraglutide. Anaphylactic reactions may potentially be life-threatening.

The majority of cancers were estrogen- and progesterone-receptor positive. There were too few cases to determine whether these cases were related to SAXENDA. In addition, there are insufficient data to determine whether SAXENDA has an effect on pre-existing breast neoplasia.

Four of these papillary thyroid carcinomas were less than 1 cm in greatest diameter and 4 were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings identified prior to treatment. Cardiac Conduction Disorders In SAXENDA clinical trials in adults, 11 (0.3%) of 3,384 SAXENDA-treated patients compared with none of the 1,941 placebo-treated patients had a cardiac conduction disorder, reported as first degree atrioventricular block, right bundle branch block, or left bundle branch block. Hypotension Adverse reactions related to hypotension (hypotension, orthostatic hypotension, circulatory collapse, and decreased blood pressure) were reported more frequently with SAXENDA (1.1%) compared with placebo (0.5%) in SAXENDA clinical trials in adults.

Systolic blood pressure decreases to less than 80 mmHg were observed in 4 (0.1%) SAXENDA-treated patients compared with no placebo-treated patients. One of the SAXENDA-treated patients had hypotension associated with gastrointestinal adverse reactions and renal failure. Because clinical evaluation to exclude alternative causes of ALT and aspartate aminotransferase (AST) increases was not done in most cases, the relationship to SAXENDA is uncertain.

Some increases in ALT and AST were associated with other confounding factors (such as gallstones). Serum Calcitonin Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. More patients treated with SAXENDA in the clinical trials were observed to have high calcitonin values during treatment, compared with placebo.

The proportion of patients with calcitonin greater than or equal to 2 times the upper limit of normal at the end of the trial was 1.2% in SAXENDA-treated patients and 0.6% in placebo-treated patients. Calcitonin values greater than 20 ng/L at the end of the trial occurred in 0.5% of SAXENDA-treated patients and 0.2% of placebo-treated patients; among patients with pre-treatment serum calcitonin less than 20 ng/L, none had calcitonin elevations to greater than 50 ng/L at the end of the trial. Serum Lipase and Amylase Serum lipase and amylase were routinely measured in the SAXENDA clinical trials.

Among SAXENDA-treated patients, 2.1% had a lipase value at anytime during treatment of greater than or equal to 3 times the upper limit of normal compared with 1.0% of placebo-treated patients. 0.1% of SAXENDA-treated patients had an amylase value at anytime in the trial of greater than or equal to 3 times the upper limit of normal versus 0.1% of placebo-treated patients. The clinical significance of elevations in lipase or amylase with SAXENDA is unknown in the absence of other signs and symptoms of pancreatitis.

Postmarketing Experience

The following adverse reactions have been reported during post-approval use of liraglutide, the active ingredient of SAXENDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Acute pancreatitis; hemorrhagic and necrotizing pancreatitis, sometimes resulting in death; ileus, intestinal obstruction, severe constipation including fecal impaction, nausea, vomiting and diarrhea leading to dehydration Hepatobiliary Hyperbilirubinemia, elevations of liver enzymes, cholestasis and hepatitis Hypersensitivity Rash, pruritus, angioedema and anaphylactic reactions Neoplasms Medullary thyroid carcinoma Neurologic Dysesthesia, headache Pulmonary Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation.

Renal Acute kidney injury, sometimes requiring hemodialysis; increased serum creatinine General Disorders and Administration Site Conditions Allergic reactions: rash and pruritus Immune System Angioedema and anaphylactic reactions Skin and Subcutaneous Tissue Cutaneous amyloidosis, alopecia

Oral Medications

SAXENDA causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide did not affect the absorption of the tested orally administered medications to any clinically relevant degree. Nonetheless, monitor for potential consequences of delayed absorption of oral medications concomitantly administered with SAXENDA.

Pregnancy Risk Summary Based on animal reproduction studies, there may be risks to the fetus from exposure to SAXENDA during pregnancy. SAXENDA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Additionally, weight loss offers no benefit to a pregnant patient and may cause fetal harm.

When a pregnancy is recognized, advise the pregnant patient of the risk to a fetus, and discontinue SAXENDA (see Clinical Considerations ). Animal reproduction studies identified increased adverse embryofetal developmental outcomes from exposure during pregnancy. Liraglutide exposure was associated with early embryonic deaths and an imbalance in some fetal abnormalities in pregnant rats administered liraglutide during organogenesis at doses that approximate clinical exposures at the maximum recommended human dose (MRHD) of 3 mg/day.

In pregnant rabbits administered liraglutide during organogenesis, decreased fetal weight and an increased incidence of major fetal abnormalities were seen at exposures below the human exposures at the MRHD (see Animal Data ). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies is respectively.

Clinical Considerations Disease-associated maternal and/or embryofetal risk Appropriate weight gain based on pre-pregnancy weight is currently recommended for all pregnant patients, including those who already have overweight or obesity, because of the obligatory weight gain that occurs in maternal tissues during pregnancy. Animal Data Liraglutide has been shown to be teratogenic in rats at or above 0.8-times systemic exposures in obese humans resulting from the maximum recommended human dose (MRHD) of 3 mg/day based on plasma area under the time-concentration curve (AUC) comparison. Liraglutide has been shown to cause reduced growth and increased total major abnormalities in rabbits at systemic exposures below exposure in obese humans at the MRHD 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. 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), greater than or equal to 0.01 mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral vertebrae, major blood vessels and heart, umbilicus), greater than or equal to 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.

A slight delay in parturition was observed in 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 F 2 generation rats descended from liraglutide-treated rats compared to F 2 generation rats descended from controls, but differences did not reach statistical significance for any group.

Pediatric Use The safety and effectiveness of SAXENDA as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management have been established in pediatric patients aged 12 years and older with body weight above 60 kg and an initial BMI corresponding to 30 kg/m 2 or greater for adults (obese) by international cut-offs. Use of SAXENDA for this indication is supported by a 56-week double-blind, placebo-controlled clinical trial in 251 pediatric patients aged 12 to 17 years, a pharmacokinetic study in pediatric patients, and studies in adults with obesity. In the pediatric clinical trial, one SAXENDA-treated patient had an event of pancreatitis; more episodes of hypoglycemia confirmed by self blood glucose monitoring occurred in SAXENDA-treated patients compared to placebo; and mean increases in resting heart rate of 3 to 7 bpm from baseline were observed with SAXENDA-treated patients.

The safety and effectiveness of SAXENDA have not been established in patients less than 12 years of age.

• 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).
• Patients with a serious hypersensitivity reaction to liraglutide or to any of the excipients in SAXENDA. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with SAXENDA.
• Personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2.
• Hypersensitivity to liraglutide or any excipients in SAXENDA.

Overdoses have been reported in clinical trials and post-marketing use of liraglutide. Effects have included severe nausea, severe vomiting and severe hypoglycemia. In the event of overdosage, consider contacting the Poison Helpline (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

Initiate appropriate supportive treatment according to the patient’s clinical signs and symptoms.