Saxenda (liraglutide)

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Liraglutide or the fixed combination of insulin degludec and liraglutide (insulin degludec/liraglutide) is administered by subcutaneous injection into the abdomen, thigh, or upper arm using a prefilled injection pen; the drug must not be administered IV or IM.

Liraglutide is administered once daily at any time of day, without regard to meals. The injection site and timing can be changed without dosage adjustment. Rotate injection sites within the same region to reduce the risk of cutaneous amyloidosis.

The fixed combination of insulin degludec/liraglutide is administered by subcutaneous injection once daily at the same time each day without regard to meals.

If a dose of liraglutide orinsulin degludec/liraglutide is missed, the regular schedule should be resumed with the next scheduled dose; an extra dose or increase in dose should not be taken to replace a missed dose. If more than 3 days have elapsed since the last dose of liraglutide orinsulin degludec/liraglutide, the initial dosage should be restarted and retitrated.

When using liraglutide in combination with insulin for the management of type 2 diabetes mellitus, the drugs should be administered as separate injections; insulin and liraglutide should never be mixed. Liraglutide and insulin may be injected in the same body regions; however, the injections should not be adjacent to each other. Liraglutide in fixed combination with insulin degludec is commercially available as Xultophy(R). The fixed combination of insulin degludec and liraglutide should not be mixed with any other insulin preparations or solutions.

There is no enhanced messaging for this drug.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Antidiabetic Agents/Gatifloxacin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of gatifloxacin may result in hypoglycemia and/or hyperglycemia.(1-4) Hypoglycemia is more common during the first three days of concurrent therapy. Hyperglycemia is more common after the first three days of concurrent therapy.(2)

PREDISPOSING FACTORS: Elderly patients, especially those with decreased renal function may be predisposed to this interaction.(2)

PATIENT MANAGEMENT: Patients receiving concurrent gatifloxacin should be closely monitored for hypoglycemia during the first three days of concurrent therapy and for hyperglycemia after the first three days of concurrent therapy. Patients should be instructed to discontinue gatifloxacin if hypoglycemia or hyperglycemia occur.(2)

DISCUSSION: Hypoglycemia has been reported with gatifloxacin and glyburide(1,5,6) or glimepiride.(7) In a study in patients with type 2 diabetes mellitus, concurrent gatifloxacin (400 mg daily for 10 days) had no effect on the pharmacokinetics of glyburide (steady state daily regimen); however, pharmacodynamic interactions have been reported.(2) Health Canada has received 19 reports of hypoglycemia in patients taking gatifloxacin. Seventeen of these involved concurrent hypoglycemic agents. Health Canada has received 2 reports of hyperglycemia in patients taking gatifloxacin and hypoglycemic agents. Health Canada has received 2 reports of patients experiencing hypoglycemia and hyperglycemia during concurrent gatifloxacin and hypoglycemic agents.(3) In a study, 13 reports of dysglycemia were reported in patients taking gatifloxacin. Ten of these patients had diabetes mellitus and were on concurrent hypoglycemic agents. Of these ten patients, nine patients experienced hypoglycemia, while one patient experienced hyperglycemia.(8)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Antidiabetic Agents/Gymnema

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Gymnema has been shown to increase the number of insulin-secreting beta cells in animals. It has also been shown to increase the activity of enzymes responsible for glucose uptake and utilization and inhibit peripheral utilization of glucose.(1)

CLINICAL EFFECTS: Use of gymnema may result in decreased requirements of antidiabetic agents.(2-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Diabetic patients should be carefully monitored if gymnema is initiated or discontinued from concurrent therapy. The dosage of the patient's antidiabetic agent(s) may need to be adjusted.(2)

DISCUSSION: In a study in 22 non-insulin-dependent patients, patients had decreased blood glucose, glycosylated hemoglobin, and glycosylated plasma proteins during gymnema therapy. Patients were able to decrease the dosage of their conventional antidiabetic therapy and five patients were able to discontinue their conventional antidiabetic therapy.(3) In a study in 27 insulin-dependent patients, patients had decreased insulin requirements, fasting blood glucose, glycosylated hemoglobin, and glycosylated plasma protein levels.(4)

Glp-1 Receptor Agonists/Anesthesia Agents

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: GLP-1 receptor agonists can cause delayed gastric emptying.(1,2)

CLINICAL EFFECTS: Gastric contents may remain in the stomach after preoperative fasting, which could increase the risk of regurgitation and aspiration.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The American Society of Anesthesiologists (ASA) recommends the following for patients receiving elective procedures: - For patients on daily dosing, consider holding GLP-1 agonists on the day of the procedure. For patients on weekly dosing, consider holding GLP-1 agonists a week prior to the procedure. - Consult an endocrinologist for patients taking GLP-1 agonists for diabetes management if the GLP-1 agonist is held longer than the dosing schedule to avoid hyperglycemia. - For patients requiring urgent or emergent procedures, proceed and treat the patient as 'full stomach.'(3)

DISCUSSION: In one case report, a 31-year-old patient taking semaglutide followed preoperative fasting guidelines but food residue was discovered upon endoscopy, leading to cancellation of the surgical procedure.(4) In a case report, a semaglutide-treated patient experienced regurgitation upon induction of general anesthesia despite a 20 hour preoperative fasting period. The patient received semaglutide two days before the scheduled procedure.(5) A case report of a 42-year-old patient after fasting for 18 hours showed substantial gastric content upon endoscopy. The patient experienced intraoperative pulmonary aspiration of gastric contents which were suctioned from the trachea and bronchi using bronchoscopy.(6)

Glp-1 Receptor Agonists/Lithium

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown but may be related to nausea, vomiting, and/or diarrhea caused by volume depletion resulting in the decreased renal clearance of lithium. Weight loss may also cause stable doses of lithium to be too high for weight-based dosing.(1-6)

CLINICAL EFFECTS: Lithium has a narrow therapeutic range; even modest, unintended increases in lithium concentration may result in lithium toxicity. Early symptoms of lithium toxicity may include: lethargy, muscle weakness or stiffness, new onset or coarsening of hand tremor, vomiting, diarrhea, confusion, ataxia, blurred vision, tinnitus and nystagmus. Severe toxicity may produce multiple organ dysfunction (e.g. seizures, coma, renal failure, cardiac arrhythmias, cardiovascular collapse) and may be fatal.

PREDISPOSING FACTORS: Risk factors for lithium toxicity include: renal impairment or worsening of existing renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ARBs, ACE Inhibitors, NSAIDs, diuretics). Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors.

PATIENT MANAGEMENT: The manufacturer of semaglutide states consider increased clinical or laboratory monitoring for medications that have a narrow therapeutic index or that require clinical monitoring.(1) An expert review article on the interaction between GLP-1 agonists and lithium states that clinicians may need to monitor lithium more closely when a GLP-1 agonist is initiated, whether clinically or through therapeutic drug monitoring. A cautious approach might be to consider monitoring at the following time points when there is a plan to introduce a GLP-1 agonist with lithium: 1. Before GLP-1 agonist initiation, 2. Near 1 week after starting a GLP-1 agonist, 3. Near 1 weak after each dose increases (i.e., several monthly intervals for weekly subcutaneous semaglutide and tirzepatide), and 4. Longitudinally, at more frequent intervals than guidelines recommend during the first year after GLP-1 agonist initiation, when weight loss begins to plateau. Increased monitoring may also be considered when switching between GLP-1 agonists.(7) Monitor closely to decrease the risk for lithium toxicity. Evaluate renal function and most recent lithium levels. If renal function is not stable, it would be prudent to withhold combination therapy until renal function is stable. Counsel patient to assure they know signs and symptoms of lithium toxicity and understand the importance of follow-up laboratory testing.

DISCUSSION: The impact of GLP-1 agonists on the pharmacokinetics of lithium has not been investigated in clinical studies. Literature is limited to a small number of case reports. In a case report, a 23-year-old male established on semaglutide was started on lithium and titrated to 1800 mg daily, corresponding to a lithium level of 0.9mEq/L. The patient was then switched from semaglutide to tirzepatide 5 mg weekly. Four days after his first dose of tirzepatide, he reported early symptoms of potential lithium toxicity, which progressed significantly after his second dose. Symptoms corresponded to a 15-hour post-dose level of 1.7 mEq/L, despite no changes in renal function, hydration status, or other concurrent medications. Management with intravenous fluids was sufficient, and close monitoring of lithium levels and tapering of the lithium dose prevented future toxicity. The patient remained on tirzepatide and a maintenance dose of lithium extended-release 1200 mg daily, with a lithium level measured 15-hour post-dose of 0.6mEq/L. The patient's weight remained the same from the start of tirzepatide therapy.(8) In a case report, a 62-year-old male stable on lithium for 6 years (lithium ER 600 mg daily) started semaglutide 0.25 mg twice weekly 2 to 3 weeks prior to visiting the emergency department. Patient had multiple comorbidities and medications were unchanged except for semaglutide. 6 weeks prior to visiting the ED, the patient was instructed to decrease his fluid intake due to urinary proteinuria symptoms. Lithium level was 1.8mmol/L in ED. Both lithium and semaglutide were discontinued. Lithium was restarted at 300 mg, increased to lithium ER 450 mg 10 days later and lithium levels increased to 0.8 and 0.9mmol/L. Further dose adjustment back to 300 mg resulted in a steady lithium serum level of 0.6mmol/L. No significant changes to kidney function were observed. Semaglutide was not reintroduced.(9) In another case report, a 23-year-old female was admitted to hospital for lithium toxicity. Medication list included lithium carbonate ER 900 mg and she was reported as restarting semaglutide recently. Further questioning revealed inconsistent semaglutide use over the previous 2 years, with unclear timing of a recent restart. Her lithium level on admission was found to be 2.1mmol/L. Both lithium and semaglutide were discontinued. Lithium ER had been a long-standing medication at 900 mg dose since she was 9 years old with no previous incidents of clinical lithium toxicity. She was recorded as having significant side effects to semaglutide, including nausea and vomiting. At the time of discharge, 4 days after admission, the lithium level was 0.5mmol/L and it was recommended to avoid combining lithium and semaglutide in the future. No significant changes to kidney function were observed.(9) In a case report, a 22-year-old-male stable on 2100 mg lithium carbonate ER daily was initiated on semaglutide for weight management. Patient had regular monitoring of his lithium level prior to and during dose escalation with semaglutide. During the semaglutide increase and tapering of his lithium dose, there were no report of nausea, vomiting, diarrhea, decreased oral/fluid intake, and no medication changes were made. There were no changes in mental status, symptoms concerning psychiatric decompensation, or symptoms of lithium toxicity.(9) In a 40-week study of patients with stable bipolar disorder, liraglutide resulted in a significantly greater weight loss as compared with placebo. 7 of the 60 participants were on lithium, no instances of lithium toxicity was reported and liraglutide was well tolerated.(10)

Glp-1 Receptor Agonists/Thyroid Preparations

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown but may be related to decreased GI motility resulting in increased absorption of levothyroxine. Weight loss may also cause stable doses of levothyroxine to be too high for weight-based dosing.(1)

CLINICAL EFFECTS: Concurrent administration of GLP-1 receptor agonists and thyroid preparations may increase the clinical effects of the thyroid agent, resulting in symptoms of hyperthyroidism.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients taking thyroid preparations and GLP-1 receptor agonists should be monitored for changes in thyroid function. Symptoms of hyperthyroidism include weight loss, rapid heartbeat, nervousness, sweating, tremor, fatigue, and difficulty sleeping. The dosage of levothyroxine may need to be adjusted accordingly.

DISCUSSION: In an open-label, one-sequence, crossover, 2-part trial examining the effect of administering 14 mg oral semaglutide and levothyroxine together, a 33% increase in levothyroxine AUC was identified. The trial also examined the impact of SNAC , the absorption enhancer in oral GLP-1 receptor agonists, and found that SNAC alone did not impact absorption of levothyroxine.(2) In a single-center, prospective trial, participants with diabetes without thyroid disease were given exenatide and TSH levels were measured. After 6 months of treatment, mean TSH concentration decreased from 2.3 to 1.8 without impact to T4 and T3. The mechanism that was proposed was that exenatide can increase the sensitivity of the hypothalamus or pituitary gland to the thyroid hormone negative feedback or increase the number of receptors on the hypothalamus or pituitary gland. No relationship was found between weight change and TSH level.(3) In a case report, a post-thyroidectomy patient on a stable dose of levothyroxine (125 mcg daily) started concurrent subcutaneous semaglutide therapy. Five months after starting treatments together, she started experiencing palpitations, perspiration, and heat intolerance. The levothyroxine dose was decreased to 88 mcg daily resulting in a resolution of symptoms.(4) In another case report, a 43-year-old female patient was on a stable dose of levothyroxine (200 mcg) and started on subcutaneous semaglutide. After 5 months, her TSH level dropped to 0.01 ng/dL and levothyroxine was reduced to 150 mcg daily.(5)

Selected Antidiabetic Agents/Chloroquine; Hydroxychloroquine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. Chloroquine and hydroxychloroquine may increase insulin sensitivity by inhibiting insulin metabolism and inflammation and increasing cellular uptake of glucose and glycogen synthesis.(1,2) These effects may result in additive hypoglycemia with anti-diabetic agents.

CLINICAL EFFECTS: Concurrent use of chloroquine or hydroxychloroquine and antidiabetic agents may result in severe hypoglycemia.(3) Hypoglycemia can lead to coma.

PREDISPOSING FACTORS: Elderly patients, especially those with decreased renal function may be predisposed to this interaction.

PATIENT MANAGEMENT: Patients maintained on antidiabetic agents who require concurrent therapy with chloroquine or hydroxychloroquine should be closely monitored for hypoglycemia. A decrease in the dose of insulin or other anti-diabetic medications may be required. Patients should be advised of the risk and symptoms of hypoglycemia and to contact their doctor if hypoglycemia occurs.(3) Signs of hypoglycemia may include confusion, dizziness, feeling shaky, unusual hunger, headaches, irritability, pounding heart or very fast pulse, pale skin, sweating, trembling, weakness, or unusual anxiety.

DISCUSSION: Hydroxychloroquine has been shown to cause severe hypoglycemia including loss of consciousness that could be life threatening.(3) Concomitant hypoglycemic agents may increase the risk and/or severity of this effect. A 77 year old man who was stable on twice daily insulin suffered two episodes of hypoglycemic coma 2 weeks after starting prednisone 5 mg daily and hydroxychloroquine 400 mg daily for rheumatoid arthritis. His insulin dosage required a decrease of 37%.(4) Many studies have investigated the glucose-lowering effect of hydroxychloroquine. In a clinical trial of type II diabetics on maximal doses of sulfonylureas, addition of hydroxychloroquine lowered hemoglobin A1C (HbA1C) up to 1% more than placebo.(5) Another clinical trial of type II diabetics on metformin and glimepiride or gliclazide found that hydroxychloroquine 400 mg daily reduced fasting blood glucose (FBG), post-prandial glucose (PPG), and HbA1C to a similar degree as pioglitazone 15 mg daily at 24 weeks.(6) In a prospective observational study, 250 uncontrolled type II diabetics on metformin, glimepiride, pioglitazone, sitagliptin, and a SGLT-2 inhibitor received hydroxychloroquine 400 mg daily for 48 weeks. HbA1C decreased from 8.83% to 6.44%, FBG decreased by 40.78%, and PPG decreased by 58.95%. The doses of metformin were reduced by 50%, glimepiride and sitagliptin by 75%, and SGLT-2 inhibitors were discontinued in most patients.(7)

Selected Antidiabetic Agents/Selected Quinolones

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of quinolones and antidiabetic agents may result in severe hypoglycemia.(1-7) Hypoglycemia can lead to coma.

PREDISPOSING FACTORS: Elderly patients, especially those with decreased renal function may be predisposed to this interaction.(5)

PATIENT MANAGEMENT: Patients maintained on antidiabetic agents who require concurrent therapy with a quinolone should be closely monitored for hypoglycemia.(1-4) Patients should be instructed to discontinue quinolone use and contact their doctor if hypoglycemia occurs.(2,4) Signs of hypoglycemia may include confusion, dizziness, feeling shaky, unusual hunger, headaches, irritability, pounding heart or very fast pulse, pale skin, sweating, trembling, weakness, or unusual anxiety.

DISCUSSION: Hypoglycemia has been reported with concurrent ciprofloxacin and glyburide,(1,8,9) levofloxacin and glyburide,(2,10,11) norfloxacin and glyburide,(3) levofloxacin and glipizide (12) as well as levofloxacin and metformin-glibenclamide.(14) There has been one report of fatal hypoglycemia with concurrent levofloxacin and glyburide(9) and one of the above reports of hypoglycemia with concurrent levofloxacin and glyburide resulted in hypoxic brain injury.(11) A review of postmarketing adverse event data for the fluoroquinolones and hypoglycemic coma identified 56 reports in FAERS search from October 1987- April 2017 and 11 additional cases in the medical literature. Most patients had risk factors for hypoglycemia. 41 patients were taking one or more hypoglycemic drugs. 13 deaths occurred (some of these patients had renal insufficiency). 9 patients did not fully recover and had resultant disability.(13)

Liraglutide alone or in fixed combination with insulin degludec (Xultophy(R)) is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) and in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2).

Liraglutide alone or in fixed combination with insulin degludec also is contraindicated in patients with a history of serious hypersensitivity to liraglutide or to any of the product components.

The fixed combination of insulin degludec and liraglutide is contraindicated during episodes of hypoglycemia.

Liraglutide is contraindicated forchronic weight management in women who are pregnant.

• Acute pancreatitis
• Pregnancy

• Family history of medullary thyroid carcinoma
• Gastroparesis
• Medullary thyroid carcinoma
• Multiple endocrine neoplasia type 2

• Dehydration
• Hypoglycemic disorder
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Tachyarrhythmia

Adverse effects reported in at least 5% of patients receiving liraglutide monotherapy for the management of type 2 diabetes mellitus in clinical trials include nausea, diarrhea, vomiting, constipation, and headache.

Adverse effects reported in at least 2% of patients receiving liraglutide for the management of obesity and more frequently than with placebo include nausea, hypoglycemia (in patients with both obesity and type 2 diabetes mellitus), headache, diarrhea, constipation, dizziness, fatigue, vomiting, gastroenteritis, abdominal pain, urinary tract infection, abdominal distention, dyspepsia, upper abdominal pain, flatulence, decreased appetite, increased lipase, gastroesophageal reflux disease, insomnia, anxiety, viral gastroenteritis, dry mouth, asthenia, injection site reaction, eructation, and injection site erythema.

Adverse effects occurring in at least 5% of patients with type 2 diabetes mellitus who received the fixed combination of insulin degludec and liraglutide include nasopharyngitis, headache, nausea, diarrhea, increased lipase concentrations, and upper respiratory tract infection.

More Frequent

• Hypoglycemic disorder

Less Frequent

• Biliary calculus
• Elevated serum amylase
• Hyperbilirubinemia
• Hypotension

Rare or Very Rare

• Abnormal hepatic function tests
• Acute pancreatitis
• Acute renal failure
• Anaphylaxis
• Angioedema
• Atrioventricular block
• Bundle branch block
• Cholecystitis
• Cholestasis
• Colorectal cancer
• Dehydration
• Fecal impaction
• Gastrointestinal obstruction
• Heart block
• Hepatitis
• Hypersensitivity drug reaction
• Ileus
• Increased alanine transaminase
• Increased aspartate transaminase
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Medullary thyroid carcinoma
• Necrotizing pancreatitis
• Orthostatic hypotension
• Papillary thyroid carcinoma
• Urticaria

More Frequent

• Acute abdominal pain
• Anorexia
• Constipation
• Diarrhea
• Dizziness
• Dyspepsia
• Elevated serum lipase
• Fatigue
• Fever
• Gastroenteritis
• Headache disorder
• Injection site sequelae
• Nausea
• Pharyngitis
• Vomiting
• Weight loss

Less Frequent

• Abdominal distension
• Back pain
• Eructation
• Flatulence
• Gastroesophageal reflux disease
• General weakness
• Insomnia
• Malaise
• Symptoms of anxiety
• Tachycardia
• Upper respiratory infection
• Xerostomia

Rare or Very Rare

• Alopecia
• Body fluid retention
• Depression
• Dysesthesia
• Dysgeusia
• Localized cutaneous amyloidosis
• Pruritus of skin
• Skin rash

No enhanced messaging available.

Safety and efficacy of liraglutide for the management of type 2 diabetes mellitus have not been established in children or adolescents younger than 10 years of age. Safety and efficacy of liraglutide for chronic weight management have not been established in children or adolescents younger than 18 years of age, and the manufacturer of Saxenda(R) states that the drug is not recommended for use in pediatric patients.

Safety and efficacy of the fixed combination of insulin degludec and liraglutide have not been established in pediatric patients.

Data are lacking on the use of liraglutide (Victoza(R)) in pregnant women. Reproduction studies in rats using liraglutide at dosages resulting in systemic exposures 0.8 times the exposure from the maximum recommended human dosage (1.8 mg daily) have shown teratogenic effects. Studies in rabbits have shown reduced growth and major abnormalities at systemic exposures below the maximum recommended human dosage. Liraglutide for the management of diabetes mellitus should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

The manufacturer states that liraglutide (Saxenda(R)) is contraindicated for the management of obesity in women who are pregnant because weight loss offers no potential benefit to pregnant women and may result in fetal harm. If a woman taking liraglutide for the management of obesity becomes pregnant or plans to become pregnant, the drug should be discontinued.

Liraglutide is distributed into milk in rats. It is not known whether liraglutide is distributed into milk in humans; a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

No substantial differences in safety and efficacy relative to younger adults have been observed with liraglutide or the fixed combination of insulin degludec and liraglutide, but increased sensitivity of some older patients cannot be ruled out. Hypoglycemia may be difficult to recognize in geriatric patients.