Xultophy 100-3.6 (insulin degludec/liraglutide)

No dosing information is available for this tab.

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.

Insulin degludec is administered by subcutaneous injection once daily. Because of its delayed absorption and long duration of action, insulin degludec may be administered at any time of the day in adults. However, in pediatric patients, the drug should be administered once daily at the same time every day.

The fixed combination of insulin degludec and liraglutide (Xultophy(R)) is administered by subcutaneous injection once daily at the same time each day without regard to meals in adults; the injection is commercially available for administration in a prefilled, single-patient-use injection pen. The accompanying labeling should be consulted for proper methods of administration and care of the injection pen

Insulin degludec or the fixed combination of insulin degludec and liraglutide should not be given IV or IM, nor should it be given via an insulin infusion pump. Insulin degludec or the fixed combination with liraglutide should not be mixed with any other insulin preparations or solutions.

Insulin degludec or the fixed combination of insulin degludec and liraglutide is administered subcutaneously into the thigh, abdomen, or upper arm. A planned rotation of sites within an area should be followed to reduce the risk of lipodystrophy and localized cutaneous amyloidosis; injections should not be placed into areas of existing lipodystrophy or localized cutaneous amyloidosis.

Insulin degludec (Tresiba(R)) is commercially available for administration in the FlexTouch(R)prefilled, single-patient-use injection pen; the drug is also available in a multiple-dose vial. The accompanying labeling should be consulted for proper methods of administration and care of the FlexTouch(R) pen or the multiple-dose vial. Insulin degludec should not be transferred from the FlexTouch(R) injection pen into a syringe for administration. Dose conversions between the insulin degludec 100- and 200-units/mL FlexTouch(R) injection pens based on the differences in insulin concentration are not necessary and should not be performed. The dose window for the insulin degludec 100- and 200-units/mL FlexTouch(R) injection pens display the number of insulin degludec units to be delivered independent of insulin concentration, and no conversion is needed to calculate the dose using either injection pen. Insulin degludec may alternatively be administered by subcutaneous injection from the multiple-dose vial using a syringe and needle.

For adults who miss a dose of insulin degludec, the missed dose should be administered as soon as remembered during waking hours if at least 8 hours have elapsed between consecutive doses. If a pediatric patient misses a dose of insulin degludec, the patient or a parent or caregiver should be instructed to contact the child's clinician for guidance about dosing and monitoring blood glucose concentrations more frequently until the next scheduled insulin degludec dose. Patients who miss a dose of the fixed combination of insulin degludec and liraglutide should be instructed to resume the once-daily regimen as prescribed with the next scheduled dose; however, if more than 3 days have elapsed since the last dose, the fixed combination therapy should be re-initiated at the starting dose to mitigate GI symptoms related to the liraglutide component.

Unopened injection pens and multiple dose vials containing insulin degludec should be stored at 2-8degreesC until the expiration date. Alternatively, unopened insulin degludec injection pens and vials may be stored at room temperature (up to 30degreesC) for up to 56 days. Injection pens containing insulin degludec and vials containing insulin degludec should not be subjected to freezing; if freezing has occurred, the pen/vial should not be used. Vials containing insulin degludec should be stored in the original sealed carton to protect from light. In-use insulin degludec pens and vials may be stored at room temperature (up to 30degreesC) or under refrigeration (2-8degreesC) away from direct heat and light for up to 56 days.

Unopened injection pens containing the fixed combination of insulin degludec and liraglutide should be stored at 2-8degreesC until the expiration date. Injection pens containing the fixed combination preparation should not be subjected to freezing; if freezing has occurred, the pen should not be used. In-use pens may be stored at room temperature (15-30degreesC) or under refrigeration (2-8degreesC) away from direct heat and light for up to 21 days.

No dosing information is available for this tab.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Agents Affecting Growth Hormone/Macimorelin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

CLINICAL EFFECTS: Concurrent use of agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of macimorelin states concurrent use with agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test. Discontinue growth hormone products at least 1 week before administering the macimorelin diagnostic test. Sufficient washout time of drugs affecting growth hormone release prior to administration of macimorelin is recommended.(1) Agents affecting growth hormone include: - Drugs that directly affect the pituitary secretion of growth hormone (e.g. somatostatin, insulin, glucocorticoids, cyclooxygenase inhibitors) - Drugs that may transiently elevate growth hormone concentrations (e.g. clonidine, levodopa, insulin) - Drugs that may blunt the growth hormone response (e.g. muscarinic antagonists, anti-thyroid medications, growth hormone products)

DISCUSSION: Concurrent use of agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

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)

Insulin/Rosiglitazone

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

MECHANISM OF ACTION: The exact mechanism is unknown, but may be the result of additive fluid retention.(1,2)

CLINICAL EFFECTS: The concurrent use of rosiglitazone and insulin may increase the risk of edema, heart failure, and other cardiovascular effects such as myocardial infarction.(1,2)

PREDISPOSING FACTORS: Use in patients with NYHA Class I and II heart failure may increase the risk of other cardiovascular events.(1,2)

PATIENT MANAGEMENT: The US manufacturer of rosiglitazone states that concurrent use with insulin is not recommended.(1) If concurrent therapy is warranted, patients should be monitored for cardiovascular adverse events. If signs and symptoms of congestive heart failure develop, patients should be treated according to current standards of care. Consideration should be given to lowering the dosage of or discontinuing rosiglitazone.(2)

DISCUSSION: In a meta-analysis of 7 controlled, randomized, double-blind clinical trials in which patients were randomized to coadministration of rosiglitazone with insulin or insulin alone, the incidence of congestive heart failure in patients receiving concurrent rosiglitazone was 2.3%, compared with 1.0% in patients receiving insulin alone. More patients in the concurrent rosiglitazone group experienced myocardial infarctions, MACE (a composite of myocardial infarction, cardiovascular death, or stroke), cardiovascular deaths, and all-cause deaths than in the group receiving insulin alone.(1) In clinical trials, edema was reported in 14.7% of patients receiving concurrent rosiglitazone and insulin, compared with 5.4% on insulin alone or 4.8% on rosiglitazone alone.(1) In clinical trials, new onset or exacerbation of congestive heart failure occurred at rates of 1%, 2%, and 3%, respectively, in patients treated with insulin alone, insulin with 4 mg of rosiglitazone, and insulin with 8 mg of rosiglitazone.(1)

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)

Antidiabetics/Epinephrine

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

MECHANISM OF ACTION: Gluconeogenesis, glycogenolysis, and lipolysis are increased by epinephrine. Also, insulin secretion and glucose uptake by peripheral tissues are decreased by epinephrine.

CLINICAL EFFECTS: Increased blood glucose resulting in decreased effectiveness of the antidiabetic agent.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Caution when starting or stopping epinephrine in diabetic patients. Adjust the antidiabetic dose as needed based on blood glucose levels.

DISCUSSION: This interaction is likely to occur based upon well documented properties of the interacting drugs. However, there is individual variability in its occurrence.

Antidiabetics/Slt Ophth Non-Cardioselective Beta-Blockers

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

MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia.(1,2)

CLINICAL EFFECTS: Diminished response to sulfonylureas and insulin may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia.

DISCUSSION: A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo.(3) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(4) There have been case reports of hypoglycemia following the addition of ophthalmic timolol to a diabetic regimen.(5-7) Studies have shown that ophthalmic beta-blockers, especially the aqueous solution, have significant systemic absorption and do not undergo first-pass metabolism.(8,9)

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)

Hypoglycemics; Insulin/Bupropion

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

MECHANISM OF ACTION: Bupropion can lower the seizure threshold and when given concurrently with other medications that also lower the threshold there is an increased risk of seizure. Concurrent use of hypoglycemics or insulin increases the risk of hypoglycemia which can result in seizures.(1,2)

CLINICAL EFFECTS: Concurrent use of bupropion and hypoglycemics or insulin may increase the risk of seizure.(1,2)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; or with concomitant medications known to lower seizure threshold (antidepressants, antipsychotics, systemic steroids, theophylline).(1,2)

PATIENT MANAGEMENT: The use of bupropion in patients treated with oral hypoglycemic agents or insulin should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)

DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and oral hypoglycemic agents or insulin should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2)

Insulin/Carvedilol; Labetalol

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

MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia.

CLINICAL EFFECTS: Diminished response to insulin may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia.

DISCUSSION: A class effect of diminished glucose-lowering effects is expected with concurrent use of beta-blockers and insulin. It is prudent to monitor serum glucose closely in patients receiving beta-blocker therapy because symptoms of hypoglycemia may be masked. A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5 mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo. (1) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5 mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(2)

Insulin/Fenfluramine;Dexfenfluramine

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

MECHANISM OF ACTION: Fenfluramine increases glucose uptake at the receptor site (ie, skeletal muscle).

CLINICAL EFFECTS: The hypoglycemic effect of insulin is increased.

PREDISPOSING FACTORS: Diabetes.

PATIENT MANAGEMENT: In diabetic patients receiving insulin, monitor blood glucose levels and observe the patient for signs of hypoglycemia when initiating therapy with fenfluramine and for symptoms of hyperglycemia when fenfluramine is discontinued.

DISCUSSION: When administered before meals or to fasting patients, fenfluramine has been found to have hypoglycemic action. Numerous reports have demonstrated fenfluramine to potentiate the hypoglycemic effect of insulin in diabetic patients.

Insulin/Pioglitazone

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 the result of additive fluid retention.(1,2)

CLINICAL EFFECTS: The concurrent use of pioglitazone with insulin may increase the risk of edema and heart failure.(1,2)

PREDISPOSING FACTORS: Specific risk factors for heart failure could not be determined. Patients with ongoing edema are more likely to have edema-associated adverse effects with combination therapy.(1)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for cardiovascular adverse events. If signs and symptoms of congestive heart failure develop, patients should be treated according to current standards of care. Consideration should be given to lowering the dosage of or discontinuing pioglitazone.(1,2)

DISCUSSION: In a clinical trial, two of 191 (1.1%) of patients receiving pioglitazone (15 mg) and insulin and two of 188 (1.1%) of patients receiving pioglitazone (30 mg) and insulin developed congestive heart failure. None of the patients receiving insulin alone developed congestive heart failure.(1)

Insulin/Selected Systemic Non-Cardioselective Beta-Blockers

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

MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia. MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia.

CLINICAL EFFECTS: Diminished response to insulin may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked. CLINICAL EFFECTS: Diminished response to insulin may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked.

PREDISPOSING FACTORS: None determined. PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia. PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia.

DISCUSSION: A class effect of diminished glucose-lowering effects is expected with concurrent use of beta-blockers and insulin. It is prudent to monitor serum glucose closely in patients receiving beta-blocker therapy because symptoms of hypoglycemia may be masked. A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5 mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo. (1) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5 mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(2) DISCUSSION: A class effect of diminished glucose-lowering effects is expected with concurrent use of beta-blockers and insulin. It is prudent to monitor serum glucose closely in patients receiving beta-blocker therapy because symptoms of hypoglycemia may be masked. A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5 mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo. (1) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5 mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(2)

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)

Selected Antidiabetics/Maois

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

MECHANISM OF ACTION: The exact mechanism by which MAO inhibitors affect carbohydrate metabolism and subsequent enhancement of the hypoglycemic action of insulin is not clear. The adrenergic response to hypoglycemia may be blocked by insulin release caused by MAOI's. In vitro studies have shown that MAO inhibitors are capable of both potentiating and inhibiting insulin release, depending on their concentrations. Stimulation of glucose-mediated insulin secretion is believed to be related to the MAO inhibitory effects of the drugs.

CLINICAL EFFECTS: The hypoglycemic response to both insulin and glucose lowering agents including alpha glucosidase inhibitors, meglitinides, and sulfonylurea may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent MAO inhibitor therapy for depression in a diabetic patient will often require reduction in dosage of the hypoglycemic agent because of enhanced hypoglycemic effects. Since the extent of the reaction is highly unpredictable, any diabetic patients receiving MAO inhibitors should be monitored for possible excessive hypoglycemia.

DISCUSSION: This interaction is likely to occur. The interaction between MAOIs and insulin is well documented. Additional documentation is necessary to confirm the potential interaction of MAOI's with other glucose lowering agents including alpha glucosidase inhibitors, meglitinides, and sulfonylureas but is expected to occur based on pharmacologic similarity. It may take several weeks for the full hypoglycemic effect of the MAOI to occur. Conversely, it may take several weeks for the effect to dissipate after stopping the MAOI. Furazolidone is known to be a monoamine oxidase inhibitor. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. Metaxalone is a weak inhibitor of MAO.

Selected Antidiabetics/Safinamide

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

MECHANISM OF ACTION: The exact mechanism by which MAO inhibitors such as safinamide affect carbohydrate metabolism and subsequent enhancement of the hypoglycemic action of insulin is not clear. The adrenergic response to hypoglycemia may be blocked by insulin release caused by MAOI's. In vitro studies have shown that MAO inhibitors are capable of both potentiating and inhibiting insulin release, depending on their concentrations. Stimulation of glucose-mediated insulin secretion is believed to be related to the MAO inhibitory effects of the drugs.

CLINICAL EFFECTS: The hypoglycemic response to both insulin and glucose lowering agents including alpha glucosidase inhibitors, meglitinides, and sulfonylurea may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent MAO inhibitor therapy for depression in a diabetic patient will often require reduction in dosage of the hypoglycemic agent because of enhanced hypoglycemic effects. Since the extent of the reaction is highly unpredictable, any diabetic patients receiving MAO inhibitors should be monitored for possible excessive hypoglycemia.

DISCUSSION: This interaction is likely to occur. The interaction between MAOIs and insulin is well documented. Additional documentation is necessary to confirm the potential interaction of MAOI's with other glucose lowering agents including alpha glucosidase inhibitors, meglitinides, and sulfonylureas but is expected to occur based on pharmacologic similarity. It may take several weeks for the full hypoglycemic effect of the MAOI to occur. Conversely, it may take several weeks for the effect to dissipate after stopping the MAOI.

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.

*Insulin degludec alone or in fixed combination with liraglutide is contraindicated in patients with known hypersensitivity to insulin degludec or to any ingredient in the formulation.

*Insulin degludec alone or in fixed combination with liraglutide also is contraindicated during episodes of hypoglycemia.

*The fixed combination of insulin degludec and liraglutide is contraindicated (with a Boxed Warning) in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with multiple endocrine neoplasia type 2 (MEN 2) due to the liraglutide component. Liraglutide causes dose- and treatment duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice.

• Acute pancreatitis

• C-cell hyperplasia of thyroid
• Family history of medullary thyroid carcinoma
• Gastroparesis
• Hypoglycemic disorder
• Medullary thyroid carcinoma
• Multiple endocrine neoplasia type 2
• Pregnancy

• Disease of liver
• Hypoglycemic disorder
• Hypokalemia
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Kidney disease with reduction in glomerular filtration rate (GFr)

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.

The most common adverse effects associated with insulin degludec include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema, and weight gain.

More Frequent

• Hypoglycemic disorder

Less Frequent

• Biliary calculus
• Elevated serum amylase
• Hyperbilirubinemia
• Hypersensitivity drug reaction
• Hypertension
• Hypotension

Rare or Very Rare

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

More Frequent

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

Less Frequent

• Abdominal distension
• Back pain
• Back pain
• Bronchitis
• Cataracts
• Cough
• Depression
• Edema
• Eructation
• Flatulence
• Gastroesophageal reflux disease
• General weakness
• Injection site sequelae
• Insomnia
• Lipodystrophy
• Malaise
• Peripheral edema
• Rhinitis
• Sinusitis
• Skin rash
• Symptoms of anxiety
• Tachycardia
• Upper respiratory infection
• Urinary tract infection
• Weight gain
• Xerostomia

Rare or Very Rare

• Alopecia
• Body fluid retention
• Depression
• Diarrhea
• Dysesthesia
• Dysgeusia
• Headache disorder
• Lip swelling
• Localized cutaneous amyloidosis
• Pruritus of skin
• Pruritus of skin
• Skin rash
• Subcutaneous nodules
• Upper respiratory infection
• Urticaria

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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.

Safety and efficacy of insulin degludec have not been established in pediatric patients younger than 1 year of age. For pediatric patients requiring less than 5 units of insulin degludec per day, only the U-100 vial should be used. In pediatric patients whose therapy is being transferred from another long- or intermediate-acting insulin to insulin degludec, the drug should be initiated at a reduced dosage to minimize the risk of hypoglycemia.

Safety and efficacy of insulin degludec in pediatric patients 1 year of age and older are based on a noninferiority clinical study of 12 months' duration in patients 1-17 years of age with type 1 diabetes mellitus, a pharmacokinetic study that included approximately 200 patients 1-17 years of age with type 1 diabetes mellitus, and data from clinical trials conducted in adults with type 2 diabetes mellitus. In the noninferiority study, insulin degludec and insulin detemir provided similar glycemic control (as determined by glycosylated hemoglobin (hemoglobin A1c, HbA1c)). Adverse effects reported in pediatric patients with type 1 diabetes mellitus who were receiving insulin degludec therapy were similar to those reported in adults.

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.

Available data from one unpublished trial and the published literature with insulin degludec use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In a randomized, parallel-group, open-label active-controlled clinical trial in 91 pregnant women with type 1 diabetes mellitus who received insulin degludec once daily and insulin aspart beginning in gestational weeks 8--13 or prior to conception, no clear evidence of maternal or fetal risk associated with insulin degludec use was observed. In about two-thirds of infants, insulin degludec was detected in the infant cord blood at levels at the lower level of quantification of the assay.

In reproduction studies in animals, insulin degludec caused pre- and post-implantation loss and visceral/skeletal abnormalities in the offspring of pregnant rats and rabbits at maternal plasma concentrations 5-10 times higher than those achieved with a subcutaneous human dosage of 0.75 units/kg per day. The manufacturer states that these effects are probably secondary to maternal hypoglycemia.

Data are lacking on the use of the fixed combination of insulin degludec and liraglutide in pregnant women. Animal studies suggest that there may be risks to the fetus from exposure to liraglutide during pregnancy.

Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes mellitus also increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Insulin degludec and the fixed combination of insulin degludec and liraglutide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

Insulin degludec is distributed into milk in rats; it is not known whether the drug is distributed into human milk. Liraglutide also is distributed into milk in lactating rats. The effects of insulin degludec on the breast-fed infant or on milk production are not known.

The benefits of breast-feeding and the importance of insulin degludec alone or with liraglutide to the mother should be considered along with any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

In geriatric patients, the initial dosage, dose increments, and maintenance dosage of insulin degludec or the fixed combination of insulin degludec and liraglutide should be conservative in order to avoid hypoglycemia.

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.

In controlled clinical trials of insulin degludec, 77 (7%) patients with type 1 diabetes mellitus were >=65 years of age and 9 (1%) were >=75 years of age; in patients with type 2 diabetes, 670 (25%) were >=65 years of age and 80 (3%) were >=75 years of age. In a safety outcomes trial, 1983 (52%) of patients with type 2 diabetes mellitus who received insulin degludec were >=65 years of age and 381 (10%) were >=75 years of age. No substantial differences in safety and efficacy of insulin degludec or the fixed combination of insulin degludec and liraglutide have been observed in geriatric patients relative to younger patients; however, increased sensitivity of some older patients cannot be ruled out. Data indicate that the pharmacokinetic and pharmacodynamic properties of insulin degludec at steady sate are similar in younger adults and geriatric patients; however, greater between-subject variability has been observed among geriatric patients.

In clinical studies of the fixed combination of insulin degludec and liraglutide in 1881 patients, 375 (19.9%) were >=65 years of age and 52 (2.8 %) were >=75 years of age. No overall differences in the safety, efficacy, or pharmacokinetics of the fixed combination of insulin degludec and liraglutide were observed between patients >=65 years of age and older and younger patients.

Initial dosage, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to recognize in geriatric patients.