Xultophy is a combination of the Generic Drugs - Insulin Degludec and Liraglutide. Insulin Degludec is long-acting insulin while Liraglutide is a GLP-1 agonist.

Xultophy 100/3.6 contains 100 units of Insulin Degludec and 3.6 mg of Liraglutide per ml.

Xultophy 100/3.6 is indicated for the treatment of Diabetes Mellitus Type 2, as an adjunct to diet and exercise, in patients who have uncontrolled blood sugars on basal insulin (less than 50 units per day) and liraglutide (less than 1.8 mg per day).

It is not indicated as a first-line of treatment and has not been studied in patients with a history of pancreatitis. It is not indicated for the treatment of Diabetes Mellitus Type 1 and patients with Diabetic Ketoacidosis.

Xultophy 100/3.6 has not been studied in patients receiving prandial insulin and is not recommended with concomitant other GLP-1 agonists or other products containing liraglutide.

Xultophy Cost in the US:

Xultophy 100-3.6 units-mg/ml subQ Injection (Pen-injector) Price: $87.35.

Xultophy (Insulin Degludec and Liraglutide) Dose in the treatment of Diabetes mellitus, Type 2:

Note: Prior to treatment initiation, GLP-1 agonists and basal insulin should be discontinued.

Each pre-filled pen contains 3 ml which is equivalent to 300 units of Insulin Degludec and 10.8 mg of liraglutide.

One ml contains 100 units of Insulin Degludec and 3.6 mg of Liraglutide.

One click is equivalent to one unit of Insulin Degludec and 0.036 units of Liraglutide.

• Initial Xultophy Dosing:

  • Patients naive to basal insulin or a GLP-1 agonist:

    • 10 units (insulin Degludec 10 units/liraglutide 0.36 mg) once a day.

  • Patients already on basal insulin or a GLP-1 agonist:

    • 16 units (insulin Degludec 16 units/liraglutide 0.58 mg) once a day.

• How to titrate the Xultophy dose:

  • Titrate the dose upwards or downwards by 2 units (insulin Degludec 2 units/ liraglutide 0.072 mg) once a week or every 3 to 4 days until the target blood sugars are achieved.
  • The maximum daily dose is 50 units (Insulin Degludec 50 units/ Liraglutide 1.8 mg).

• If a Dose is missed ...

  • Do not administer a double dose or increase the dose.
  • Resume with the next regularly scheduled dose.
  • If the dose has been missed for more than 3 days, the initial dose should be reinitiated once daily.

Xultophy Dosing Chart:

XULTOPHY 100/3.6 (dose counter display)	Insulin Degludec dose	Liraglutide dose
10	10 units	0.36 mg
11	11 units	0.40 mg
12	12 units	0.43 mg
13	13 units	0.47 mg
14	14 units	0.50 mg
15	15 units	0.54 mg
16	16 units	0.58 mg
17	17 units	0.61 mg
18	18 units	0.65 mg
19	19 units	0.68 mg
20	20 units	0.72 mg
21	21 units	0.76 mg
22	22 units	0.79 mg
23	23 units	0.83 mg
24	24 units	0.86 mg
25	25 units	0.90 mg
26	26 units	0.94 mg
27	27 units	0.97 mg
28	28 units	1.01 mg
29	29 units	1.04 mg
30	30 units	1.08 mg
31	31 units	1.12 mg
32	32 units	1.15 mg
33	33 units	1.19 mg
34	34 units	1.22 mg
35	35 units	1.26 mg
36	36 units	1.30 mg
37	37 units	1.33 mg
38	38 units	1.37 mg
39	39 units	1.40 mg
40	40 units	1.44 mg
41	41 units	1.48 mg
42	42 units	1.51 mg
43	43 units	1.55 mg
44	44 units	1.58 mg
45	45 units	1.62 mg
46	46 units	1.66 mg
47	47 units	1.69 mg
48	48 units	1.73 mg
49	49 units	1.76 mg
50	50 units	1.8 mg

The usual starting dose is 10 - 16 units depending on the patients' prior history of basal insulin and GLP-1 agonist use.

The dosing guide can also be accessed in a PDF version here. 

Dose in children:

The safety and efficacy of Insulin degludec and Liraglutide combination injection are not known.

Pregnancy Risk Category: C

• In some studies on animal reproduction, adverse events were reported.
• You can contact individual agents.

Use of Insulin Degludec or Liraglutide during breastfeeding

• Although data is not available, it appears that breastmilk contains both exogenous and endogenous insulins.
• According to the manufacturer, it is important to weigh the risks and benefits of drug exposure for the infant with the benefits for the mother.

Xultophy (Insulin Degludec and Liraglutide) Dose in Kidney Disease:

 

• Mild to moderate impairment

  • The manufacturer has not recommended any adjustments to the dosage.
  • The dose might need to be adjusted due to the effects of renal impairments on insulin and glucose metabolism.
  • To avoid fluctuations, frequent monitoring of plasma glucose levels is recommended.

• Severe impairment

  • The manufacturer has not made any adjustments to the dosage.

Xultophy (Insulin Degludec and Liraglutide) Dose in Liver disease:

The manufacturer has not recommended any adjustments to the dose. The dose might need to be adjusted due to the possible effects of hepatic impairments on insulin and glucose metabolism. To avoid fluctuations, frequent monitoring of plasma glucose levels is recommended.

Common Side Effects of Xultophy (Insulin Degludec and Liraglutide):

• Endocrine & metabolic:

  • Hypoglycemia

• Immunologic:

  • Antibody development

Less Common Side Effects of Xultophy (Insulin Degludec and Liraglutide):

• Central nervous system:

  • Headache

• Gastrointestinal:

  • Diarrhea
  • Nausea
  • Increased serum lipase

• Local:

  • Injection site reaction

• Respiratory:

  • Nasopharyngitis
  • Upper respiratory tract infection

Frequency of side effects not defined:

• Cardiovascular:

  • Increased heart rate

• Local:

  • Hypertrophy at the injection site
  • Lipoatrophy at the injection site.

Contraindications to Xultophy (Insulin Degludec and Liraglutide):

• Allergy reactions to insulin Degludec or liraglutide or any component of this formulation
• Patients who have a family or personal history of medullary thyroid carcinoma (MTC), should consult a doctor immediately.
• Multiple endocrine Neoplasia Syndrome Type 2 (MEN2): Patients with multiple endocrine syndromes
• Hypoglycemia
• Breastfeeding or pregnant women

Warnings and precautions

Formation of antibodies:

• Antibodies against insulin and liraglutide may be developed by patients. The effectiveness of insulin and liraglutide was not affected by antibody formation in clinical trials.

Gallbladder disease

• Clinical trials revealed that gallstones and cholecystitis were common in patients. Most required hospitalizations or surgery.
• If patients develop symptoms that suggest gallbladder disease, they should be examined.

Gastrointestinal symptoms

• The most common are gastrointestinal adverse events.
• Patients may need to reduce the dosage, then gradually increase or stop the treatment.

Control of the glycemic index:

• Hypoglycemia, the most frequent adverse reaction to insulin, is the most common.
• Long-acting insulins such as Degludec, Detemir, and glargine can cause hypoglycemia that may last for a longer time and need to be managed more carefully.
• Hypoglycemia due to renal or hepatic impairment can also lead to delayed recovery.
• In order to avoid hypoglycemia, which can lead to seizures, unconsciousness, and brain damage, as well as death, it is important that insulin doses in the acute, stress, and emotional disorders of patients should be decreased.
• Hypoglycemic unawareness can also be dangerous for some patients. This group includes patients with neuropathy (autonomic neuropathy), hypoglycemic unawareness, and those on beta-blockers.
• Hypoglycemia can also occur in patients who use ethanol. Patients should exercise caution.

Hypersensitivity

• Patients who took the drug have experienced serious allergic reactions. Anaphylaxis, angioedema, and other severe allergic reactions were some of the cases.
• Any such reactions should be monitored by a physician. The drug should be stopped immediately.
• These reactions can occur in patients who have had an allergic reaction to any drug component before and should be monitored after injection.

Hypokalemia

• Insulin can cause a potassium shift in the cells, which may lead to severe hypokalemia in patients who are using concomitant loop diuretics.
• Hypokalemia can lead to serious cardiac arrhythmias and respiratory failure that can even lead to death.
• Hypoglycemia should be checked and treated promptly.
• Patients at high risk for hypokalemia may need potassium supplementation.

Pancreatitis

• GLP-1 agonists may cause acute pancreatitis, including necrotizing and hemorrhagic pancreatitis. This can be fatal.
• Acute pancreatitis is a condition in which the upper abdomen or epigastric pain radiates to the back and causes nausea and vomiting. Patients should be closely monitored.
• Pancreatitis patients should be questioned immediately and offered alternative treatment.
• The drug could be discontinued permanently if a causal association has been established.
• Patients who have had biliary or pancreatitis in the past should be warned.

Effects on the renal system:

• It has been shown to cause acute renal failure as well as exacerbation or worsening of chronic renal disease.
• Dehydration, concomitant use of nephrotoxic medications, and old age are all factors that increase the risk of renal failure.
• The drug liraglutide can cause nausea, vomiting, and renal failure.
• To reverse renal damage, it is necessary to stop using the drug and to correct any exacerbating factors like dehydration.

Thyroid tumors: [US Boxed Warning]

• Animal studies have shown that liraglutide, and other GLP-1 agonists, can cause tumors in the thyroid C-cells.
• These tumors can develop depending on how long and how high the treatment was.
• These tumors are not associated with cancer in humans.
• The association should counsel all patients who will be starting treatment. Any symptoms such as neck mass, difficulty swallowing, shortness or hoarseness, or difficulty breathing should be reported to the association.
• Patients who have a history of medullary tumors or MEN 2 (multiple endocrine neoplasias), should not receive the drug.
• Patients with symptoms related to thyroid disease should be examined by a physician who can perform routine monitoring of the thyroid ultrasound and calcitonin levels for the detection of MTC.

Bariatric surgery

• Dehydration
  • Before starting therapy with Insulin Degludec or Liraglutide, it is important to correct volume depletion.
  • These patients could become dehydrated and develop acute renal failure.
  • Bariatric surgery can cause nausea and may limit fluid intake. This could cause dehydration or even renal failure.
• Excessive glucagon-like peptide-1:
  • Patients may be exposed to excessive GLP-1 activity by gastric bypass or sleeve-gastrectomy (not gastric band ligation).
  • These procedures can increase endogenous GLP-1 levels. Exogenous GLP-1 can be administered concurrently, which could lead to excessive exposure and increase the risk of hypoglycemia and pancreatitis.
• Hypoglycemia
  • Hypoglycemia can occur after weight loss (after bariatric surgery).
  • It is possible that the drug will need to be switched to another treatment with less hypoglycemic potency.
  • The bariatric procedure may increase insulin secretion or sensitivity. (Gastric bypass is followed by gastric band ligation and sleeve-gastrectomy.
  • To ensure that the drug is discharged safely, blood glucose should be checked during hospitalization.
  • Although the response to surgery is variable, a 75% decrease in insulin requirements is expected in patients with preserved B cell function (measured by C-peptide levels > 0.3 nmol/L).
• Weight loss
  • Patients who have undergone bariatric surgery (gastric bypass or sleeve-gastrectomy) may need to switch to other treatments. This is because weight gain can occur in these patients.

Cardiac disease

• Concomitant PPAR (peroxisome-activated receptor) gamma agonists such as thiazolidinediones can cause fluid retention, which can lead to heart failure.
• Patients who are taking PPAR-gamma medications should be closely monitored, particularly those at high risk, for signs and symptoms of heart disease.
• These cases may call for a reduction of dose or discontinuation permanent of PPAR-gamma.

Gastroparesis

• Liraglutide reduces gastric emptying. It should not be used in patients suffering from pre-existing gastroparesis.
• Its use in patients suffering from pre-existing gastroparesis is not yet studied.

Hepatic impairment

• Patients with liver disease need to adjust their doses. Regular monitoring of blood sugar levels and liver function is necessary due to changes in insulin and glucose metabolism.

Renal impairment

• Dosage adjustment is required for patients suffering from renal disease.
• These patients should use it with caution.
• To avoid hypoglycemic episodes, frequent blood sugar monitoring is necessary.

Insulin degludec and liraglutide: Drug Interaction

Risk Factor C (Monitor therapy)
Alpha-Lipoic Acid	May enhance the hypoglycemic effect of Antidiabetic Agents.
Androgens	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol.
Antidiabetic Agents	May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents.
Beta-Blockers	May enhance the hypoglycemic effect of insulin. Exceptions: Levobunolol; Metipranolol.
Direct Acting Antiviral Agents (HCV)	May enhance the hypoglycemic effect of Antidiabetic Agents.
Edetate CALCIUM Disodium	May enhance the hypoglycemic effect of insulin.
Guanethidine	May enhance the hypoglycemic effect of Antidiabetic Agents.
Herbs (Hypoglycemic Properties)	May enhance the hypoglycemic effect of HypoglycemiaAssociated Agents.
Hyperglycemia-Associated Agents	May diminish the therapeutic effect of Antidiabetic Agents.
Hypoglycemia-Associated Agents	May enhance the hypoglycemic effect of other HypoglycemiaAssociated Agents.
Hypoglycemia-Associated Agents	Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents.
Maitake	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Monoamine Oxidase Inhibitors	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Pegvisomant	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Prothionamide	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Quinolones	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use.
Ritodrine	May diminish the therapeutic effect of Antidiabetic Agents.
Salicylates	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Selective Serotonin Reuptake Inhibitors	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Thiazide and Thiazide-Like Diuretics	May diminish the therapeutic effect of Antidiabetic Agents.
Risk Factor D (Consider therapy modification)
Dipeptidyl Peptidase-IV Inhibitors	May enhance the hypoglycemic effect of insulin. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia.
Glucagon-Like Peptide-1 Agonists	May enhance the hypoglycemic effect of insulin. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Exceptions: Liraglutide.
Insulins	Liraglutide may enhance the hypoglycemic effect of Insulins. Management: If liraglutide is used for the treatment of diabetes (Victoza), consider insulin dose reductions. The combination of liraglutide and insulin should be avoided if liraglutide is used exclusively for weight loss (Saxenda).
Liraglutide	May enhance the hypoglycemic effect of insulin. Management: If liraglutide is used for the treatment of diabetes (Victoza), consider insulin dose reductions. The combination of liraglutide and insulin should be avoided if liraglutide is used exclusively for weight loss (Saxenda).
Metreleptin	May enhance the hypoglycemic effect of insulin. Management: Insulin dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin. Monitor closely.
Pioglitazone	May enhance the adverse/toxic effect of Insulins. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone, dose reductions should be considered to reduce the risk of hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure.
Pramlintide	May enhance the hypoglycemic effect of insulin. Management: Upon initiation of pramlintide, decrease mealtime insulin dose by 50% to reduce the risk of hypoglycemia. Monitor blood glucose frequently and individualize further insulin dose adjustments based on glycemic control.
Sincalide	Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction.
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors	May enhance the hypoglycemic effect of insulin. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia.
Sulfonylureas	Glucagon-Like Peptide-1 Agonists may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists.
Risk Factor X (Avoid combination)
Macimorelin	Insulins may diminish the diagnostic effect of Macimorelin.
Rosiglitazone	Insulins may enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention, heart failure, and hypoglycemia may be increased with this combination.

 

Monitoring required includes:

Gestational diabetes mellitus

• Glycated hemoglobin at 3- to 6-month intervals. Plasma glucose before, after, and at bedtime.
• Serum electrolytes
• Renal function
• Liver function
• Weight
• You should monitor your blood glucose 4 times per day (1 postprandial and 3 fastings) until you have good control. If that happens, adjust as necessary.

How to administer Xultophy (Insulin Degludec and liraglutide)?

You should only administer it SubQ. Avoid administration via insulin infusion pumps, IV, or IM.

It is administered in the same way as insulin subQ, into the abdomen, thigh, or upper arm. 

It is best to avoid injecting it in the same place multiple times. Rotating the injection site is a good idea to avoid lipodystrophy and localized cutaneous Amyloidosis.

Avoid cold injections. It should only be given once daily and without any regard for meals.

You should not mix the injection with insulin or any other injections. 

Avoid the administration of cloudy preparations and injections containing particulate matter. Prefilled pen-injections dial-up in increments of 1 unit.

Mechanism of action of Xultophy (Insulin Degludec and Liraglutide):

Insulin Degludec, an insulin analog that is extremely long-acting, is available. It has a 25-hour half-life, which allows it to be administered once daily.

 It can be taken at any hour of the day, unlike insulin glargine. Insulin Degludec, like all insulins and insulin analogs, increases cellular carbohydrate uptake, promotes glycogenesis and triglyceride synthesis, and increases cellular potassium and protein uptake.

Liraglutide (Glucagon-like peptide -1) analog is long-acting GLP-1. It is an insulin hormone that releases insulin in a glucose-dependent way.

Liraglutide decreases glucagon production, promotes the replication and growth of Beta cells, decreases gastric emptying, and increases satiety.

Degludec's Onset of Action takes approximately one hour. It has a half-life of 25 hours. Liraglutide has a half-life of 13 hours. 

International Brands of Insulin degludec and liraglutide:

• Xultophy

Insulin Degludec and Liraglutide Brands in Pakistan:

Xultophy 100-3.6 units-mg (Novo-Nordisk)

One Pre-filled injection (3 ml) contains:

• Insulin Degludec 300 units (100 units/ml)
• Liraglutide 10.8 mg (3.6 mg/ml)

One pre-filled injection costs: Rs. 7090 Three prefilled injections cost: Rs. 20419 Five prefilled injections cost: Rs. 34032