XULTOPHY 100/3.6
Clinical safety rating: caution
Comprehensive clinical and safety monograph for XULTOPHY 100/3.6 (XULTOPHY 100/3.6).
Xultophy 100/3.6 is a combination of insulin degludec (a long-acting basal insulin analog) and liraglutide (a GLP-1 receptor agonist). Insulin degludec binds to insulin receptors, promoting cellular glucose uptake and inhibiting hepatic glucose production. Liraglutide activates GLP-1 receptors, increasing insulin secretion, decreasing glucagon secretion, and slowing gastric emptying.
| Metabolism | Insulin degludec is degraded into inactive metabolites, with the major pathway being proteolysis. Liraglutide is endogenously metabolized by dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase (NEP). |
| Excretion | Renal: insulin degludec and liraglutide are cleared primarily via degradation, with less than 2% excreted unchanged renally. Fecal: negligible. |
| Half-life | Insulin degludec: ~25 hours (range 22-28 hours); liraglutide: ~13 hours. The ultra-long half-life of insulin degludec allows once-daily dosing with flat activity profile. |
| Protein binding | Insulin degludec: >99% bound to albumin; liraglutide: >98% bound to albumin and other plasma proteins. |
| Volume of Distribution | Insulin degludec: approximately 0.1 L/kg (confined to vascular space); liraglutide: approximately 0.7 L/kg (distribution into extravascular tissues). |
| Bioavailability | Subcutaneous: insulin degludec ~65% (range 60-70%); liraglutide ~55% (range 50-60%). |
| Onset of Action | Subcutaneous: insulin degludec onset within 30-90 minutes; liraglutide onset of gastrointestinal effects within hours, but clinical glucose-lowering onset is gradual over days as steady state is reached. |
| Duration of Action | Insulin degludec: >42 hours (beyond 24 hours at steady state), providing full 24-hour coverage with once-daily dosing; liraglutide: 24 hours (once-daily dosing). |
| Molecular Weight | Liraglutide: 3751.2 Da; Insulin degludec: ~6100 Da (average) |
Subcutaneous injection once daily, starting at 10 units (10 units insulin degludec and 3.6 mcg liraglutide). Titrate by 2 units every 3-4 days based on fasting plasma glucose to a maximum of 50 units daily.
| Dosage form | SOLUTION |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR ≥30 mL/min). For severe renal impairment (eGFR <30 mL/min), use with caution due to increased risk of hypoglycemia; consider dose reduction and monitor glucose closely. |
| Liver impairment | No specific Child-Pugh based guidelines. Use with caution in moderate to severe hepatic impairment (Child-Pugh B or C) due to potential for altered glucose metabolism and increased hypoglycemia risk; may require dose reduction and close monitoring. |
| Pediatric use | Not approved for pediatric patients under 18 years of age. Safety and efficacy not established. |
| Geriatric use | Starting dose should be conservative (e.g., 10 units) with gradual titration to minimize hypoglycemia risk. Monitor renal function and glucose levels closely; dose adjustments may be needed based on individual response and tolerability. |
| 1st trimester | Insulin degludec and liraglutide cross the placenta. Liraglutide is associated with fetal malformations in animal studies; avoid in first trimester unless benefit outweighs risk. |
| 2nd trimester | Maternal hyperglycemia risks outweigh potential drug risks. Insulin requirements may change; monitor closely. Liraglutide has limited human data but animal studies show fetal toxicity; consider alternative therapy. |
| 3rd trimester | Insulin requirements often increase. Liraglutide may cause neonatal hypoglycemia if used near term; discontinue if possible. Use only if maternal benefits clearly justify potential fetal risk. |
Clinical note
Comprehensive clinical and safety monograph for XULTOPHY 100/3.6 (XULTOPHY 100/3.6).
| Placental transfer | Both components cross the placenta. Insulin degludec has high molecular weight limiting passive transfer; liraglutide crosses in animal studies. |
| Breastfeeding |
■ FDA Black Box Warning
WARNING: RISK OF THYROID C-CELL TUMORS. Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in rats and mice. It is unknown whether Xultophy 100/3.6 causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. Xultophy 100/3.6 is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
| Common Effects | Headache Nausea Diarrhea Increased lipase in the blood Hypoglycemia low blood glucose level Nasopharyngitis inflammation of the throat and nasal passages Vomiting Decreased appetite Upper respiratory tract infection Injection site bruising |
| Serious Effects |
Hypersensitivity to insulin degludec or liraglutidePersonal or family history of medullary thyroid carcinoma (MTC)Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)Severe gastrointestinal disease (e.g., gastroparesis) due to liraglutide effects
| Precautions | Risk of thyroid C-cell tumors, Acute pancreatitis (discontinue if suspected), Hypoglycemia, Never share pens, Hypersensitivity reactions, Renal impairment (acute kidney injury with liraglutide), GLP-1 receptor agonists and acute gallbladder disease, Diabetic retinopathy (insulin degludec may increase risk) |
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| Insulin degludec is excreted in breast milk in low amounts and is not orally bioavailable to infant due to digestion; liraglutide is excreted in milk in animal studies, human data lacking. Caution if breastfeeding preterm or infants with GI issues. |
| Lactation Rating | L3 - Limited Data |
| Teratogenic Risk | Insulin degludec and liraglutide: Insulin degludec does not cross placenta in significant amounts; liraglutide is contraindicated in pregnancy due to potential teratogenic effects based on animal studies. For Xultophy 100/3.6, liraglutide component presents risk: first trimester exposure may cause fetal harm; second and third trimester may cause fetal macrosomia and neonatal hypoglycemia. Use only if clearly needed and switch to insulin if possible. |
| Fetal Monitoring | Monitor maternal blood glucose levels frequently; assess for hypoglycemia/hyperglycemia. Fetal monitoring: ultrasound for growth abnormalities, macrosomia, polyhydramnios. Neonatal monitoring: observe for hypoglycemia after delivery. |
| Fertility Effects | No direct effects on fertility reported; liraglutide may improve fertility in women with PCOS due to weight loss. Insulin degludec does not impair fertility. |
| Food/Dietary | No specific food interactions. Alcohol may increase hypoglycemia risk. Dose adjustments not needed based on food intake but consistency in meal timing is important. |
| Clinical Pearls | Starting dose is 10 units (10 units insulin degludec and 0.36 mg liraglutide) subcutaneously once daily at same meal. Titrate based on fasting plasma glucose; max dose 50 units (50 units/1.8 mg). Avoid in type 1 diabetes or DKA. Monitor for hypoglycemia, pancreatitis, gallstone disease. Reduced risk of major adverse cardiovascular events in type 2 diabetes with established CVD. Not recommended in severe renal impairment (eGFR <30). |
| Patient Advice | Inject once daily with the largest meal, preferably same meal each day. · Do not mix with other insulins or share pens. · Rotate injection sites (abdomen, thigh, upper arm) to avoid lipodystrophy. · Monitor blood glucose regularly. · Report symptoms of pancreatitis (persistent severe abdominal pain) or gallbladder disease (nausea, vomiting, jaundice). · Do not drive if hypoglycemia warning signs are diminished. · Store unused pens in refrigerator; in-use pens at room temperature for up to 30 days. · Avoid skipping meals to reduce hypoglycemia risk. |