Xultophy

Important Dosage Information

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XULTOPHY 100/3.6 is a combination of insulin degludec and liraglutide.

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Administer XULTOPHY 100/3.6 by subcutaneous injection once-daily at the same time each day with or without food.

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The XULTOPHY 100/3.6 pen delivers doses from 10 to 50 units with each injection. Table 1 presents the units of insulin degludec and the milligrams of liraglutide in each dosage of XULTOPHY 100/3.6 [see Dosage and Administration ].

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The maximum dosage of XULTOPHY 100/3.6 is 50 units daily (50 units of insulin degludec and 1.8 mg of liraglutide) [see Warnings and Precautions ].

Recommended Starting Dosage

In patients naïve to basal insulin or a GLP-1 receptor agonist

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The recommended starting dosage of XULTOPHY 100/3.6 is 10 units (10 units of insulin degludec and 0.36 mg of liraglutide) injected subcutaneously once-daily (see Table 1).

In patients currently on basal insulin or a GLP-1 receptor agonist

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Discontinue therapy with basal insulin or GLP-1 receptor agonist prior to initiation of XULTOPHY 100/3.6.

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The recommended starting dosage of XULTOPHY 100/3.6 is 16 units (16 units of insulin degludec and 0.58 mg of liraglutide) injected subcutaneously once-daily (see Table 1).

Table 1: Units of Insulin Degludec and Milligrams of Liraglutide in Each Dosage of XULTOPHY 100/3.6

*The dose counter on the XULTOPHY 100/3.6 pen displays numbers for the even units and displays lines for the odd units.

Titration of XULTOPHY 100/3.6

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After starting the recommended starting dosage of XULTOPHY 100/3.6 [see Dosage and Administration ], titrate the dosage upwards or downwards by two units (see Table 2) once weekly or twice weekly (every three to four days), based on the patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal until the desired fasting plasma glucose is achieved.

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To minimize the risk of hypoglycemia or hyperglycemia, additional titration may be needed with changes in physical activity, meal patterns (i.e., macronutrient content or timing of food intake), or renal or hepatic function; during acute illness; or when used with other medications [see Warnings and Precautions and Drug Interactions ].

Table 2: Recommended Titration of XULTOPHY 100/3.6 (Once or Twice Weekly)

Recommendations Regarding Missed Doses

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Instruct patients who miss a dose of XULTOPHY 100/3.6 to resume the once-daily dosage regimen as prescribed with the next scheduled dose. Do not administer an extra dose or increase the dose to make up for the missed dose.

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If more than three days have elapsed since the last XULTOPHY 100/3.6 dose, reinitiate XULTOPHY 100/3.6 at the recommended starting dose to mitigate any gastrointestinal symptoms associated with reinitiation of treatment [see Dosage and Administration ].

Important Administration Instructions

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The XULTOPHY 100/3.6 pen is for single-patient-use only [see Warnings and Precautions ( 5.3)].

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Train patients on proper use and injection technique before initiating XULTOPHY 100/3.6.

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Always check the label on the XULTOPHY 100/3.6 pen before administration [see Warnings and Precautions ( 5.5)].

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Inspect visually for particulate matter and discoloration prior to administration. Only use XULTOPHY 100/3.6 if the solution appears clear and colorless.

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Inject XULTOPHY 100/3.6 subcutaneously into the thigh, upper arm, or abdomen.

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Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions , Adverse Reactions ].

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During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ].

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Use XULTOPHY 100/3.6 with caution in patients with visual impairment who may rely on audible clicks to dial their dose.

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The XULTOPHY 100/3.6 pen dials in one-unit increments.

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Do not administer XULTOPHY 100/3.6 intravenously or in an insulin infusion pump.

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Do not dilute or mix XULTOPHY 100/3.6 with any other insulin or solutions.

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Do not split the dose of XULTOPHY 100/3.6.

Pregnancy

Risk Summary

Based on animal reproduction studies, there may be risks to the fetus from exposure to liraglutide during pregnancy. XULTOPHY 100/3.6 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

There are no available data with XULTOPHY 100/3.6, insulin degludec or liraglutide in pregnant women to inform a drug associated risk for major birth defects and miscarriage. There are clinical considerations regarding the risks of poorly controlled diabetes in pregnancy [see Clinical Considerations].

For insulin degludec, rats and rabbits were exposed in animal reproduction studies at 5 times (rat) and 10 times (rabbit) the human exposure at a dose of 0.75 U/kg/day. No adverse outcomes were observed for pregnant animals and offspring [see Data].

For liraglutide, animal reproduction studies identified increased adverse developmental outcomes from exposure during pregnancy. Liraglutide exposure was associated with early embryonic deaths and an imbalance in some fetal abnormalities in pregnant rats administered liraglutide during organogenesis at doses that approximate clinical exposures at the maximum recommended human dose (MRHD) of 1.8 mg/day. In pregnant rabbits administered liraglutide during organogenesis, decreased fetal weight and an increased incidence of major fetal abnormalities were seen at exposures below the human exposures at the MRHD [see Data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a peri-conceptional HbA1c >7 and has been reported to be as high as 20 to 25% in women with a peri-conceptional HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/fetal Risk

Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, macrosomia related morbidity.

Data

Animal Data Insulin degludec

Insulin degludec was investigated in studies covering fertility, embryo-fetal development and pre- and post-natal development in rats and during the period of embryo-fetal development in rabbits. Human insulin (NPH insulin) was included as comparator. In these studies insulin degludec was given subcutaneously at up to 21 U/kg/day in rats and 3.3 U/kg/day in rabbits, resulting in 5 times (rat) and 10 times (rabbit) the human exposure (AUC) at a human subcutaneous dose of 0.75 U/kg/day. Overall the effects of insulin degludec were similar to those observed with human insulin.

Liraglutide

Female rats given subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day liraglutide beginning 2 weeks before mating through gestation day 17 had estimated systemic exposures 0.8-, 3-, and 11-times the human exposure at the MRHD based on plasma AUC comparison. The number of early embryonic deaths in the 1 mg/kg/day group increased slightly. Fetal abnormalities and variations in kidneys and blood vessels, irregular ossification of the skull, and a more complete state of ossification occurred at all doses. Mottled liver and minimally kinked ribs occurred at the highest dose. The incidence of fetal malformations in liraglutide-treated groups exceeding concurrent and historical controls were misshapen oropharynx and/or narrowed opening into larynx at 0.1 mg/kg/day and umbilical hernia at 0.1 and 0.25 mg/kg/day.

Pregnant rabbits given subcutaneous doses of 0.01, 0.025 and 0.05 mg/kg/day liraglutide from gestation day 6 through day 18 inclusive, had estimated systemic exposures less than the human exposure at the MRHD of 1.8 mg/day at all doses, based on plasma AUC. Liraglutide decreased fetal weight and dose dependently increased the incidence of total major fetal abnormalities at all doses. The incidence of malformations exceeded concurrent and historical controls at 0.01 mg/kg/day (kidneys, scapula), ≥ 0.01 mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral vertebrae, major blood vessels and heart, umbilicus), ≥ 0.025 mg/kg/day (sternum) and at 0.05 mg/kg/day (parietal bones, major blood vessels). Irregular ossification and/or skeletal abnormalities occurred in the skull and jaw, vertebrae and ribs, sternum, pelvis, tail, and scapula; and dose-dependent minor skeletal variations were observed. Visceral abnormalities occurred in blood vessels, lung, liver, and esophagus. Bilobed or bifurcated gallbladder was seen in all treatment groups, but not in the control group.

In pregnant female rats given subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day liraglutide from gestation day 6 through weaning or termination of nursing on lactation day 24, estimated systemic exposures were 0.8-, 3-, and 11-times human exposure at the MRHD of 1.8 mg/day, based on plasma AUC. A slight delay in parturition was observed in the majority of treated rats. Group mean body weight of neonatal rats from liraglutide-treated dams was lower than neonatal rats from control group dams. Bloody scabs and agitated behavior occurred in male rats descended from dams treated with 1 mg/kg/day liraglutide. Group mean body weight from birth to postpartum day 14 trended lower in F2 generation rats descended from liraglutide-treated rats compared to F2 generation rats descended from controls, but differences did not reach statistical significance for any group.

Lactation

Risk Summary

There are no data on the presence of liraglutide or insulin degludec in human milk, the effects on the breastfed infant, or the effects on milk production. In lactating rats, insulin degludec and liraglutide, the two components of XULTOPHY 100/3.6, were present in milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XULTOPHY 100/3.6 and any potential adverse effects on the breastfed infant from XULTOPHY 100/3.6 or from the underlying maternal condition.

Data

Insulin degludec

In lactating rats, insulin degludec was present in milk at a concentration lower than that in plasma.

Liraglutide

In lactating rats, liraglutide was present unchanged in milk at concentrations approximately 50% of maternal plasma concentrations.

Pediatric Use

Safety and effectiveness of XULTOPHY 100/3.6 have not been established in pediatric patients.

Geriatric Use

Of the total number of 1881 subjects in clinical studies of XULTOPHY 100/3.6, 375 (19.9%) were 65 years and over, while 52 (2.8%) were 75 years and over [see Clinical Studies ]. No overall differences in safety or effectiveness of XULTOPHY 100/3.6 were observed between patients 65 years of age and older and younger patients.

Age had no clinically relevant effect on the pharmacokinetics of XULTOPHY 100/3.6 [see Clinical Pharmacology ].

In geriatric patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be more difficult to recognize in geriatric patients.

Renal Impairment

XULTOPHY 100/3.6

There is limited experience with XULTOPHY 100/3.6 in patients with mild and moderate kidney impairment and when used in these patients, additional glucose monitoring and XULTOPHY 100/3.6 dose adjustments may be required on an individual basis. XULTOPHY 100/3.6 has not been studied in patients with severe kidney impairment [see Warnings and Precautions and Clinical Pharmacology ].

Insulin degludec

No clinically relevant difference in the pharmacokinetics of insulin degludec was identified in a study comparing healthy subjects and subjects with kidney impairment including subjects with end stage kidney disease.

Liraglutide

The safety and efficacy of liraglutide was evaluated in a 26 week clinical study that included patients with moderate kidney impairment (eGFR 30 to 60 mL/min/1.73 m2). In the liraglutide treatment arm of a cardiovascular outcomes trial (LEADER trial) [see Clinical Studies ], 1932 (41.4%) patients had mild kidney impairment, 999 (21.4%) patients had moderate renal impairment and 117 (2.5%) patients had severe kidney impairment at baseline. No overall differences in safety or efficacy were seen in these patients compared to patients with normal kidney function.

There is limited experience with liraglutide in patients with end stage kidney disease. There have been postmarketing reports of acute kidney failure and worsening of chronic kidney failure, which may sometimes require hemodialysis [see Warnings and Precautions and Adverse Reactions ].

Hepatic Impairment

XULTOPHY 100/3.6

XULTOPHY 100/3.6 has not been studied in patients with hepatic impairment.

Insulin degludec

No clinically relevant difference in the pharmacokinetics of insulin degludec, one of the components of XULTOPHY 100/3.6, was identified in a study comparing healthy subjects and subjects with hepatic impairment (mild, moderate, and severe hepatic impairment) [see Clinical Pharmacology ].

Liraglutide

There is limited experience in patients with mild, moderate or severe hepatic impairment with liraglutide, one of the components of XULTOPHY 100/3.6 [see Clinical Pharmacology ].

Gastroparesis

Liraglutide, one of the components of XULTOPHY 100/3.6, slows gastric emptying. XULTOPHY 100/3.6 has not been studied in patients with pre-existing gastroparesis.