Dosage & Administration
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Xultophy Prescribing Information
• Liraglutide, one of the components of XULTOPHY 100/3.6, causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether XULTOPHY 100/3.6 causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined[see Warnings and Precautions (5.1 Risk of Thyroid C-cell TumorsLiraglutide, one of the components of XULTOPHY 100/3.6, causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice
[see Nonclinical Toxicology ]. Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether XULTOPHY 100/3.6 will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined.Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans.
XULTOPHY 100/3.6 is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of XULTOPHY 100/3.6 and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness).
Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with XULTOPHY 100/3.6. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.
) and Nonclinical Toxicology (.)]13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityXULTOPHY 100/3.6No studies have been conducted with the XULTOPHY 100/3.6 combination to evaluate carcinogenesis, mutagenesis or impairment of fertility. The following data are based upon studies with insulin degludec and liraglutide individually.
Insulin degludecStandard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of insulin degludec.
In a 52-week study including human insulin (NPH insulin) as comparator, Sprague-Dawley rats were dosed subcutaneously with insulin degludec at 3.3, 6.7, and 10 U/kg/day, resulting in 5 times the human exposure (AUC) when compared to a human subcutaneous dose of 0.75 U/kg/day. Human insulin was dosed at 6.7 U/kg/day. No treatment-related increases in incidences of hyperplasia, benign or malignant tumors were recorded in female mammary glands from rats dosed with insulin degludec and no treatment related changes in the female mammary gland cell proliferation were found using BrdU incorporation. Further, no treatment related changes in the occurrence of hyperplastic or neoplastic lesions were seen in any animals dosed with insulin degludec when compared to vehicle or human insulin.
Genotoxicity testing of insulin degludec was not performed.
In a combined fertility and embryo-fetal study in male and female rats, treatment with insulin degludec up to 21 U/kg/day (approximately 5 times the human subcutaneous dose of 0.75 U/kg/day, based on U/body surface area) prior to mating and in female rats during gestation had no effect on mating performance and fertility.
LiraglutideA 104-week carcinogenicity study was conducted in male and female CD-1 mice at doses of 0.03, 0.2, 1.0, and 3.0 mg/kg/day liraglutide administered by bolus subcutaneous injection yielding systemic exposures 0.2-, 2-, 10- and 45-times the human exposure, respectively, at the MRHD of 1.8 mg/day based on plasma AUC comparison. A dose-related increase in benign thyroid C-cell adenomas was seen in the 1.0 and the 3.0 mg/kg/day groups with incidences of 13% and 19% in males and 6% and 20% in females, respectively. C-cell adenomas did not occur in control groups or 0.03 and 0.2 mg/kg/day groups. Treatment-related malignant C-cell carcinomas occurred in 3% of females in the 3.0 mg/kg/day group. Thyroid C-cell tumors are rare findings during carcinogenicity testing in mice. A treatment-related increase in fibrosarcomas was seen on the dorsal skin and subcutis, the body surface used for drug injection, in males in the 3 mg/kg/day group. These fibrosarcomas were attributed to the high local concentration of drug near the injection site. The liraglutide concentration in the clinical formulation (6 mg/mL) is 10-times higher than the concentration in the formulation used to administer 3 mg/kg/day liraglutide to mice in the carcinogenicity study (0.6 mg/mL).
A 104-week carcinogenicity study was conducted in male and female Sprague Dawley rats at doses of 0.075, 0.25 and 0.75 mg/kg/day liraglutide administered by bolus subcutaneous injection with exposures 0.5-, 2- and 8-times the human exposure, respectively, resulting from the MRHD based on plasma AUC comparison. A treatment-related increase in benign thyroid C-cell adenomas was seen in males in 0.25 and 0.75 mg/kg/day liraglutide groups with incidences of 12%, 16%, 42%, and 46% and in all female liraglutide-treated groups with incidences of 10%, 27%, 33%, and 56% in 0 (control), 0.075, 0.25, and 0.75 mg/kg/day groups, respectively. A treatment-related increase in malignant thyroid C-cell carcinomas was observed in all male liraglutide-treated groups with incidences of 2%, 8%, 6%, and 14% and in females at 0.25 and 0.75 mg/kg/day with incidences of 0%, 0%, 4%, and 6% in 0 (control), 0.075, 0.25, and 0.75 mg/kg/day groups, respectively. Thyroid C-cell carcinomas are rare findings during carcinogenicity testing in rats.
Studies in mice demonstrated that liraglutide-induced C-cell proliferation was dependent on the GLP-1 receptor and that liraglutide did not cause activation of the REarranged during Transfection (RET) proto-oncogene in thyroid C-cells.
Human relevance of thyroid C-cell tumors in mice and rats is unknown and has not been determined by clinical studies or nonclinical studies
[see Boxed Warning, Warnings, Precautions ].Liraglutide was negative with and without metabolic activation in the Ames test for mutagenicity and in a human peripheral blood lymphocyte chromosome aberration test for clastogenicity. Liraglutide was negative in repeat-dose
in vivomicronucleus tests in rats.In rat fertility studies using subcutaneous doses of 0.1, 0.25 and 1 mg/kg/day liraglutide, males were treated for 4 weeks prior to and throughout mating and females were treated 2 weeks prior to and throughout mating until gestation day 17. No direct adverse effects on male fertility was observed at doses up to 1 mg/kg/day, a high dose yielding an estimated systemic exposure 11- times the human exposure at the MRHD, based on plasma AUC. In female rats, an increase in early embryonic deaths occurred at 1 mg/kg/day. Reduced body weight gain and food consumption were observed in females at the 1 mg/kg/day dose.
• XULTOPHY 100/3.6 is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of XULTOPHY 100/3.6 and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with XULTOPHY 100/3.6[see Contraindications (.), Warnings and Precautions (4 CONTRAINDICATIONSXULTOPHY 100/3.6 is contraindicated:
• In patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)[see Warnings and Precautions ].• During episodes of hypoglycemia[see Warnings and Precautions ].• In patients with hypersensitivity to insulin degludec, liraglutide, or any of the excipients in XULTOPHY 100/3.6. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with liraglutide, one of the components of XULTOPHY 100/3.6[see Warnings and Precautions ].
• Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2• During episodes of hypoglycemia• Patients with a serious hypersensitivity reaction to insulin degludec, liraglutide, or any of the excipients in XULTOPHY 100/3.6
)]5.1 Risk of Thyroid C-cell TumorsLiraglutide, one of the components of XULTOPHY 100/3.6, causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice
[see Nonclinical Toxicology ]. Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether XULTOPHY 100/3.6 will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined.Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans.
XULTOPHY 100/3.6 is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of XULTOPHY 100/3.6 and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness).
Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with XULTOPHY 100/3.6. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.
Indications and Usage…………………………05/2025
Warnings and Precautions, Severe Gastrointestinal Adverse Reactions (
Severe, life-threatening, generalized allergy, including anaphylaxis, angioedema, bronchospasm, hypotension, and shock can occur with insulins, including XULTOPHY 100/3.6. Allergic reactions (manifested with signs and symptoms such as urticaria, rash, pruritus) have been reported with XULTOPHY 100/3.6. There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with liraglutide, one of the components of XULTOPHY 100/3.6
Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to these reactions with XULTOPHY 100/3.6. XULTOPHY 100/3.6 is contraindicated in patients who have had hypersensitivity reactions to insulin degludec, liraglutide or one of the excipients of these products
Warnings and Precaution, Pulmonary Aspiration During General Anesthesia or Deep Sedation………..11/2024
XULTOPHY 100/3.6 is a combination of insulin degludec and liraglutide and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
• XULTOPHY 100/3.6 contains liraglutide. Coadministration with any other product containing liraglutide or another glucagon-like peptide-1 (GLP-1) receptor agonist is not recommended [see Warnings and Precautions (5.5 Overdose due to Medication ErrorsXULTOPHY 100/3.6 contains two drugs: insulin degludec and liraglutide. Administration of more than 50 units of XULTOPHY 100/3.6 daily can result in overdose of the liraglutide component. Do not exceed the 1.8 mg maximum recommended dose of liraglutide or use with other GLP-1 receptor agonists.
Accidental mix-ups between insulin products have been reported. To avoid medication errors between XULTOPHY 100/3.6 (an insulin containing product) and other insulin products, instruct patients to always check the label before each injection.
)].• XULTOPHY 100/3.6 is not recommended for the treatment of diabetic ketoacidosis.• XULTOPHY 100/3.6 has not been studied in combination with prandial insulin.
• Administer once daily at same time each day with or without food ().2.1 Important Dosage Information• XULTOPHY 100/3.6 is a combination of insulin degludec and liraglutide.• Administer XULTOPHY 100/3.6 by subcutaneous injection once-daily at the same time each day with or without food.• The XULTOPHY 100/3.6 pen delivers doses from 10 to 50 units with each injection.Table 1presents the units of insulin degludec and the milligrams of liraglutide in each dosage of XULTOPHY 100/3.6[see Dosage and Administration ].• 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 ].
• XULTOPHY 100/3.6 pen delivers doses from 10 to 50 units with each injection (,2.1 Important Dosage Information• XULTOPHY 100/3.6 is a combination of insulin degludec and liraglutide.• Administer XULTOPHY 100/3.6 by subcutaneous injection once-daily at the same time each day with or without food.• The XULTOPHY 100/3.6 pen delivers doses from 10 to 50 units with each injection.Table 1presents the units of insulin degludec and the milligrams of liraglutide in each dosage of XULTOPHY 100/3.6[see Dosage and Administration ].• 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 ].
); each XULTOPHY 100/3.6 dosage unit contains 1 unit of insulin degludec and 0.036 mg of liraglutide (2.2 Recommended Starting DosageIn patients naïve to basal insulin or a GLP-1 receptor agonist• 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 (seeTable 1).
In patients currently on basal insulin or a GLP-1 receptor agonist• Discontinue therapy with basal insulin or GLP-1 receptor agonist prior to initiation of XULTOPHY 100/3.6.• 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 (seeTable 1).
Table 1. Units of Insulin Degludec and Milligrams of Liraglutide in Each Dosage of XULTOPHY 100/3.6XULTOPHY 100/3.6(dose counter display)*insulin degludeccomponent doseliraglutidecomponent doseComment▪▪ ─
---
---
Priming symbol
10
10 units
0.36 mg
Recommended starting dose for patients naïve to basal insulin or GLP-1 receptor agonist11
11 units
0.4 mg
12
12 units
0.43 mg
13
13 units
0.47 mg
14
14 units
0.5 mg
15
15 units
0.54 mg
1616 units0.58 mg- Recommended starting dose for patients currently on basal insulin or GLP-1 receptor agonist
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
0.9 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
1.3 mg
37
37 units
1.33 mg
38
38 units
1.37 mg
39
39 units
1.4 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
5050 units1.8 mgMaximum daily dosage[see Warnings and Precautions (5.5)]*The dose counter on the XULTOPHY 100/3.6 pen displays numbers for the even units and displays lines for the odd units.
).2.1 Important Dosage Information• XULTOPHY 100/3.6 is a combination of insulin degludec and liraglutide.• Administer XULTOPHY 100/3.6 by subcutaneous injection once-daily at the same time each day with or without food.• The XULTOPHY 100/3.6 pen delivers doses from 10 to 50 units with each injection.Table 1presents the units of insulin degludec and the milligrams of liraglutide in each dosage of XULTOPHY 100/3.6[see Dosage and Administration ].• 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 ].
• Maximum daily dosage is 50 units (50 units of insulin degludec and 1.8 mg of liraglutide) ().2.1 Important Dosage Information• XULTOPHY 100/3.6 is a combination of insulin degludec and liraglutide.• Administer XULTOPHY 100/3.6 by subcutaneous injection once-daily at the same time each day with or without food.• The XULTOPHY 100/3.6 pen delivers doses from 10 to 50 units with each injection.Table 1presents the units of insulin degludec and the milligrams of liraglutide in each dosage of XULTOPHY 100/3.6[see Dosage and Administration ].• 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 GLP-1 receptor agonist is 10 units (10 units of insulin degludec and 0.36 mg of liraglutide) injected subcutaneously once-daily).2.2 Recommended Starting DosageIn patients naïve to basal insulin or a GLP-1 receptor agonist• 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 (seeTable 1).
In patients currently on basal insulin or a GLP-1 receptor agonist• Discontinue therapy with basal insulin or GLP-1 receptor agonist prior to initiation of XULTOPHY 100/3.6.• 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 (seeTable 1).
Table 1. Units of Insulin Degludec and Milligrams of Liraglutide in Each Dosage of XULTOPHY 100/3.6XULTOPHY 100/3.6(dose counter display)*insulin degludeccomponent doseliraglutidecomponent doseComment▪▪ ─
---
---
Priming symbol
10
10 units
0.36 mg
Recommended starting dose for patients naïve to basal insulin or GLP-1 receptor agonist11
11 units
0.4 mg
12
12 units
0.43 mg
13
13 units
0.47 mg
14
14 units
0.5 mg
15
15 units
0.54 mg
1616 units0.58 mg- Recommended starting dose for patients currently on basal insulin or GLP-1 receptor agonist
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
0.9 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
1.3 mg
37
37 units
1.33 mg
38
38 units
1.37 mg
39
39 units
1.4 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
5050 units1.8 mgMaximum daily dosage[see Warnings and Precautions (5.5)]*The dose counter on the XULTOPHY 100/3.6 pen displays numbers for the even units and displays lines for the odd units.
• Discontinue therapy with liraglutide or basal insulin prior to initiation of XULTOPHY 100/3.6 ().2.2 Recommended Starting DosageIn patients naïve to basal insulin or a GLP-1 receptor agonist• 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 (seeTable 1).
In patients currently on basal insulin or a GLP-1 receptor agonist• Discontinue therapy with basal insulin or GLP-1 receptor agonist prior to initiation of XULTOPHY 100/3.6.• 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 (seeTable 1).
Table 1. Units of Insulin Degludec and Milligrams of Liraglutide in Each Dosage of XULTOPHY 100/3.6XULTOPHY 100/3.6(dose counter display)*insulin degludeccomponent doseliraglutidecomponent doseComment▪▪ ─
---
---
Priming symbol
10
10 units
0.36 mg
Recommended starting dose for patients naïve to basal insulin or GLP-1 receptor agonist11
11 units
0.4 mg
12
12 units
0.43 mg
13
13 units
0.47 mg
14
14 units
0.5 mg
15
15 units
0.54 mg
1616 units0.58 mg- Recommended starting dose for patients currently on basal insulin or GLP-1 receptor agonist
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
0.9 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
1.3 mg
37
37 units
1.33 mg
38
38 units
1.37 mg
39
39 units
1.4 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
5050 units1.8 mgMaximum daily dosage[see Warnings and Precautions (5.5)]*The dose counter on the XULTOPHY 100/3.6 pen displays numbers for the even units and displays lines for the odd units.
• Recommended starting dosage in patients currently on basal insulin or GLP-1 receptor agonist is 16 units (16 units of insulin degludec and 0.58 mg of liraglutide) injected subcutaneously once-daily ().2.2 Recommended Starting DosageIn patients naïve to basal insulin or a GLP-1 receptor agonist• 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 (seeTable 1).
In patients currently on basal insulin or a GLP-1 receptor agonist• Discontinue therapy with basal insulin or GLP-1 receptor agonist prior to initiation of XULTOPHY 100/3.6.• 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 (seeTable 1).
Table 1. Units of Insulin Degludec and Milligrams of Liraglutide in Each Dosage of XULTOPHY 100/3.6XULTOPHY 100/3.6(dose counter display)*insulin degludeccomponent doseliraglutidecomponent doseComment▪▪ ─
---
---
Priming symbol
10
10 units
0.36 mg
Recommended starting dose for patients naïve to basal insulin or GLP-1 receptor agonist11
11 units
0.4 mg
12
12 units
0.43 mg
13
13 units
0.47 mg
14
14 units
0.5 mg
15
15 units
0.54 mg
1616 units0.58 mg- Recommended starting dose for patients currently on basal insulin or GLP-1 receptor agonist
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
0.9 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
1.3 mg
37
37 units
1.33 mg
38
38 units
1.37 mg
39
39 units
1.4 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
5050 units1.8 mgMaximum daily dosage[see Warnings and Precautions (5.5)]*The dose counter on the XULTOPHY 100/3.6 pen displays numbers for the even units and displays lines for the odd units.
• See Full Prescribing Information for titration recommendations ().2.3 Titration of XULTOPHY 100/3.6• After starting the recommended starting dosage of XULTOPHY 100/3.6[see Dosage and Administration ], titrate the dosage upwards or downwards by two units (seeTable 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.• 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 , Drug Interactions ].
Table 2. Recommended Titration of XULTOPHY 100/3.6 (Once or Twice Weekly)Self-Monitored Fasting Plasma GlucoseXULTOPHY 100/3.6 Dosage AdjustmentAbove target range
+ 2 units (2 units of insulin degludec and 0.072 mg of liraglutide)
Within target range
0 units
Below target range
- 2 units (2 units of insulin degludec and 0.072 mg of liraglutide)
• Inject XULTOPHY 100/3.6 subcutaneously into the thigh, upper arm, or abdomen ().2.5 Important Administration Instructions• The XULTOPHY 100/3.6 pen is for single-patient-use only[see Warnings and Precautions (5.3)].• Train patients on proper use and injection technique before initiating XULTOPHY 100/3.6.• Always check the label on the XULTOPHY 100/3.6 pen before administration[see Warnings and Precautions(5.5)].• Inspect visually for particulate matter and discoloration prior to administration. Only use XULTOPHY 100/3.6 if the solution appears clear and colorless.• Inject XULTOPHY 100/3.6 subcutaneously into the thigh, upper arm, or abdomen.• 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 ].• During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring[see Warnings and Precautions ].• Use XULTOPHY 100/3.6 with caution in patients with visual impairment who may rely on audible clicks to dial their dose.• The XULTOPHY 100/3.6 pen dials in one-unit increments.• Do not administer XULTOPHY 100/3.6 intravenously or in an insulin infusion pump.• Do not dilute or mix XULTOPHY 100/3.6 with any other insulin or solutions.• Do not split the dose of XULTOPHY 100/3.6.
• Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis ().2.5 Important Administration Instructions• The XULTOPHY 100/3.6 pen is for single-patient-use only[see Warnings and Precautions (5.3)].• Train patients on proper use and injection technique before initiating XULTOPHY 100/3.6.• Always check the label on the XULTOPHY 100/3.6 pen before administration[see Warnings and Precautions(5.5)].• Inspect visually for particulate matter and discoloration prior to administration. Only use XULTOPHY 100/3.6 if the solution appears clear and colorless.• Inject XULTOPHY 100/3.6 subcutaneously into the thigh, upper arm, or abdomen.• 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 ].• During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring[see Warnings and Precautions ].• Use XULTOPHY 100/3.6 with caution in patients with visual impairment who may rely on audible clicks to dial their dose.• The XULTOPHY 100/3.6 pen dials in one-unit increments.• Do not administer XULTOPHY 100/3.6 intravenously or in an insulin infusion pump.• Do not dilute or mix XULTOPHY 100/3.6 with any other insulin or solutions.• Do not split the dose of XULTOPHY 100/3.6.
• Do not administer intravenously or by an infusion pump ().2.5 Important Administration Instructions• The XULTOPHY 100/3.6 pen is for single-patient-use only[see Warnings and Precautions (5.3)].• Train patients on proper use and injection technique before initiating XULTOPHY 100/3.6.• Always check the label on the XULTOPHY 100/3.6 pen before administration[see Warnings and Precautions(5.5)].• Inspect visually for particulate matter and discoloration prior to administration. Only use XULTOPHY 100/3.6 if the solution appears clear and colorless.• Inject XULTOPHY 100/3.6 subcutaneously into the thigh, upper arm, or abdomen.• 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 ].• During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring[see Warnings and Precautions ].• Use XULTOPHY 100/3.6 with caution in patients with visual impairment who may rely on audible clicks to dial their dose.• The XULTOPHY 100/3.6 pen dials in one-unit increments.• Do not administer XULTOPHY 100/3.6 intravenously or in an insulin infusion pump.• Do not dilute or mix XULTOPHY 100/3.6 with any other insulin or solutions.• Do not split the dose of XULTOPHY 100/3.6.
• Do not dilute or mix with any other insulin products or solutions ().2.5 Important Administration Instructions• The XULTOPHY 100/3.6 pen is for single-patient-use only[see Warnings and Precautions (5.3)].• Train patients on proper use and injection technique before initiating XULTOPHY 100/3.6.• Always check the label on the XULTOPHY 100/3.6 pen before administration[see Warnings and Precautions(5.5)].• Inspect visually for particulate matter and discoloration prior to administration. Only use XULTOPHY 100/3.6 if the solution appears clear and colorless.• Inject XULTOPHY 100/3.6 subcutaneously into the thigh, upper arm, or abdomen.• 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 ].• During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring[see Warnings and Precautions ].• Use XULTOPHY 100/3.6 with caution in patients with visual impairment who may rely on audible clicks to dial their dose.• The XULTOPHY 100/3.6 pen dials in one-unit increments.• Do not administer XULTOPHY 100/3.6 intravenously or in an insulin infusion pump.• Do not dilute or mix XULTOPHY 100/3.6 with any other insulin or solutions.• Do not split the dose of XULTOPHY 100/3.6.
Injection: 100 units/mL insulin degludec and 3.6 mg/mL liraglutide available as a clear, colorless solution in a 3 mL pre-filled, disposable, single-patient-use pen injector.
Pregnancy: XULTOPHY 100/3.6 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (
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
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
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
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 pregestational 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.
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, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, macrosomia related morbidity.
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.
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.