TRULICITY

Dulaglutide, marketed by Eli Lilly as Trulicity, is a once-weekly subcutaneous glucagon-like peptide-1 (GLP-1) receptor agonist designed using recombinant DNA technology; it has been approved as an adjunct therapy to diet and exercise in the management of 2 diabetes (T2DM).

Dulaglutide was initially approved by the

FDA in 2014, and in February was approved for use in patients with T2DM and multiple cardiovascular risk factors for the prevention of cardiovascular events.

It is the first

T2DM drug approved to reduce major adverse cardiovascular events (MACE) risk in primary and secondary prevention populations.

Dulaglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients ≥10 years of age with type 2 diabetes mellitus.

It is also indicated to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors.

Dulaglutide reduces fasting glucose concentrations and reduces postprandial glucose (PPG) concentrations in patients with type 2 diabetes mellitus through the agonism of the GLP-1 receptor.

This drug primarily acts as an incretin mimetic hormone or analog of human glucagon-like peptide-1, which normally acts on the GLP-1 receptor.

Dulaglutide is slowly absorbed after subcutaneous injection.

In a pharmacokinetic study of 20 healthy adults, Cmax occurred within 24-48 hours after dosing.

The average absolute bioavailability of dulaglutide after subcutaneous injections of single 0.75 mg and 1.5 mg doses was 65% and 47%, respectively.

The apparent volume of distribution of dulaglutide was 3.09 L in a pharmacokinetic study; the apparent population mean peripheral volume of distribution was approximately 6 L.

Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways.

Elimination of dulaglutide is expected to occur through degradation to individual amino acids.

In a pharmacokinetic study of 20 healthy adults, the average half-life of dulaglutide administered at various doses was approximately 3.75 days (89.9 hours).

This extended half-life allows for once-weekly dosing.

Prescribing information indicates a half-life of approximately 5 days.

The apparent population mean clearance of dulaglutide was 0.142 L/h in a pharmacokinetic study.

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LD50 information for dulaglutide is not readily available in the literature.

Cases of overdose with dulaglutide have resulted in gastrointestinal disturbance.

Appropriate supportive treatment is recommended to manage signs and symptoms.

Additionally, hypoglycemia has been observed after an overdose with dulaglutide; frequent plasma glucose monitoring should be performed.

is contraindicated in patients with: Personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) .

Serious hypersensitivity reaction to dulaglutide or to any of the product components.

Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with TRULICITY.

Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.

Patients with a serious hypersensitivity reaction to dulaglutide or any of the product components.

Recommended starting dosage is 0.75 mg injected subcutaneously once weekly.

Increase dosage to 1.5 mg once weekly for additional glycemic control.

If additional glycemic control is needed, increase dosage in 1.5 mg increments after at least 4 weeks on the current dosage.

Maximum recommended dosage is 4.5 mg injected subcutaneously once weekly.

If additional glycemic control is needed, increase dosage to the maximum recommended dosage of 1.5 mg once weekly after at least 4 weeks on the 0.75 mg dosage.

If a dose is missed, administer the missed dose as soon as possible if there are at least 3 days (72 hours) until the next scheduled dose.

Administer once weekly at any time of day with or without food.

Inject subcutaneously in the abdomen, thigh, or upper arm. 2.1 Adult Dosage The recommended starting dosage of TRULICITY is 0.75 mg injected subcutaneously once weekly.

Increase the dosage to 1.5 mg once weekly for additional glycemic control.

If additional glycemic control is needed, increase the dosage in 1.5 mg increments after at least 4 weeks on the current dosage.

The maximum recommended dosage is 4.5 mg injected subcutaneously once weekly. 2.2 Pediatric Dosage The recommended starting dosage of TRULICITY is 0.75 mg injected subcutaneously once weekly.

If additional glycemic control is needed, increase the dosage to the maximum recommended dosage of 1.5 mg once weekly after at least 4 weeks on the 0.75 mg dosage. 2.3 Recommendations Regarding Missed Dose If a dose is missed, instruct patients to administer the dose as soon as possible if there are at least 3 days (72 hours) until the next scheduled dose.

If less than 3 days remain before the next scheduled dose, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule.

The day of weekly administration can be changed, if necessary, as long as the last dose was administered 3 or more days before the new day of administration. 2.4 Important Administration Instructions Prior to initiation, train patients and caregivers on proper injection technique.

TRULICITY once weekly, any time of day, with or without food.

TRULICITY subcutaneously in the abdomen, thigh, or upper arm.

Rotate injection sites with each dose.

TRULICITY visually before use.

It should appear clear and colorless.

Do not use

TRULICITY if particulate matter or coloration is seen.

When using

TRULICITY with insulin, administer as separate injections and never mix.

It is acceptable to inject

TRULICITY and insulin in the same body region, but the injections should not be adjacent to each other.

50090-6571 NDC: 50090-6571-0.5 mL in a SYRINGE / 4 in a CARTON.

Risk Summary Limited data with

TRULICITY in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage.

There are clinical considerations regarding the risks of poorly controlled diabetes in pregnancy.

Based on animal reproduction studies, there may be risks to the fetus from exposure to dulaglutide during pregnancy.

TRULICITY should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In pregnant rats administered dulaglutide during organogenesis, early embryonic deaths, fetal growth reductions, and fetal abnormalities occurred at systemic exposures at least 6-times human exposure at the maximum recommended human dose (MRHD) of 4.5 mg/week.

In pregnant rabbits administered dulaglutide during organogenesis, major fetal abnormalities occurred at 5-times human exposure at the MRHD.

Adverse embryo/fetal effects in animals occurred in association with decreased maternal weight and food consumption attributed to the pharmacology of dulaglutide.

The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with an HbA1c >7% and has been reported to be as high as 20–25% in women with an HbA1c >10%.

The estimated background risk of miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery and delivery complications.

Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.

Pregnant rats given subcutaneous doses of 0.49, 1.63, or 4.89 mg/kg dulaglutide every 3 days during organogenesis had systemic exposures 2-, 6-, and 18-times human exposure at the maximum recommended human dose (MRHD) of 4.5 mg/week, respectively, based on plasma area under the time-concentration curve (AUC) comparison.

Reduced fetal weights associated with decreased maternal food intake and decreased weight gain attributed to the pharmacology of dulaglutide were observed at ≥1.63 mg/kg. Irregular skeletal ossifications and increases in post-implantation loss also were observed at 4.89 mg/kg. In pregnant rabbits given subcutaneous doses of 0.04, 0.12, or 0.41 mg/kg dulaglutide every 3 days during organogenesis, systemic exposures in pregnant rabbits were 0.5-, 2-, and 5-times human exposure at the MRHD, based on plasma AUC comparison.

Fetal visceral malformation of lung lobular agenesis and skeletal malformations of the vertebrae and/or ribs were observed in conjunction with decreased maternal food intake and decreased weight gain attributed to the pharmacology of dulaglutide at 0.41 mg/kg. In a prenatal-postnatal study in F 0 maternal rats given subcutaneous doses of 0.2, 0.49, or 1.63 mg/kg every third day from implantation through lactation, systemic exposures in pregnant rats were 1-, 2-, and 7-times human exposure at the MRHD, based on plasma AUC comparison.

F 1 pups from F 0 maternal rats given 1.63 mg/kg dulaglutide had statistically significantly lower mean body weight from birth through postnatal day for males and postnatal day for females.

F 1 offspring from F 0 maternal rats receiving 1.63 mg/kg dulaglutide had decreased forelimb and hindlimb grip strength and males had delayed balano-preputial separation.

Females had decreased startle response.

These physical findings may relate to the decreased size of the offspring relative to controls as they appeared at early postnatal assessments but were not observed at a later assessment.

F 1 female offspring of the F 0 maternal rats given 1.63 mg/kg of dulaglutide had a longer mean escape time and a higher mean number of errors relative to concurrent control during of 2 trials in the memory evaluation portion of the Biel water maze.

These findings occurred in conjunction with decreased F 0 maternal food intake and decreased weight gain attributed to the pharmacologic activity at 1.63 mg/kg. The human relevance of these memory deficits in the F 1 female rats is not known.

The safety and effectiveness of

TRULICITY as an adjunct to diet and exercise to improve glycemic control in pediatric patients 10 years of age and older with type 2 diabetes mellitus have been established.

Use of

TRULICITY for this indication is supported by a 26-week, multicenter, randomized, double-blind, parallel arm, placebo-controlled trial in 154 pediatric patients 10 years of age and older with type 2 diabetes mellitus.

TRULICITY-treated pediatric patients reported a higher incidence of injection site-related reactions compared to TRULICITY-treated adults.

TRULICITY have not been established in pediatric patients less than 10 years of age.

In the adult glycemic control trials, 620 (19%) of TRULICITY-treated patients were 65 years of age or older and 65 (2%) of TRULICITY-treated patients were 75 years of age or older at baseline.

In the

TRULICITY 1.5 mg treatment arm of the REWIND trial (cardiovascular outcomes trial in adults with type 2 diabetes mellitus and cardiovascular disease or multiple cardiovascular risk factors) , 2,619 (53%) patients were 65 years of age or older, and 484 (10%) patients were 75 years of age or older at baseline.

No overall differences in safety or effectiveness for TRULICITY have been observed between patients 65 years of age and older and younger adult patients.