Trulicity

Question 1

What are the pregnancy-related risks associated with TRULICITY use?

Accepted Answer

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 [see Clinical Considerations]. 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.

Question 2

What is the estimated background risk of major birth defects and miscarriage in women with pre-gestational diabetes?

Accepted Answer

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.

Question 3

What are the clinical considerations regarding pregnancy and TRULICITY use?

Accepted Answer

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.

Question 4

What animal data is available regarding TRULICITY use during pregnancy?

Accepted Answer

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 F0 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. F1 pups from F0 maternal rats given 1.63 mg/kg dulaglutide had statistically significantly lower mean body weight from birth through postnatal day 63 for males and postnatal day 84 for females. F1 offspring from F0 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. F1 female offspring of the F0 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 1 of 2 trials in the memory evaluation portion of the Biel water maze. These findings occurred in conjunction with decreased F0 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 F1 female rats is not known.

Question 5

What are the risks associated with TRULICITY use during lactation?

Accepted Answer

There are no data on the presence of dulaglutide in human milk, the effects on the breastfed infant, or the effects on milk production. The presence of dulaglutide in milk of treated lactating animals was not determined. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TRULICITY and any potential adverse effects on the breastfed infant from TRULICITY or from the underlying maternal condition.

Question 6

Is TRULICITY safe and effective for pediatric use?

Accepted Answer

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 [see Clinical Studies (14.6)].

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

The safety and effectiveness of TRULICITY have not been established in pediatric patients less than 10 years of age.

Question 7

What is the experience with TRULICITY use in geriatric patients?

Accepted Answer

In the adult glycemic control trials [see Clinical Studies (14.2, 14.3)], 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.

Question 8

Is dosage adjustment necessary for patients with renal impairment using TRULICITY?

Accepted Answer

TRULICITY has been studied in patients with varying degrees of renal function, including a dedicated clinical trial in patients with moderate to severe chronic kidney disease. No overall differences in safety or effectiveness were observed in these studies according to renal function.

In a clinical pharmacology study in patients with renal impairment, including end-stage renal disease (ESRD), no clinically relevant change in dulaglutide pharmacokinetics (PK) was observed. In the 52-week trial in patients with type 2 diabetes and moderate to severe renal impairment, the PK behavior of TRULICITY 0.75 mg and 1.5 mg once weekly was similar to that demonstrated in previous clinical studies.

No dose adjustment is recommended in patients with renal impairment including end-stage renal disease (ESRD). Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions. Use TRULICITY with caution in patients with ESRD.

Question 9

Is dosage adjustment necessary for patients with hepatic impairment using TRULICITY?

Accepted Answer

In a clinical pharmacology study in patients with varying degrees of hepatic impairment, no clinically relevant change in dulaglutide PK was observed. However, there is limited clinical experience in patients with mild, moderate, or severe hepatic impairment; therefore, use TRULICITY with caution in these patient populations.

Question 10

What precautions should be taken for patients with gastroparesis using TRULICITY?

Accepted Answer

Dulaglutide slows gastric emptying. TRULICITY has not been studied in patients with preexisting gastroparesis. Use TRULICITY with caution in patients with gastroparesis.