Prescription Drug Information: Zegalogue (Page 2 of 5)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on dasiglucagon use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

Untreated hypoglycemia in pregnancy can cause complications and may be fatal.

In animal reproduction studies, daily subcutaneous administration of dasiglucagon to pregnant rabbits and rats during the period of organogenesis did not cause adverse developmental effects at exposures 7 and 709 times the human dose of 0.6 mg based on AUC, respectively (see Data) .

Data

Animal Data

In an embryo-fetal development study, pregnant rats were treated daily with subcutaneous doses of 2, 10, and 24 mg/kg/day during the period of organogenesis (gestation day 6 to 17). Maternal toxicity, in terms of decreased body weight gain, lower fetal body weight, and delayed bone ossification, was observed at ≥10 mg/kg/day (≥475 times the human dose, based on AUC).

In an embryo-fetal development study, pregnant rabbits were treated daily with subcutaneous doses of 0.1, 0.3, and 1 mg/kg/day during the period of organogenesis (gestation day 6 to 19). Lower fetal body weight and delayed bone ossification were observed at 1 mg/kg/day (100 times the human dose, based on AUC), a dose that also induced maternal toxicity in terms of decreased body weight gain. At ≥0.3 mg/kg/day (≥20 times the human dose), dasiglucagon caused fetal skeletal and visceral malformations. No adverse fetal developmental effects were observed at 0.1 mg/kg/day, corresponding to exposure 7 times the human dose.

8.2 Lactation

Risk Summary

There is no information on the presence of dasiglucagon in either human or animal milk, or the effects of the drug on the breastfed infant or milk production. Dasiglucagon is a peptide and would be expected to be broken down to its constituent amino acids in the infant’s digestive tract and is therefore unlikely to cause harm to an exposed infant.

8.4 Pediatric Use

The safety and effectiveness of ZEGALOGUE for the treatment of severe hypoglycemia in patients with diabetes have been established in pediatric patients aged 6 years and above. Use of ZEGALOGUE for this indication is supported by evidence from a study in 42 pediatric patients with type 1 diabetes [see Clinical Studies (14.2)] .

The safety and effectiveness of ZEGALOGUE have not been established in pediatric patients younger than 6 years of age.

8.5 Geriatric Use

Clinical studies of ZEGALOGUE included too few patients 65 years of age and older to determine whether these patients respond differently from younger adult patients.

10 OVERDOSAGE

If overdosage occurs, the patient may experience nausea, vomiting, inhibition of GI tract motility, and/or increases in blood pressure and heart rate. In case of suspected overdosing, serum potassium may decrease and should be monitored and corrected if needed. If the patient develops a marked increase in blood pressure, phentolamine mesylate has been shown to be effective in lowering blood pressure for the short time that control would be needed.

Appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.

11 DESCRIPTION

ZEGALOGUE contains dasiglucagon hydrochloride, which is a glucagon analog and an antihypoglycemic agent. Dasiglucagon is comprised of 29 amino acids. The molecular formula of dasiglucagon (anhydrous, free-base) is C 152 H 222 N 38 O 50 , and its molecular mass is 3382 g/mol (anhydrous, free-base). Dasiglucagon hydrochloride has the following chemical structure:

Chemical Structure
(click image for full-size original)

ZEGALOGUE injection is a preservative free, sterile, aqueous, clear, and colorless solution for subcutaneous use in a single-dose prefilled syringe and an autoinjector. Each prefilled syringe and autoinjector contains 0.63 mg of dasiglucagon provided as dasiglucagon hydrochloride, which is a salt with 3 — 5 equivalents of hydrochloride, and contains the following inactive ingredients: 3.82 mg tromethamine, 6.44 mg sodium chloride, and water for injection. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH to 6.5.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Dasiglucagon is a glucagon receptor agonist, which increases blood glucose concentration by activating hepatic glucagon receptors, thereby stimulating glycogen breakdown and release of glucose from the liver. Hepatic stores of glycogen are necessary for dasiglucagon to produce an antihypoglycemic effect.

12.2 Pharmacodynamics

After administration of ZEGALOGUE in adult patients with type 1 diabetes, the mean glucose increase from baseline at 90 minutes was 168 mg/dL (Figure 1).

Figure 1
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Figure 1 Mean plasma glucose over time in adults with type 1 diabetes administered 0.6 mg dasiglucagon

In pediatric patients (7 to 17 years) with type 1 diabetes, the mean glucose increase at 60 minutes after administration of ZEGALOGUE was 162 mg/dL (Figure 2).

Figure 2
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Figure 2 Mean plasma glucose over time in pediatric patients with type 1 diabetes administered 0.6 mg dasiglucagon

Cardiac Electrophysiology

At a dose resulting in more than 5 times the concentration achieved with the recommended therapeutic dose, ZEGALOGUE does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

Absorption

ZEGALOGUE absorption following subcutaneous injection of 0.6 mg resulted in a mean peak plasma concentration of 5110 pg/mL (1510 pmol/L) at around 35 minutes.

Distribution

The mean apparent volume of distribution was 47 L to 57 L following subcutaneous administration.

Elimination

The half-life was approximately 30 minutes.

Metabolism

Metabolism data indicated that dasiglucagon is cleared like native glucagon through proteolytic degradation pathways in blood, liver, and kidney.

Specific Populations

After administration of ZEGALOGUE in pediatric patients with type 1 diabetes, the mean peak plasma concentration of 3920 pg/mL occurred at around 21 minutes.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals to evaluate carcinogenicity of dasiglucagon have not been performed.

Mutagenesis

Dasiglucagon was not mutagenic or clastogenic in a standard battery of genotoxicity tests: bacterial mutagenicity (Ames), human lymphocyte chromosome aberration, and rat bone marrow micronucleus.

Impairment of Fertility

In a fertility and early embryofetal development study in rats, dasiglucagon administered by subcutaneous injection (0.5, 2, and 8 mg/kg/day) did not impair fertility in male and female rats at exposures 179 and 269 times the human dose of 0.6 mg (based on AUC), respectively.

14 CLINICAL STUDIES

Three randomized, double-blind, placebo-controlled, multicenter trials were conducted in patients with type 1 diabetes. Two trials (Trial A and Trial B) were conducted in adult patients, and one trial (Trial C) was conducted in pediatric patients aged 6 to 17 years. In all 3 trials, patients were randomized to ZEGALOGUE 0.6 mg, placebo, or (in Trials A and C) glucagon for injection 1.0 mg. ZEGALOGUE and the comparators were administered as single subcutaneous injections following a controlled induction of hypoglycemia using intravenous administration of insulin. During this procedure, a plasma glucose concentration of <60 mg/dL was targeted in Trials A and B, whereas the target was <80 mg/dL in Trial C.

The primary efficacy endpoint for all 3 trials was time to plasma glucose recovery (treatment success), defined as an increase in blood glucose of ≥20 mg/dL from time of administration, without additional intervention within 45 minutes. In Trials A and B, plasma glucose values were collected and assessed at pre-dose, and at 4, 6, 8, 10, 12, 15, 17, 20, 25, 30, 40, 45, 50, 60, 75, 90 minutes after treatment. Trial C assessed plasma glucose at the same timepoints as did Trials A and B, with the exception of the 25, 40, 50, 75 and 90-minute post-treatment timepoints. The primary hypothesis test was superiority of ZEGALOGUE versus placebo. There was no formal hypothesis test of ZEGALOGUE versus glucagon for injection.

14.1 Adult Patients

Trial A, NCT03378635: A total of 170 patients were randomized 2:1:1 to ZEGALOGUE, placebo, and glucagon for injection, stratified by injection sites (abdominal region, buttocks, thigh). The mean age of the patients was 39.1 years (96% were < 65 years), and the mean duration of diabetes was 20.0 years; 63% were male; 92% were White. The mean baseline plasma glucose was 58.8 mg/dL. The median time to plasma glucose recovery was statistically significantly shorter for ZEGALOGUE (10 minutes) versus placebo (40 minutes) (Table 4). Figure 3 shows the cumulative proportions of patients achieving plasma glucose recovery over time. The median time to plasma glucose recovery was numerically similar between ZEGALOGUE (10 minutes) and glucagon for injection (12 minutes).

Trial B, NCT03688711: A total of 45 patients were randomized 3:1 to ZEGALOGUE and placebo stratified by injection sites (buttocks, deltoid). The mean age of the patients was 41.0 years (95% were < 65 years), and the mean duration of diabetes was 22.5 years; 57% were male; 93% were White. The mean baseline plasma glucose was 55.0 mg/dL. The median time to plasma glucose recovery was statistically significantly shorter for ZEGALOGUE (10 minutes) versus placebo (35 minutes) (Table 4).

Table 4 Plasma Glucose Recovery in Adult Patients
Trial ATrial B
ZEGALOGUE N=82 Placebo N=43 ZEGALOGUE N=34 Placebo N=10
N is the number of patients who were randomized and treated.
*
log-log confidence interval
p < 0.001 versus placebo (log-rank test stratified by injection sites)
Median time to recovery [95% CI *] 10 min [10; 10] 40 min [30; 40] 10 min [8; 12] 35 min [20; -)
Figure 3
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Figure 3 Time to plasma glucose recovery in Trial A

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