DAWNZERA Solution for injection Ref.[116065] Active ingredients: Donidalorsen

5.1 Risk of Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including anaphylaxis, have been reported in patients treated with DAWNZERA [see Adverse Reactions (6.1)]. If signs and symptoms of serious hypersensitivity reactions occur, discontinue DAWNZERA and institute appropriate therapy.

The following clinically significant adverse reactions are discussed elsewhere in the labeling:

• Risk of Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.1)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of DAWNZERA reflects the exposure in a total of 171 adult and pediatric patients 12 years and older with hereditary angioedema (HAE) from a placebo-controlled trial (OASIS-HAE) [see Clinical Studies (14)], and 2 other clinical studies. The average duration of DAWNZERA treatment exposure across the 3 clinical studies was 14 months.

The safety data below is based on the 24-week multicenter, randomized, double-blind, placebo-controlled trial (OASIS-HAE), in which patients received at least one subcutaneous dose of DAWNZERA 80 mg once every 4 weeks (n=45), DAWNZERA 80 mg once every 8 weeks (n=23), or matching placebo (n=22). Demographics of the patients in OASIS-HAE are summarized in Clinical Studies [see Clinical Studies (14)].

Table 1 provides the most common adverse reactions with DAWNZERA with incidence ≥5% and more common than placebo.

Table 1. Adverse Reactions with DAWNZERA with Incidence ≥5% and More Common than Placebo in Patients with HAE (OASIS-HAE):

N = number of patients; n = number of patients experiencing the event; q4wks = every 4 weeks; q8wks = every 8 weeks.
^* Injection site reactions include: erythema, discoloration, pain, pruritus, induration, bruising, haematoma, hypersensitivity, swelling, reaction, and urticaria.
^† All injection site reactions were mild, nonserious, and the majority of them resolved without receiving any treatment.

Specific Adverse Reactions

Hypersensitivity Reactions, Including Anaphylaxis

In clinical trials, hypersensitivity reactions, including anaphylaxis, have occurred. Symptoms included generalized rash, dyspnea, chest pain, and peri-oral swelling.

Laboratory Tests

Decrease in Platelet Count

DAWNZERA can cause reductions in platelet count. In OASIS-HAE, the mean platelet count at baseline was 266,000/mm³ for the DAWNZERA 80 mg every 4 weeks group, 265,000/mm³ for the DAWNZERA 80 mg every 8 weeks group, and 245,000/mm³ for the placebo group. The mean percent change in platelet count at Week 25 was -9.6% for the DAWNZERA 80 mg every 4 weeks group, -7.9% for the DAWNZERA 80 mg every 8 weeks group, and -1.4% for the placebo group. In OASIS-HAE and 2 other clinical studies no DAWNZERA-treated patient had a platelet count of <50,000/mm³ , and there were no major bleeding events associated with a low platelet count.

Increase in Liver Function Tests

Increases from baseline in liver enzymes (alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase) were observed with DAWNZERA use. The increased levels were generally below 3 times the upper limit of normal and stabilized. Discontinuations due to liver function test increases were infrequent.

The observed incidence of anti‑drug antibodies (ADAs) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of donidalorsen or of other donidalorsen products.

In OASIS-HAE, with a treatment duration up to 24 weeks, the incidence rate of treatment‑emergent ADAs in adult and pediatric patients (≥12 years of age) with HAE was 20% (9 of 45 patients) in the DAWNZERA 80 mg every 4 weeks group and 22% (5 of 23 patients) in the DAWNZERA 80 mg every 8 weeks group. In an open‑label extension trial, patients that rolled over from OASIS-HAE continued treatment with DAWNZERA in the 80 mg every 4 weeks or every 8 weeks groups for up to 3 years (median exposure duration of 227 days). The incidence rate of treatment‑emergent ADAs was 35% (22 of 63 patients) in the DAWNZERA 80 mg every 4 weeks group, including patients initially randomized to DAWNZERA 80 mg every 4 weeks in OASIS-HAE (36%, 16/44) and patients initially randomized to placebo in OASIS-HAE (32%, 6/19). The incidence rate of treatment-emergent ADAs was 21% (3 of 14 patients) among patients who received DAWNZERA 80 mg every 8 weeks in OASIS-HAE and open-label extension.

In general, the development of ADAs was not found to affect the pharmacodynamics, safety, or efficacy of DAWNZERA. An increase in donidalorsen plasma C_trough was observed in ADA-positive patients with high titers. Because of small sample size, the effect of ADA on the pharmacokinetics, pharmacodynamics, safety and effectiveness of DAWNZERA is inconclusive.

Risk Summary

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

In animal reproduction studies, subcutaneous administration of donidalorsen or a pharmacologically active mouse‑specific surrogate in a combined fertility and embryo‑fetal development study in mice and a pre‑ and postnatal development study in mice with F0 parental doses up to 5 times the maximum recommended human dose (MRHD, 80 mg) on a body surface area (BSA, mg/m²) basis did not result in any adverse effects on embryofetal development, or behavioral, fertility, and reproductive development in the F1 offspring. Donidalorsen does not cross the placental barrier (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Data

Animal Data

In reproductive toxicity studies with donidalorsen, the unconjugated form was not detected (below the limit of quantitation) in fetal tissues. Donidalorsen does not cross the placental barrier.

In a combined fertility and embryofetal development study, subcutaneous administration of donidalorsen (up to 10 mg/kg/week [2.5-times the MRHD on a BSA basis]) or a mouse‑specific surrogate (4 mg/kg/week) to male and female F0 mice weekly, prior to and during mating, and continuing every other day in females throughout the periods of implantation and organogenesis (Gestation Days 0 to 16), resulted in no adverse effects on embryofetal development. There was no evidence of maternal toxicity with doses up to 10 mg/kg/week.

In a pre- and postnatal development study, subcutaneous administration of donidalorsen (up to 20 mg/kg/week [5-times the MRHD on a BSA basis]) or a mouse-specific surrogate (5 mg/kg/week) to F0 female mice every other day throughout pregnancy (from Gestation Day 6 to 18) and weekly throughout lactation (from Lactation Day 1 to 20) produced no adverse effects on behavioral, fertility, and reproductive development in the F1 offspring. There was no evidence of maternal toxicity with doses up to 20 mg/kg/week.

Risk Summary

There are no data on the presence of donidalorsen in human milk, the effects on the breast‑fed infant, or the effects on milk production. Donidalorsen was excreted into the milk of lactating mice; however, due to species-specific differences in lactation physiology, animal lactation data may not reliably predict levels in human milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DAWNZERA and any potential adverse effects on the breast‑fed infant from DAWNZERA or from the underlying maternal condition.

Data

Animal Data

In the mouse pre‑ and postnatal development study, the concentrations of donidalorsen in breast milk from lactating mice on Lactation Day 15 increased in a dose‑dependent manner at doses ≥10 mg/kg/week, but these concentrations of donidalorsen in breast milk were lower than the observed concentrations in the liver where the drug is preferentially taken up. Even though donidalorsen was detected in the maternal mouse milk, systemic exposure in pups was not expected due to the lack of oral absorption of donidalorsen.

The safety and effectiveness of DAWNZERA for prophylaxis to prevent attacks of HAE have been established in pediatric patients aged 12 years and older. Use of DAWNZERA for this indication is supported by evidence from an adequate and well‑controlled trial (OASIS-HAE) that included 7 pediatric patients (aged 12 to 17 years) who received DAWNZERA 80 mg subcutaneously every 4 weeks (n=4) or every 8 weeks (n=3). The safety and effectiveness of DAWNZERA in pediatric patients aged 12 years and older is extrapolated from adults from OASIS-HAE with support from pharmacokinetic analysis and pharmacodynamic response [see Clinical Pharmacology (12.2, 12.3) and Clinical Studies (14)]. No new safety signals were identified in pediatric patients aged 12 years and older who received DAWNZERA [see Adverse Reactions (6.1)].

The safety and effectiveness of DAWNZERA have not been established in pediatric patients younger than 12 years of age.

Clinical studies of DAWNZERA did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

No dosage adjustment of DAWNZERA is recommended for patients with mild renal impairment (estimated glomerular filtration rate [eGFR] ≥60 to <90 mL/min/1.73 m²) [see Clinical Pharmacology (12.3)].

DAWNZERA has not been studied in patients with moderate or severe renal impairment or end‑stage renal disease.

No dosage adjustment of DAWNZERA is required for patients with mild hepatic impairment (defined by National Cancer Institute Organ Dysfunction Working Group [NCI-ODWG] Criteria: total bilirubin ≤1 × upper limit of normal [ULN] and aspartate aminotransferase [AST] >1 × ULN, or total bilirubin >1 to 1.5 × ULN and any AST level) [see Clinical Pharmacology (12.3)].

DAWNZERA has not been studied in patients with moderate or severe hepatic impairment. Use of DAWNZERA is not recommended in patients with moderate or severe hepatic impairment (defined by NCI-ODWG Criteria: total bilirubin >1.5 x ULN regardless of AST level).