Dawnzera

Description for Dawnzera

Donidalorsen is a prekallikrein-directed antisense oligonucleotide (ASO) covalently linked to a ligand containing three N-acetyl galactosamine (GalNAc) residues to facilitate delivery of the ASO to hepatocytes.

DAWNZERA contains donidalorsen sodium as the active ingredient. Donidalorsen sodium is a white to yellow solid and it is freely soluble in water and in sodium phosphate buffer. The molecular formula of donidalorsen sodium is sub>296H₄₁₅N₈₃O₁₅₁P₂₀S₁₅Na₂₀ and the molecular weight is 9112.27 daltons. The chemical name of donidalorsen is DNA, d([2′-O-(2-methoxyethyl)]m⁵rU-s^p-[2′-O-(2- methoxyethyl)]rG-s^p- [2′-O-(2-methoxyethyl)]m⁵rC-[2′-O-(2-methoxyethyl)]rA-[2′-O-(2-methoxyethyl)]rA-s^p-G-s^p-T-s^p-m⁵C-s^p-T-s^p-m⁵C-s^p-T-s^p-T-s^p-G-s^p-G-s^p-m⁵C-s^p-[2′-O-(2-methoxyethyl)]rA-[2′-O-(2-methoxyethyl)]rA-[2′-O-(2-methoxyethyl)]rA-s^p-[2′-O-(2-methoxyethyl)]m⁵rC-s^p-[2′-O-(2-methoxyethyl)]rA), 5′-[26-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]-14,14-bis[[3-[[6-[[2-(acetylamino)-2-deoxy-β-D- galactopyranosyl]oxy]hexyl]amino]-3-oxopropoxy]methyl]-8,12,19-trioxo-16-oxa-7,13,20- triazahexacos-1-yl hydrogen phosphate], sodium salt (1:20).

The chemical structure of donidalorsen sodium is presented below:

DAWNZERA (donidalorsen) injection is a sterile, preservative-free solution for subcutaneous injection supplied as a single-dose autoinjector. Each single-dose autoinjector contains 80 mg of donidalorsen (equivalent to 84 mg donidalorsen sodium) in 0.8 mL of solution. The solution also contains disodium hydrogen phosphate; sodium chloride; sodium dihydrogen phosphate; water for injection; and may include hydrochloric acid and/or sodium hydroxide for pH adjustment between 6.9 to 7.9. Each dose of DAWNZERA injection contains 6 mg of phosphorous and 5 mg of sodium.

INDICATIONS AND USAGE

DAWNZERAâ„¢ is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients 12 years of age and older.

Dosage for Dawnzera

Recommended Dosage

The recommended dosage of DAWNZERA is 80 mg administered subcutaneously every 4 weeks.

• A dosage of 80 mg administered subcutaneously every 8 weeks may be considered.

Missed Dose(s)

If a dose of DAWNZERA is missed, administer DAWNZERA as soon as possible. Resume treatment at the recommended dosing frequency from the date of the most recently administered dose.

Administration Instructions

• For subcutaneous use.
• DAWNZERA is intended for self-administration or administration by a caregiver. Prior to treatment initiation, train patients and/or caregivers on proper preparation and subcutaneous administration technique of DAWNZERA autoinjector [see Instructions for Use].
• Remove the single-dose autoinjector from the refrigerator 30 minutes prior to the injection and allow to warm to room temperature. Do not use other warming methods.
• Inspect DAWNZERA visually for particulate matter and discoloration prior to administration. The solution should appear clear and colorless to yellow. Do not use if cloudiness, particulate matter, or discoloration is observed prior to administration.
• Administer DAWNZERA subcutaneously into the abdomen or upper thigh region. The back of the upper arm can also be used as an injection site if a caregiver or healthcare provider administers the injection.

HOW SUPPLIED

Dosage Forms And Strengths

Injection: 80 mg/0.8 mL of donidalorsen as a sterile, clear, colorless to yellow solution in a single-dose autoinjector.

DAWNZERA (donidalorsen) 80 mg/0.8 mL injection is a sterile, preservative-free, clear, colorless to yellow solution supplied in a single-dose autoinjector. Each autoinjector of DAWNZERA is filled to deliver 0.8 mL of solution containing 80 mg of donidalorsen. Table 5 provides the presentation and strength for DAWNZERA.

Presentation	Strength	Unit Count	NDC
Autoinjector	80 mg/0.8 mL	1	71860-103-01

Storage and Handling

• Store the DAWNZERA autoinjector in the refrigerator between 36°F to 46°F (2°C to 8°C) in the original carton.
• The DAWNZERA autoinjector can be stored at room temperature up to 86°F (30°C) in the original carton for up to 6 weeks; if not used within the 6 weeks stored at room temperature, discard DAWNZERA.
• Do not freeze. Do not expose to heat. Protect from direct light.

Distributed by: Ionis Pharmaceuticals Inc., Carlsbad, CA 92010
DAWNZERA is a trademark of Ionis Pharmaceuticals Inc. All other trademarks are the property of their respective owners.
©2025 Ionis Pharmaceuticals Inc.

Warnings for Dawnzera

Included as part of the PRECAUTIONS section.

Precautions for Dawnzera

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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 6-month carcinogenicity study in transgenic (Tg.rasH2) mice, subcutaneous administration of donidalorsen, up to the highest dose tested (20 mg/kg in males and 60 mg/kg in females) or a mousespecific surrogate (10 mg/kg) once every 2 weeks did not result in an increase in malignant tumors.

Mutagenesis

Donidalorsen was negative for genotoxicity in the in vitro bacterial reverse mutation test and chromosomal aberration assay in Chinese hamster lung cells and in vivo mouse bone marrow micronucleus assay.

Fertility

Fertility and reproductive performance were unaffected by 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 mice weekly, prior to and during mating, and continuing every other day in females throughout the periods of implantation and organogenesis.

PATIENT INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Administration Instructions

Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and withholding or discontinuation of OPDIVO, including:

• Instruct patients that DAWNZERA is for subcutaneous use and intended for self-administration or administration by a caregiver.
• Instruct patients and/or caregivers on proper preparation and subcutaneous administration technique of DAWNZERA autoinjector [see Dosage and Administration (2.2) and Instructions for Use] .
• Instruct patients to administer DAWNZERA subcutaneously into the abdomen or upper thigh region for self-administration. The back of the upper arm can be used as an injection site if a caregiver or healthcare provider administers DAWNZERA.

Missed Dose(s)

Instruct patients to use DAWNZERA as prescribed. If a dose is missed, instruct patients to administer DAWNZERA as soon as they remember. Instruct patients to resume treatment at the recommended dosing frequency (every 4 weeks or every 8 weeks) from the date of the most recently administered dose [see Dosage and Administration (2.1)].

Risk of Hypersensitivity Reactions, Including Anaphylaxis

Advise patients hypersensitivity reactions, including anaphylaxis, have been reported following administration of DAWNZERA. Instruct patients to immediately discontinue DAWNZERA and seek medical attention if they experience signs and symptoms of serious hypersensitivity reaction [see Warnings and Precautions (5.1)] .

Manufactured by:
Ionis Pharmaceuticals Inc., Carlsbad, CA 92010
DAWNZERA is a trademark of Ionis Pharmaceuticals Inc. All other trademarks are the property of their respective owners.
©2025 Ionis Pharmaceuticals Inc.

OVERDOSAGE

No information provided

Contraindications for Dawnzera

DAWNZERA is contraindicated in patients with a history of serious hypersensitivity reactions, including anaphylaxis, to donidalorsen or any of the excipients in DAWNZERA [see Warnings and Precautions (5.1) and Adverse Reactions (6)] .

Clinical Pharmacology for Dawnzera

Mechanism Of Action

Donidalorsen is an ASO-GalNAc conjugate that causes ribonuclease H1 (RNase H1)-mediated degradation of PKK mRNA through binding to PKK mRNA, which results in reduced production of PKK protein. PKK is a pro-enzyme for plasma kallikrein, which results in the release of bradykinin, a potent vasodilator causing swelling and pain in HAE. In patients with HAE, C1-inhibitor (C1-INH) deficiency or dysfunction leads to excessive plasma kallikrein activity, bradykinin generation, and angioedema attacks. Donidalorsen lowers PKK concentration, preventing excessive bradykinin production in patients with HAE.

Pharmacodynamics

In OASIS-HAE in adult and pediatric patients (≥12 years) with HAE-1 or HAE-2 [see Clinical Studies (14)], a decrease in plasma PKK concentrations was observed at the first assessment (Week 4) following treatment with DAWNZERA 80 mg. The mean percentage reduction from baseline at Week 4 across both treatment groups was 48%. The mean percentage change from baseline to Week 24 in trough plasma PKK concentrations indicated reductions of 73% and 47% following treatment with DAWNZERA 80 mg every 4 weeks and every 8 weeks, respectively, compared with a slight increase (2%) observed in the placebo group.

Cardiac Electrophysiology

At the maximum recommended dose of DAWNZERA 80 mg every 4 weeks, clinically significant QTc interval prolongation was not observed.

Pharmacokinetics

The pharmacokinetic properties of DAWNZERA were evaluated following subcutaneous administration of multiple doses every 4 weeks in healthy subjects and every 4 weeks or every 8 weeks in patients with HAE. The pharmacokinetics of DAWNZERA were similar between healthy subjects and patients with HAE.

Donidalorsen exposure (area under the plasma concentration-time curve [AUC]) at steady state following subcutaneous administration in healthy subjects increased in a greater than dose-proportional manner over the dose range of 0.25 times the maximum recommended dosage to 80 mg every 4 weeks.

Geometric Mean (Coefficient of Variation (CV%)) of steady-state maximum plasma concentration (C_max,ss), trough plasma concentration (C_trough,ss), and area under the plasma concentration-time curve over the dosing interval (AUC_τ,ss) are presented in Table 2. No accumulation of donidalorsen C_max and AUC was observed in plasma after repeated dosing every 4 weeks. However, a 2-fold increase of plasma donidalorsen C_trough was observed following repeated dosing every 4 weeks.

Table 2: Summary of Geometric Mean (CV%) Steady-State Donidalorsen Pharmacokinetic Parameters Following Dosage of
DAWNZERA 80 mg Every 4 Weeks or 80 mg Every 8 Weeks in Patients with HAE

Pharmacokinetic Parameters (Geometric Mean)	DAWNZERA
	80 mg q4wks	80 mg q8wks
Cmax,ss (ng/mL)	417 (81%)	416 (78%)
Ctrough,ss (ng/mL)	0.755 (63%)	0.255 (73%)
AUCτ,ss (ng·h/mL)	5240 (52%)	5210 (52%)
AUCτ,ss = area under the plasma concentration-time curve over each dosing interval at steady-state; Cmax,ss = maximum plasma concentration at steady-state; Ctrough,ss = trough plasma concentration at steady-state; q4wks = every 4 weeks; q8wks = every 8 weeks.

Absorption

Following subcutaneous administration, donidalorsen is absorbed with the median (range) time to maximum plasma concentration of approximately 2 (0.25, 8) hours post dose.

Distribution

Donidalorsen is expected to distribute primarily to the liver and kidney cortex after subcutaneous dosing. The apparent volume of distribution for the central (V_c/F) and peripheral (V_p/F) compartment were 69.8 L and 1840 L, respectively. Donidalorsen is highly bound to human plasma proteins (>98% bound) in vitro.

Elimination

The terminal plasma elimination half-life of donidalorsen in a typical patient with HAE is approximately 1 month. The half-life of the initial rapid clearance phase, reflecting tissue distribution, was approximately 5 hours.

Metabolism

The oligonucleotide moiety of donidalorsen is expected to be metabolized by endo- and exonucleases to short oligonucleotide fragments of varying sizes within the liver. Based on in vitro studies, donidalorsen is not a substrate of cytochrome P450 (CYP) enzymes.

The linker that covalently connects the ASO to the GalNAc residues is cleaved via hydrolysis and undergoes dephosphorylation and subsequent oxidative metabolism to form inactive metabolites, which are minimally released in circulation. The most abundant linker-related metabolite (M8) is a substrate of CYP3A4.

Excretion

The mean fraction of unchanged ASO eliminated in urine was less than 1% of the administered dose in healthy subjects within 24 hours post-dose. The renal route of elimination is minor for linker-related metabolites.

Specific Populations

No clinically meaningful differences in the pharmacokinetics or pharmacodynamics of donidalorsen were observed based on age (12 to 68 years), body weight (37 to 152 kg), sex, race (68% White, 24% Black, and 4% Asian), ethnicity, disease status (healthy subjects or subjects with HAE), mild renal impairment (eGFR ≥60 to <90mL/min/1.73 m2), or mild hepatic impairment (defined using NCIODWG Criteria: total bilirubin ≤1 × ULN and AST >1 × ULN, or total bilirubin >1 to 1.5 × ULN and any AST).

Donidalorsen has not been studied in patients with moderate or severe renal impairment, end-stage renal disease, or moderate or severe hepatic impairment.

Drug Interaction Studies

No clinical drug-drug interaction studies have been performed with donidalorsen. In vitro studies show that donidalorsen is not a substrate or inhibitor of transporters, does not interact with highly plasma protein bound drugs, and is not an inhibitor/inducer of CYP enzymes. In vitro studies show that linkerrelated metabolite M8 is not an inhibitor or inducer of CYP enzymes. M8 is a substrate of transporters bile salt export pump (BSEP) and organic anion transporting polypeptide 1B3 (OATP1B3), and is an inhibitor of multidrug and toxin extrusion protein 1 (MATE1) transporter.

Immunogenicity

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.

INSTRUCTIONS FOR USE
DAWNZERA^TM [dawn-ZAIR-ah]
(donidalorsen)
injection, for subcutaneous use

This Instructions for Use contains information on how to inject DAWNZERA using the autoinjector.

Read this Instructions for Use before you start using your DAWNZERA autoinjector and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Your healthcare provider should show you or your caregiver how to use the DAWNZERA autoinjector the right way. If you or your caregiver have any questions, talk to your healthcare provider.

Important information:

• DAWNZERA is injected under the skin (subcutaneous use)
• Each autoinjector contains 1 single-dose and can only be used 1
• Do not remove the clear cap until you are ready to inject DAWNZERA (See Step 5).
• Do not share your autoinjector with
• Do not use if the autoinjector appears

Storage information:

• Store the autoinjector in the refrigerator between 36°F to 46°F (2°C to 8°C) in the original
• If needed, DAWNZERA can be stored at room temperature up to 86°F (30°C) in the original carton for up to 6 weeks.
• Do not store DAWNZERA at room temperatures above 86°F.
• Throw away the DAWNZERA if kept at room temperature longer than 6
• Do not
• Do not expose the autoinjector to
• Protect from direct
• Keep the autoinjector in the carton until ready to
• Do not store the autoinjector with the clear cap

Keep DAWNZERA and all medicine out of the reach of children.

Parts of your DAWNZERA autoinjector

Preparing to inject DAWNZERA

Step 1 Remove from the refrigerator 30 minutes before you inject a) Remove the autoinjector from the refrigerator. b) Keep the autoinjector in the original carton and let the autoinjector come to room temperature for 30 minutes before injecting. Do not try to speed up the warming process using other heat sources, such as a microwave or hot water. Step 2 Check the medicine Check the expiration (EXP) Check the medicine through the viewing window. The DAWNZERA medicine should be clear and colorless to yellow. There should be no particles. It is normal to see air bubbles in the solution. Do not use the autoinjector if the: clear cap is missing or not expiration (EXP) date has medicine looks cloudy, discolored, or has autoinjector appears Step 3 Choose the injection site Choose an injection site on the stomach or the front of the thigh. Only healthcare providers or caregivers may choose the back of the upper arm. Do not inject: within 2 inches of the belly button (navel). into skin that is bruised, tender, red, or into scars or damaged skin. Step 4 Wash hands and clean the injection site Wash your hands with soap and water. Clean the injection site with an alcohol wipe in a circular motion. Let the skin air dry. Do not touch the cleaned skin before injecting. Injecting DAWNZERA Step 5 Remove and throw away the clear cap Hold the autoinjector by the middle with the clear cap facing away from you. Remove the clear cap by pulling it straight off. Do not twist it off. The needle is inside the orange needle shield. Throw away the clear cap in the trash or sharps container. Do not remove the clear cap until right before you inject. Do not recap the autoinjector. Do not push the orange needle shield against the hand or finger. Step 6 Begin injection Hold the autoinjector in 1 hand. Place the orange needle shield at a 90-degree angle against your Make sure you can see the viewing window. Push firmly and hold the autoinjector straight against the You will hear a click as the injection starts. You may hear a second click. This is normal. The procedure is not finished. Hold the autoinjector against the skin for 10 seconds to make sure the full dose has been given. Do not move, turn, or change the angle of the autoinjector during the injection. Step 7 Finish injection Check that the orange plunger rod has moved down to fill the entire viewing window. If the orange plunger rod does not fill the viewing window, you may not have received the full dose. If this happens or if you have other concerns, contact your healthcare Remove the autoinjector by lifting it straight up. After removal from the skin, the orange needle shield locks into place and covers the There may be a small amount of blood or liquid where you injected. This is normal. If needed, press a cotton ball or gauze on the area and apply a small bandage. The autoinjector contains 1 dose. Do not reuse the autoinjector. Throwing away DAWNZERA Step 8 Throw away autoinjector Put the used autoinjector in a sharps container right away after use. Do not throw away the autoinjector in your household trash. Do not recycle your used sharps disposal container. Do not reuse the autoinjector or clear cap. If you do not have an FDA-cleared sharps container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labelled to warn of hazardous waste inside the When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used autoinjectors. For more information about safe sharps disposal, and specific information about sharps disposal in the state that you live in, go to the FDA's website at: https://www.fda.gov/safesharpsdisposal. Do not throw away your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

For more information, go to https://www.DAWNZERA.com or call 1-833-644-6647. If you still have questions, contact your healthcare provider.
Distributed by: Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010

This Instructions for Use has been approved by the U.S. Food and Drug Administration