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| {{DrugProjectFormSinglePage | | {{DrugProjectFormSinglePage |
| |authorTag=Mohammad Nikoohemmat | | |authorTag={{MNH}} |
| |genericName=Eplontersen | | |genericName=Eplontersen |
| |aOrAn=a | | |aOrAn=a |
| |drugClass=transthyretin-directed antisense oligonucleotide | | |drugClass=transthyretin-directed antisense oligonucleotide |
| |indicationType=treatment | | |indicationType=treatment |
| |indication=WAINUA is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. | | |indication=polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults |
| |adverseReactions=Most common adverse reactions (that occurred in at least 9% of patients treated with WAINUA) were vitamin A decreased and vomiting. | | |adverseReactions=vitamin A decreased and vomiting (that occurred in at least 9% of patients treated with WAINUA) |
| |fdaLIADAdult=The recommended dosage of WAINUA is 45 mg administered by subcutaneous injection once monthly (45 mg/0.8 mL of eplontersen as a clear, colorless-to-yellow solution in a single-dose autoinjector). | | |fdaLIADAdult=The recommended dosage of WAINUA is 45 mg administered by subcutaneous injection once monthly. |
| |contraindications=None
| | Administer WAINUA into the abdomen or upper thigh region; the back of the upper arm can be used if a healthcare provider or caregiver administers the injection. |
| |warnings=Reduced Serum Vitamin A Levels and Recommended Supplementation:
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| WAINUA treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking WAINUA. Higher doses than the recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with WAINUA, as serum vitamin A levels do not reflect the total vitamin A in the body. | |
| Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness, dry eyes).
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| |clinicalTrials=Most common adverse reactions (that occurred in at least 9% of patients treated with WAINUA) were vitamin A decreased and vomiting.
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| |drugInteractions=No clinical drug-drug interaction studies have been performed with eplontersen. In vitro studies show that eplontersen is not a substrate or inhibitor of transporters, does not interact with highly plasma protein bound drugs, and is not an inhibitor or inducer of cytochrome P450 (CYP) enzymes. Oligonucleotide therapeutics, including eplontersen, are not typically substrates of CYP enzymes. Therefore, eplontersen is not expected to cause or be affected by drug-drug interactions mediated through drug transporters, plasma protein binding or CYP enzymes.
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| |useInPregnancyFDA=There are no available data on WAINUA use in pregnant women to inform drug-associated risk of adverse developmental outcomes. WAINUA treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking WAINUA. Vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects. The effect of vitamin A supplementation on the fetus in the setting of a reduction in maternal serum TTR caused by WAINUA administration is unknown.
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| No adverse developmental effects were observed when eplontersen or a mouse-specific surrogate was administered to mice prior to mating and continuing throughout organogenesis.
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| 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. The background risk of major birth defects and miscarriage for the indicated population is unknown.
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| Animal Data
| | =====Missed Dose===== |
| Subcutaneous administration of eplontersen (0, 5, 25, or 75 mg/kg) or a mouse-specific surrogate (25 mg/kg) to male and female mice weekly prior to and during mating and administration continued every other day in females throughout the period of organogenesis resulted in no adverse effects on embryofetal development.
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| |useInPed=Safety and effectiveness in pediatric patients have not been established.
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| |useInGeri=No dose adjustment is required in patients ≥65 years of age. In Study 1 , 44 (31%) patients were 65 to 74 years of age, and 8 (5.6%) patients were ≥75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.
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| |useInRenalImpair=No dose adjustment is necessary in patients with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR]≥30 to <90 mL/min/1.73 m2). WAINUA has not been studied in patients with severe renal impairment or end-stage renal disease.
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| |useInHepaticImpair=No dose adjustment is necessary in patients with mild hepatic impairment (total bilirubin ≤1 x ULN and AST >1 x ULN, or total bilirubin >1.0 to 1.5 x ULN and any AST). WAINUA has not been studied in patients with moderate or severe hepatic impairment.
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| |othersTitle=Lactation
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| |useInOthers=There is no information regarding the presence of eplontersen in human milk, the effects on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for WAINUA and any potential adverse effects on the breast-fed infant from WAINUA or from the underlying maternal condition.
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| |administration=Administer WAINUA into the abdomen or upper thigh region; the back of the upper arm can be used if a healthcare provider or caregiver administers the injection.
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| Prior to initiation, train patients and/or caregivers on proper preparation and administration of WAINUA.
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| 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.
| | Administer WAINUA as soon as possible after a missed dose. Resume dosing at monthly intervals from the date of the most recently administered dose. |
| | | |offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Eplontersen in adult patients. |
| Inspect WAINUA visually for particulate matter and discoloration prior to administration. The solution should appear colorless to yellow. Do not use if cloudiness, particulate matter, or discoloration is observed prior to administration.
| | |offLabelAdultNoGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Eplontersen in adult patients. |
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| Administer WAINUA as a subcutaneous injection into the abdomen or upper thigh region. The back of the upper arm can also be used as an injection site if a healthcare provider or caregiver administers the injection. | |
| |mechAction=Eplontersen is an antisense oligonucleotide-GalNAc conjugate that causes degradation of mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.
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| |structure=Eplontersen is a transthyretin-directed antisense oligonucleotide (ASO), covalently linked to a ligand containing three N-acetyl galactosamine (GalNAc) residues to enable delivery of the ASO to hepatocytes.
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| WAINUA contains eplontersen sodium as the active ingredient. Eplontersen sodium is a white to yellow solid and it is freely soluble in water and in phosphate buffer. The molecular formula of eplontersen sodium is C296H417N77O156P20S13Na20 and the molecular weight is 9046.1 daltons. The chemical name of eplontersen sodium is DNA, d([2′-O-(2-methoxyethyl)]m5rU-sp-[2′-O-(2-methoxyethyl)]m5rC-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]rG-G-sp-T-sp-T-sp-A-sp-m5C-sp-A-sp-T-sp-G-sp-A-sp-A-sp-[2′-O-(2-methoxyethyl)]rA-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]m5rC-sp-[2′-O-(2-methoxyethyl)]m5rC-sp-[2′-O-(2-methoxyethyl)]m5rC), 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).
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| WAINUA is a sterile, preservative-free, aqueous solution for subcutaneous injection. Each single-dose autoinjector contains 45 mg eplontersen (equivalent to 47 mg eplontersen sodium) in 0.8 mL of solution. The solution also contains dibasic sodium phosphate, anhydrous (to adjust pH); monobasic sodium phosphate, dihydrate (to adjust pH); sodium chloride (to adjust tonicity); water for injection; and may include hydrochloric acid and/or sodium hydroxide for pH adjustment between 6.9 – 7.9. Each dose of WAINUA injection contains 5 mg of sodium and 5 mg of phosphorus.
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| |PD=In Study 1, following administration of the recommended WAINUA dosage every 4 weeks to patients with hATTR amyloidosis, a decrease in serum TTR levels was observed at the first assessment and the (least square) mean serum TTR at Week 35 was reduced by 81% from baseline. Similar TTR reductions were observed across subgroups including Val30Met variant status, body weight, sex, age, or race.
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| |PK=The pharmacokinetic (PK) properties of WAINUA were evaluated following subcutaneous administration of single and multiple doses (once every 4 weeks) in healthy subjects and multiple doses (once every 4 weeks) in patients with hATTR amyloidosis.
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| Eplontersen Cmax and AUC showed a slightly greater than dose-proportional increase following single subcutaneous doses ranging from 45 to 120 mg (i.e., 1- to 2.7-times the recommended dose) in healthy volunteers.
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| Population estimates (mean ± SD) of steady state maximum concentrations (Cmax), and area under the curve (AUCτ) were 283 ± 152 ng/mL, and 2190 ± 689 ng/mL, respectively, following 45 mg monthly dosing in patients with hATTR amyloidosis. No accumulation of eplontersen Cmax and AUC was observed in repeated dosing (once every 4 weeks).
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| |nonClinToxic=Carcinogenesis, Mutagenesis, Impairment of Fertility: | |
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| Carcinogenesis
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| Carcinogenicity studies have not been conducted with eplontersen.
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| Mutagenesis
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| Eplontersen was negative for genotoxicity in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster lung cells) and in vivo (mouse bone marrow micronucleus) assays.
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| Impairment of Fertility
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| Subcutaneous administration of eplontersen (0, 5, 25, or 75 mg/kg) or a mouse-specific surrogate (25 mg/kg) to male and female mice weekly prior to and during mating and continuing in females throughout the period of organogenesis resulted in no adverse effects on fertility.
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| |clinicalStudies=The efficacy of WAINUA was demonstrated in a randomized, open-label, multicenter clinical trial in adult patients with polyneuropathy caused by hATTR amyloidosis (Study 1; NCT04136184). Patients were randomized in a 6:1 ratio to receive either 45 mg of WAINUA once every 4 weeks (N=144), or 284 mg of inotersen once per week (N=24), respectively, as subcutaneous injections. Ninety-seven percent of WAINUA-treated patients and 83% of inotersen-treated patients completed at least 35 weeks of the assigned treatment.
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| Efficacy assessments were based on a comparison of the WAINUA arm of Study 1 with an external placebo group (N=60) in another study (NCT01737398) composed of a comparable population of adult patients with polyneuropathy caused by hATTR amyloidosis.
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| The efficacy endpoints were the change from baseline to Week 35 in the modified Neuropathy Impairment Scale+7 (mNIS+7) composite score and the change from baseline to Week 35 in the Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) total score.
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| The mNIS+7 is an objective assessment of neuropathy and comprises the neuropathy impairment score (NIS) and Modified +7 composite scores. In the version of the mNIS+7 used in the trial, the NIS objectively measures deficits in cranial nerve function, muscle strength, reflexes, and sensations, and the Modified +7 assesses heart rate response to deep breathing, quantitative sensory testing (touch-pressure and heat-pain), and peripheral nerve electrophysiology. The validated version of the mNIS+7 score used in the trial has a range of -22.3 to 346.3 points, with higher scores representing a greater severity of disease.
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| The clinical meaningfulness of effects on the mNIS+7 was assessed by the change from baseline to Week 35 in Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) total score. The Norfolk QoL-DN scale is a patient-reported assessment that evaluates the subjective experience of neuropathy in the following domains: physical functioning/large fiber neuropathy, activities of daily living, symptoms, small fiber neuropathy, and autonomic neuropathy. The version of the Norfolk QoL-DN that was used in the trial has a range from -4 to 136 points, with higher scores representing greater impairment.
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| Treatment with WAINUA resulted in statistically significant improvements in the mNIS+7 and the Norfolk QoL-DN total scores, compared to the external placebo control (p<0.001) at Week 35 (Table 2, Figures 1 and 3). The distributions of changes in mNIS+7 and Norfolk QoL-DN scores from baseline to Week 35 by percent of patients in each category are shown in Figure 2 and Figure 4, respectively.
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| |howSupplied=How Supplied | |
| WAINUA injection is a sterile, preservative-free, clear, colorless to yellow solution supplied in a single-dose autoinjector. Each autoinjector of WAINUA is filled to deliver 0.8 mL of solution containing 45 mg of eplontersen.
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| WAINUA is available in cartons containing one 45 mg single-dose autoinjector each.
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| The NDC is: 0310-9400-01.
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| |storage=Storage and Handling
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| Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton protected from light.
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| If needed, WAINUA can be kept at room temperature (up to 30°C [86°F]) in the original carton for up to 6 weeks. If not used within the 6 weeks stored at room temperature, discard WAINUA.
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| Do not freeze. Do not expose to heat.
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| |packLabel=NDC 0310-9400-01 Rx only
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| WAINUA™ 45 mg/0.8 mL
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| (eplontersen) injection
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| for subcutaneous use
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| Each WAINUA autoinjector contains 45 mg eplontersen
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| (equivalent to 47 mg eplontersen sodium) in 0.8 mL of solution, for single-dose only.
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| Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton protected from light.
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| Do not freeze. Do not expose to heat.
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| 1 single-dose autoinjector
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| IONIS™ AstraZeneca
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| |fdaPatientInfo=Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
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| Recommended Vitamin A Supplementation:
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| Inform patients that WAINUA treatment leads to a decrease in vitamin A levels measured in the serum. Instruct patients to take the recommended daily allowance of vitamin A. Advise patients to contact their healthcare provider if they experience ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness, dry eyes) and refer them to an ophthalmologist if they develop these symptoms.
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| Pregnancy:
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| Instruct patients that if they are pregnant or plan to become pregnant while taking WAINUA they should inform their healthcare provider. Advise patients of the potential risk to the fetus, including that WAINUA treatment leads to a decrease in serum vitamin A levels.
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| Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850
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| ©AstraZeneca 2023
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| |brandNames=WAINUA
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| }} | | }} |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammad Nikoohemmat, M.D.[2]
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Overview
Eplontersen is a transthyretin-directed antisense oligonucleotide that is FDA approved for the treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. Common adverse reactions include vitamin A decreased and vomiting (that occurred in at least 9% of patients treated with WAINUA).
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
The recommended dosage of WAINUA is 45 mg administered by subcutaneous injection once monthly.
Administer WAINUA into the abdomen or upper thigh region; the back of the upper arm can be used if a healthcare provider or caregiver administers the injection.
Missed Dose
Administer WAINUA as soon as possible after a missed dose. Resume dosing at monthly intervals from the date of the most recently administered dose.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eplontersen in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eplontersen in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Eplontersen FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Contraindications
There is limited information regarding Eplontersen Contraindications in the drug label.
Warnings
There is limited information regarding Eplontersen Warnings' in the drug label.
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Eplontersen Clinical Trials Experience in the drug label.
Postmarketing Experience
There is limited information regarding Eplontersen Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Eplontersen Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Eplontersen in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eplontersen in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Eplontersen during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Eplontersen in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Eplontersen in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Eplontersen in geriatric settings.
Gender
There is no FDA guidance on the use of Eplontersen with respect to specific gender populations.
Race
There is no FDA guidance on the use of Eplontersen with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Eplontersen in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Eplontersen in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Eplontersen in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Eplontersen in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Eplontersen Administration in the drug label.
Monitoring
There is limited information regarding Eplontersen Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Eplontersen and IV administrations.
Overdosage
There is limited information regarding Eplontersen overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Eplontersen Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Eplontersen Mechanism of Action in the drug label.
Structure
There is limited information regarding Eplontersen Structure in the drug label.
Pharmacodynamics
There is limited information regarding Eplontersen Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Eplontersen Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Eplontersen Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Eplontersen Clinical Studies in the drug label.
How Supplied
There is limited information regarding Eplontersen How Supplied in the drug label.
Storage
There is limited information regarding Eplontersen Storage in the drug label.
Images
Drug Images
{{#ask: Page Name::Eplontersen
|?Pill Name
|?Drug Name
|?Pill Ingred
|?Pill Imprint
|?Pill Dosage
|?Pill Color
|?Pill Shape
|?Pill Size (mm)
|?Pill Scoring
|?NDC
|?Drug Author
|format=template
|template=DrugPageImages
|mainlabel=-
|sort=Pill Name
}}
Package and Label Display Panel
{{#ask: Label Page::Eplontersen
|?Label Name
|format=template
|template=DrugLabelImages
|mainlabel=-
|sort=Label Page
}}
Patient Counseling Information
There is limited information regarding Eplontersen Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Eplontersen interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Eplontersen Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Eplontersen Look-Alike Drug Names in the drug label.
Price
References
The contents of this FDA label are provided by the National Library of Medicine.