Vutrisiran
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Edzel Lorraine Co, DMD, MD[2]
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Overview
Vutrisiran is a transthyretin-directed small interfering RNA that is FDA approved for the treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.. Common adverse reactions include pain in extremity, arthralgia, dyspnea, and decreased vitamin A levels..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Recommended Dosage
The recommended dosage of AMVUTTRA is 25 mg administered by subcutaneous injection once every 3 months
Missed Dose
If a dose is missed, administer AMVUTTRA as soon as possible. Resume dosing every 3 months from the most recently administered dose.
Administration Instructions AMVUTTRA is for subcutaneous use only and should be administered by a healthcare professional.
Syringe Appearance Before and After Use
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Vutrisiran FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Contraindications
None
Warnings
Reduced Serum Vitamin A Levels and Recommended Supplementation
AMVUTTRA treatment leads to a decrease in serum vitamin A levels
Supplementation at the recommended daily allowance of vitamin A is advised for patients taking AMVUTTRA. 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 AMVUTTRA, 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).
Adverse Reactions
Clinical Trials Experience
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
Reduced Serum Vitamin A Levels and Recommended Supplementation
Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of AMVUTTRA cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In Study 1, a total of 122 patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) received AMVUTTRA. Of these, 118 patients received at least 18 months of treatment. The mean duration of treatment was 18.8 months (range: 1.7 to 19.4 months). The median patient age at baseline was 60 years and 65% of the patients were male. Seventy percent of AMVUTTRA-treated patients were Caucasian, 17% were Asian, 3% were Black, and 9% were reported as Other. Forty-four percent of patients had the Val30Met mutation in the transthyretin gene; the remaining patients had one of 21 other mutations. At baseline, 70% of patients were in Stage 1 of the disease and 30% were in Stage 2.
The most common adverse reactions (at least 5%) were pain in extremity, arthralgia, dyspnea, and vitamin A decreased.
In Study 1, patients were instructed to take the recommended daily allowance of vitamin A. Seventy-four percent of patients treated with AMVUTTRA had normal vitamin A levels at baseline, and 98% of those with a normal baseline developed low vitamin A levels. In some cases, the decreased vitamin A level was reported as an adverse reaction.
Two serious adverse reactions of atrioventricular (AV) heart block (1.6%) occurred in patients treated with AMVUTTRA, including one case of complete AV block.
Injection site reactions were reported in 5 (4%) patients treated with AMVUTTRA. Reported symptoms included bruising, erythema, pain, pruritus, and warmth. Injection site reactions were mild and transient.
Immunogenicity As with all oligonucleotides, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
In Study 1, 3 (2.5%) patients treated with AMVUTTRA developed anti-drug antibodies. Although anti-drug antibody development was not found to affect the pharmacokinetics, safety, or efficacy of AMVUTTRA in these patients, the available data are too limited to make definitive conclusions.
Postmarketing Experience
There is limited information regarding Vutrisiran Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Vutrisiran Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): There are no available data on AMVUTTRA use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. AMVUTTRA treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking AMVUTTRA. Vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects. The effects on the fetus of a reduction in maternal serum TTR caused by AMVUTTRA and of vitamin A supplementation are unknown
In animal studies, subcutaneous administration of vutrisiran to pregnant rats resulted in developmental toxicity (reduced fetal body weight and embryofetal mortality) at doses associated with maternal toxicity
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vutrisiran in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Vutrisiran during labor and delivery.
Nursing Mothers
There is no information regarding the presence of vutrisiran in human milk, the effects on the breastfed 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 AMVUTTRA and any potential adverse effects on the breastfed infant from AMVUTTRA or the underlying maternal condition.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatic Use
No dose adjustment is required in patients ≥65 years of age. A total of 46 (38%) patients ≥65 years of age, including 7 (6%) patients ≥75 years of age, received AMVUTTRA in Study 1. No overall differences in safety or effectiveness were observed between these patients and younger patients, but the greater sensitivity of some older individuals cannot be ruled out.
Gender
There is no FDA guidance on the use of Vutrisiran with respect to specific gender populations.
Race
There is no FDA guidance on the use of Vutrisiran with respect to specific racial populations.
Renal Impairment
No dose adjustment is recommended in patients with mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥30 to <90 mL/min/1.73 m2). AMVUTTRA has not been studied in patients with severe renal impairment or end-stage renal disease.
Hepatic Impairment
No dose adjustment is recommended in patients with mild hepatic impairment (total bilirubin ≤1 × ULN and AST >1 × ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST). AMVUTTRA has not been studied in patients with moderate or severe hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vutrisiran in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Vutrisiran in patients who are immunocompromised.
Administration and Monitoring
Administration
Preparation and Administration
1. Prepare the syringe If stored cold, allow the syringe to warm to room temperature for 30 minutes prior to use. Remove the syringe from the packaging by gripping the syringe body.
Do not touch the plunger rod until ready to inject. Visually inspect the drug solution for discoloration and particulate matter prior to administration. AMVUTTRA is a sterile, preservative-free, clear, colorless-to-yellow solution. Do not use if it contains particulate matter or if it is cloudy or discolored. Check the following: Syringe is not damaged, such as cracked or leaking Needle cap is attached to the syringe Expiration date on syringe label
Do not use the syringe if any issues are found while checking the syringe.
2. Choose and prepare the injection site Choose an injection site from the following areas: the abdomen, thighs, or upper arms. Avoid the following: 5-cm area around the navel Scar tissue or areas that are reddened, inflamed, or swollen Clean the chosen injection site.
3. Prepare the syringe for injection Hold the syringe body with one hand. Pull the needle cap straight off with other hand and dispose of needle cap immediately. It is normal to see a drop of liquid at the tip of the needle.
Do not touch the needle or let it touch any surface.
Do not recap the syringe.
Do not use the syringe if it is dropped.
4. Perform the injection Pinch the cleaned skin. Fully insert the needle into the pinched skin at a 45°-90° angle.
Inject all of the medication.
Push the plunger rod as far as it will go to administer the dose and activate the needle shield.
Release the plunger rod to allow the needle shield to cover the needle.
Do not block plunger rod movement.
5. Dispose of the syringe
Immediately dispose of the used syringe into a sharps container.
Monitoring
There is limited information regarding Vutrisiran Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Vutrisiran and IV administrations.
Overdosage
There is limited information regarding Vutrisiran overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
AMVUTTRA contains vutrisiran, a chemically modified double-stranded small interfering ribonucleic acid (siRNA) that targets mutant and wild-type transthyretin (TTR) messenger RNA (mRNA) and is covalently linked to a ligand containing three N-acetylgalactosamine (GalNAc) residues to enable the delivery of the siRNA to hepatocytes.
Mechanism of Action
Vutrisiran is a double-stranded siRNA-GalNAc conjugate that causes degradation of mutant and wild-type TTR mRNA through RNA interference, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.
Structure
AMVUTTRA is supplied as a sterile, preservative-free, clear, colorless-to-yellow solution for subcutaneous injection. Each 0.5 mL of solution contains 25 mg of vutrisiran (equivalent to 26.5 mg vutrisiran sodium), 0.2 mg sodium phosphate monobasic dihydrate, 0.7 mg sodium phosphate dibasic dihydrate, 3.2 mg sodium chloride, water for injection, and sodium hydroxide and/or phosphoric acid to adjust the pH to ~7.
Pharmacodynamics
In Study 1, following administration of the recommended AMVUTTRA dosage every 3 months to patients with hATTR amyloidosis, vutrisiran reduced mean serum TTR at steady state by 83%. Similar TTR reductions were observed regardless of Val30Met genotype status, weight, sex, age, or race.
Vutrisiran also reduced the mean steady-state serum vitamin A by 62% over 9 months.
Cardiac Electrophysiology
At a dose 12 times the recommended dosage of 25 mg once every three months, AMVUTTRA does not prolong the QT interval to any clinically relevant extent.
Pharmacokinetics
The pharmacokinetic (PK) properties of AMVUTTRA were evaluated following a single dose in healthy subjects and multiple doses in patients with hATTR amyloidosis.
Dose Proportionality
Vutrisiran Cmax showed dose proportional increase while AUClast and AUCinf were slightly more than dose proportional following single subcutaneous doses ranging from 5 to 300 mg (i.e., 0.2 to 12 times the recommended dose)
Accumulation
No accumulation of vutrisiran was observed in plasma after repeated every 3 months dosage*
Absorption
Tmax [Median (Range)] = 4 (0.17, 12.0) hours
Distribution
Estimated Vd/F (%RSE) = 10.1 (5.8) L Protein Binding = 80%
Organ Distribution = Vutrisiran distributes primarily to the liver after subcutaneous dosing
Elimination Half-Life [Median (Range)] = 5.2 (2.2, 6.4) hours Apparent Clearance [Median (Range)] = 21.4 (19.8, 30) L/hour
Metabolism
Primary Pathway Vutrisiran is metabolized by endo- and exonucleases to short nucleotide fragments of varying sizes within the liver
Excretion
Primary Pathway The mean fraction of unchanged vutrisiran eliminated in urine was approximately 19.4% at the recommended dose of 25 mg. The mean renal clearance of vutrisiran ranged from 4.5 to 5.7 L/hour.
Specific Populations
No clinically significant differences in the pharmacokinetics of vutrisiran were observed based on age, sex, race, mild and moderate renal impairment (eGFR≥30 to <90 mL/min/1.73 m2), or mild hepatic impairment (total bilirubin ≤1 × ULN and AST >1 × ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST). Vutrisiran has not been studied in patients with severe renal impairment, end-stage renal disease, moderate or severe hepatic impairment, or in patients with prior liver transplant.
Drug Interaction Studies
No clinical drug-drug interaction studies have been performed with vutrisiran. In vitro studies suggest that vutrisiran is not a substrate or inhibitor of cytochrome P450 enzymes. Vutrisiran is not expected to cause drug-drug interactions by inducing CYP enzymes or modulating the activities of drug transporters.
Nonclinical Toxicology
Carcinogenesis
Subcutaneous administration of vutrisiran to male rats (0, 4, 7.5, or 15 mg/kg once every 4 weeks or 15 mg/kg once every 12 weeks) for 99 weeks and to female rats (0, 6, 12.5, or 25 mg/kg once every 4 weeks or 25 mg/kg once every 12 weeks) for 86-87 weeks resulted in no increase in tumors.
Mutagenesis
Vutrisiran was negative for mutagenicity in in vitro (bacterial mutagenicity, chromosomal aberration in human blood peripheral lymphocytes) and in vivo (rat bone marrow micronucleus) assays.
Impairment of Fertility
Subcutaneous administration of vutrisiran (0, 15, 30, or 70 mg/kg/week) to male and female rats before and during mating and continuing in females to gestation day 6 resulted in no adverse effects on fertility or reproductive performance.
Clinical Studies
The efficacy of AMVUTTRA was evaluated in a randomized, open-label clinical trial in adult patients with polyneuropathy caused by hATTR amyloidosis (Study 1; NCT03759379). Patients were randomized 3:1 to receive 25 mg of AMVUTTRA subcutaneously once every 3 months (N=122), or 0.3 mg/kg patisiran intravenously every 3 weeks (N=42) as a reference group. Ninety-seven percent of AMVUTTRA-treated patients and 93% of patisiran-treated patients completed at least 9 months of the assigned treatment.
Efficacy assessments were based on a comparison of the AMVUTTRA arm of Study 1 with an external placebo group in another study (NCT01960348) composed of a comparable population of adult patients with polyneuropathy caused by hATTR amyloidosis.
The primary efficacy endpoint was the change from baseline to Month 9 in modified Neuropathy Impairment Score +7 (mNIS+7). The mNIS+7 is an objective assessment of neuropathy and comprises the 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, and reflexes, and the +7 assesses postural blood pressure, quantitative sensory testing, and peripheral nerve electrophysiology. The mNIS+7 has a total score range from 0 to 304 points, with higher scores representing a greater severity of disease.
The clinical meaningfulness of effects on the mNIS+7 was assessed by the change from baseline to Month 9 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 Norfolk QoL-DN has a total score range from -4 to 136, with higher scores representing greater impairment.
Additional endpoints were gait speed, as measured by the 10-meter walk test (10MWT), and modified body mass index (mBMI).
Treatment with AMVUTTRA in Study 1 resulted in statistically significant improvements in the mNIS+7, Norfolk QoL-DN total score, and 10-meter walk test at Month 9 compared to placebo in the external study (p<0.001). The distributions of changes in mNIS+7 and Norfolk QoL-DN total scores from baseline to Month 9 by percent of patients.
The change from baseline to Month 9 in modified body mass index nominally favored AMVUTTRA .
Patients receiving AMVUTTRA in Study 1 experienced similar improvements relative to those in the external placebo group in mNIS+7 and Norfolk QoL-DN total score across all subgroups including age, sex, race, region, NIS score, Val30Met genotype status, and disease stage.
How Supplied
AMVUTTRA is a sterile, preservative-free, clear, colorless-to-yellow solution for subcutaneous injection. AMVUTTRA is supplied as 25 mg/0.5 mL solution in a single-dose 1-mL prefilled syringe made from Type I glass with a stainless steel 29-gauge needle with a needle shield. The prefilled syringe components are not made with natural rubber latex.
AMVUTTRA is available in cartons containing one single-dose prefilled syringe each.
The NDC is 71336-1003-1.
Storage
Store at 2°C to 30°C (36°F to 86°F) in the original carton, until ready for use. Do not freeze.
Images
Drug Images
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Package and Label Display Panel
NDC 71336-1003-1
amvuttra ™ (vutrisiran) injection
25 mg/0.5 mL
For Subcutaneous Injection by Healthcare Professional Only
Rx Only
Do not use it ifseal is broken
1 x 25 mg single-dose prefilled syringe {{#ask: Label Page::Vutrisiran |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}
Patient Counseling Information
Recommended Vitamin A Supplementation
Inform patients that AMVUTTRA treatment leads to a decrease in serum vitamin A levels. 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) and refer them to an ophthalmologist if they develop these symptoms.
Pregnancy
Instruct patients that if they are pregnant or plan to become pregnant while taking AMVUTTRA they should inform their healthcare provider. Inform patients of the potential risk to the fetus, including that AMVUTTRA treatment leads to a decrease in serum vitamin A levels.
Precautions with Alcohol
Alcohol-Vutrisiran interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
AMVUTTRA
Look-Alike Drug Names
There is limited information regarding Vutrisiran Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.