Prescription Drug Information: AMVUTTRA

AMVUTTRA- vutrisiran injection
Alnylam Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

AMVUTTRA is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of AMVUTTRA is 25 mg administered by subcutaneous injection once every 3 months [see Dosage and Administration (2.2)].

Missed Dose

If a dose is missed, administer AMVUTTRA as soon as possible. Resume dosing every 3 months from the most recently administered dose.

2.2 Administration Instructions

AMVUTTRA is for subcutaneous use only and should be administered by a healthcare professional.

Syringe Appearance Before and After Use

Before Use
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After Use
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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.
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.
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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.
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4.
Perform the injection Pinch the cleaned skin.Fully insert the needle into the pinched skin at a 45°-90° angle.
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Inject all of the medication.
Push the plunger rod as far as it will go to administer the dose and activate the needle shield.
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Release the plunger rod to allow the needle shield to cover the needle.
Do not block plunger rod movement.
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5.
Dispose of the syringe Immediately dispose of the used syringe into a sharps container.

3 DOSAGE FORMS AND STRENGTHS

Injection: 25 mg/0.5 mL of vutrisiran as a clear, colorless-to-yellow solution in a single-dose prefilled syringe.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Reduced Serum Vitamin A Levels and Recommended Supplementation

AMVUTTRA treatment leads to a decrease in serum vitamin A levels [see Adverse Reactions (6.1) and Clinical Pharmacology (12.2)].

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).

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

6.1 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 [see Clinical Studies (14)] , 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 (see Table 1).

In Study 1, patients were instructed to take the recommended daily allowance of vitamin A [see Warnings and Precautions (5.1)]. 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 (see Table 1).

Table 1: Adverse Reactions Reported in at least 5% of Patients Treated with AMVUTTRA (Study 1)
Adverse Reaction AMVUTTRAN=122%
*
Comprised of several similar terms
Percentage only reflects those reported as an adverse reaction
Pain in extremity * 15
Arthralgia * 11
Dyspnea * 7
Vitamin A decreased 7

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.

6.2 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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 [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].

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 (see Data).

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. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

Subcutaneous administration of vutrisiran (0, 3, 10, or 30 mg/kg/day) to pregnant rats during the period of organogenesis resulted in embryofetal mortality at the high dose and reduced fetal body weight at the mid and high doses, which were associated with maternal toxicity.

Subcutaneous administration of vutrisiran (0, 3, 10, or 30 mg/kg/day) to pregnant rabbits resulted in no adverse effects on embryofetal development.

Subcutaneous administration of vutrisiran (0, 5, 10, or 20 mg/kg) to pregnant rats every 6 days throughout pregnancy and lactation resulted in no adverse developmental effects on the offspring.

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