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 | After Use |
Preparation and Administration
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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:
- Reduced Serum Vitamin A Levels and Recommended Supplementation [see Warnings and Precautions (5.1)]
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).
Adverse Reaction | AMVUTTRAN=122% |
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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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