Vutrisiran: Use in Patients Undergoing Dialysis

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The full Prescribing Information for AMVUTTRA® (vutrisiran) is provided here. Alnylam Pharmaceuticals does not recommend the use of its products in any manner that is inconsistent with the approved Prescribing Information. This resource may contain information that is not in the approved Prescribing Information.

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SUMMARY

Patients with severe renal impairment or ESRD were excluded from vutrisiran clinical studies; therefore, the use of vutrisiran in patients undergoing dialysis is unknown.1,2
A cumulative post-marketing review of Alnylam Pharmaceuticals’ global safety database did not identify any new safety concerns with the use of vutrisiran in patients with severe renal impairment or ESRD.3

INDEX

Clinical Data – Global Safety Database – Label Information – Abbreviations – References

Clinical Data

Clinical Pharmacology Information

Across various clinical pharmacology studies including both healthy subjects and patients with hATTR-PN, the mean serum t1/2 ranged from 4 to 7.5 hours following subcutaneous administration of vutrisiran. After reaching the Cmax, vutrisiran concentration declined rapidly to the LLOQ by 24 to 48 hours. Clinical pharmacology data have shown that renal clearance is not a major route of elimination of vutrisiran.4

Pooled Safety Population

In a pooled PK/PD population (n=202) including data from the Phase 1 and HELIOS-A studies, patients with mild to moderate renal impairment showed similar TTR reductions compared to those with no renal impairment. No significant impact of impaired renal function was observed, with a less than 25% increase in Cmax and AUC0-24 predicted in patients with mild or moderate renal impairment compared to patients with normal renal function.4

Global Safety Database

A cumulative post-marketing review of Alnylam Pharmaceuticals’ global safety database did not identify any new safety concerns with the use of vutrisiran in patients with severe renal impairment or ESRD.3

Amvuttra Prescribing Information – Relevant content

The USE IN SPECIFIC POPULATIONS section provides the following information5:

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.

The CLINICAL PHARMACOLOGY section provides the following information5:

Pharmacokinetics

The pharmacokinetic (PK) properties of AMVUTTRA were evaluated following a single dose in healthy subjects and multiple doses in patients with hATTR amyloidosis, as summarized in Table 2.

Table 2: Pharmacokinetic Parameters of Vutrisiran

	Vutrisiran
General Information
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 dosagea
Absorption
Tmax [Median (Range)]	4 (0.17, 12.0) hoursb
Distribution
Estimated Vd/F (%RSE)	10.1 (5.8) Lc
Protein Binding	80%d
Organ Distribution	Vutrisiran distributes primarily to the liver after subcutaneous dosing
Elimination
Half-Life [Median (Range)]	5.2 (2.2, 6.4) hoursb
Apparent Clearance [Median (Range)]	21.4 (19.8, 30) L/hourb
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/houre
AUCinf = area under the concentration-time curve from the time of dosing extrapolated to infinity; AUClast = area under the concentration-time curve from the time of dosing to the last measurable concentration; Cmax = maximum plasma concentration; CV = coefficient of variation; RSE = relative standard error; Tmax = time to maximum concentration; Vd/F = apparent volume of distribution aAfter 25 mg every 3 months dosage in hATTR amyloidosis patients bAfter 25 mg single dose in healthy subjects cBased on population PK model estimation dVutrisiran plasma protein binding was concentration-dependent and decreased with increasing vutrisiran concentrations (from 78% at 0.5 mcg/mL to 19% at 50 mcg/mL) eAfter single subcutaneous vutrisiran dose from 5 to 300 mg (i.e., 0.2 to 12 times the recommended dose) in healthy subjects

Abbreviations

AUC0-24 = area under the concentration time curve from 0 to 24 hours; AUCinf = area under the concentration-time curve from the time of dosing extrapolated to infinity; AUClast = area under the concentration-time curve from the time of dosing to the last measurable concentration; Cmax = maximum plasma concentration; CV = coefficient of variation; ESRD = end-stage renal disease; hATTR-PN = hereditary transthyretin amyloidosis with polyneuropathy; LLOQ = lower limit of quantification; PD = pharmacodynamics; PK = pharmacokinetics; RSE = relative standard error; t1/2 = half-life; Tmax = time to maximum concentration; TTR = transthyretin; Vd/F = apparent volume of distribution.

Updated 20 December 2024

References

1. Alnylam Pharmaceuticals. Data on file. MED-ALL-TTRSC02-2300015.

2. Protocol for: Fontana M, Berk JL, Gillmore JD, et al. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. N Engl J Med. 2025;392(1):33-44. doi:10.1056/NEJMoa2409134

3. Alnylam Pharmaceuticals. Data on file. MED-ALL-TTRSC02-2400036.

4. Amvuttra : EPAR – Public assessment report. European Medicines Agency. Published October 12, 2022. Accessed December 20, 2024. https://www.ema.europa.eu/documents/assessment-report/amvuttra-epar-public-assessment-report_en.pdf.

5. AMVUTTRA (vutrisiran) Prescribing Information. Cambridge, MA: Alnylam Pharmaceuticals, Inc.


MED-ALL-TTRSC02-2300040 2.0 Approved through Jan 2027

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