Drug Information

Indication:

BRIEF SUMMARY

VUTRISRAN- (June 2022)

Indn- To Treat Polynervopathy of Heriditary Amyloidosis

Dosage- Injection: 25 mg/0.5 mL in a single-dose prefilled syringe. The recommended dosage is 25 mg administered by subcutaneous injection once every 3 months.

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

ADR- The most common adverse reactions (=5%) were arthralgia, dyspnea,

CONTRAINDICATIONS-

None.

WARNINGS-

Reduced serum vitamin A levels and recommended supplementation:

Supplement with the recommended daily allowance of vitamin A. Refer

to an ophthalmologist if ocular symptoms suggestive of vitamin A

Pat inform-

Recommended Vitamin A Supplementation

Inform patients that 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 the drug they should inform their healthcare provider.

Inform patients of the potential risk to the fetus, including that treatment leads to a decrease in serum vitamin A levels .

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U.S. APPROVED DRUGS SURING 2022

Serial No 16

Name- AMVUTTRA

Active Ingredient - Vutrisiran

Pharmacological Classification- To Treat Polynervopathy of Heriditary Amyloidosis

Date of Approval- 6/13/22

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use AMVUTTRATM safely and effectively. See full prescribing information for AMVUTTRA. AMVUTTRA (vutrisiran) injection, for subcutaneous use

Initial U.S. Approval: 2022

INDICATIONS AND USAGE-

AMVUTTRA is a transthyretin-directed small interfering RNA indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

Adverse Reaction:

ADVERSE REACTIONS-

The most common adverse reactions (=5%) were arthralgia, dyspnea,

and vitamin A decreased.

Contra-Indications:

CONTRAINDICATIONS-

None.

WARNINGS AND PRECAUTIONS-

Reduced serum vitamin A levels and recommended supplementation:

Supplement with the recommended daily allowance of vitamin A. Refer

to an ophthalmologist if ocular symptoms suggestive of vitamin A

Dosages/ Overdosage Etc:

DOSAGE AND ADMINISTRATION-

• The recommended dosage of AMVUTTRA is 25 mg administered by subcutaneous injection once every 3 months.

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

DOSAGE FORMS AND STRENGTHS-

Injection: 25 mg/0.5 mL in a single-dose prefilled syringe.

Patient Information:

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 .

Manufactured for: Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142

AMVUTTRA is a pending trademark of Alnylam Pharmaceuticals, Inc.

Reference ID:

Pharmacology/ Pharmacokinetics:

CLINICAL PHARMACOLOGY

1 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.

2. Pharmacodynamics

In Study, 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.

3. 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-.

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 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¶

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

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 x ULN and AST

>1 x ULN, or total bilirubin >1.0 to 1.5 x 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.

Pregnancy and lactation:

USE IN SPECIFIC POPULATIONS

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.

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.

2 Lactation

Risk Summary

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 from the underlying maternal condition.

4. Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

5 Geriatric 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

No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older

individuals cannot be ruled out.

6 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) [see Clinical Pharmacology (12.3)]. AMVUTTRA has not been studied in patients with

severe renal impairment or end-stage renal disease.

7. Hepatic Impairment

No dose adjustment is recommended 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) [see Clinical Pharmacology (12.3)].

AMVUTTRA has not been studied in patients with moderate or severe hepatic impairment.

16/22. Vutrisiran -(AMVUTTRA)- (June 2022)- To treat Polynervopathy or Heriditary - Mediated Amyloidosis

Indication

Adverse Reaction

Contra-Indications

Dosages/ Overdosage Etc

Patient Information

Pharmacology/ Pharmacokinetics

Pregnancy and lactation