Viltolarsen (Monograph)

Drug class: Antisense Oligonucleotides

Introduction

Antisense oligonucleotide of the phosphorodiamidate morpholino oligomer subclass.

Uses for Viltolarsen

Duchenne Muscular Dystrophy

Treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. This indication is approved under accelerated approval based on an increase in dystrophin production in skeletal muscle; continued approval may be contingent upon verification of clinical benefit in confirmatory trials.

Designated an orphan drug by FDA for treatment of DMD.

Current standard of care for patients with DMD is use of corticosteroids. While several antisense oligonucleotides are available for treatment of DMD, current guidelines do not specifically address use of these therapies.

Viltolarsen Dosage and Administration

General

Pretreatment Screening

Obtain serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio (UPCR).
Consider measurement of glomerular filtration rate.

Patient Monitoring

Monitor for kidney toxicity during treatment. Creatinine may not be a reliable measure of renal function in patients with DMD because of their lower muscle mass.
Monitor urine dipstick every month.
Monitor serum cystatin C and UPCR every 3 months.

Administration

IV Administration

Administer by IV infusion using a peripheral or central venous catheter.

Supplied in single-dose vial as a 50 mg/mL injection.

Dilution may or may not be required depending on volume of drug needed for dose. If volume of viltolarsen <100 mL, dilution in 0.9% sodium chloride required (see Dilution below). If volume of viltolarsen ≥100 mL, dilution not required; place required amount of viltolarsen into empty infusion bag for administration.

Allow vial to warm to room temperature prior to administration; mix contents by gently inverting 2-3 times. Do not shake.

Do not mix with medications; do not co-administer other medications through same IV line. Visually inspect infusion prior to administration for particulates. Gently invert infusion bag to ensure equal distribution of product. Do not shake.

Begin infusion as soon as possible, but no more than 6 hours after preparation (including the 1 hour infusion time) when the infusion solution is at 20–26°C.

Flush IV access line with 0.9% sodium chloride injection after infusion.

Filtration is not required.

Dilution

If required viltolarsen volume <100 mL, dilute in 0.9% sodium chloride.

To dilute, withdraw a volume of 0.9% sodium chloride injection equivalent to the calculated volume of viltolarsen from 100 mL infusion bag and add viltolarsen to infusion bag for a total volume of 100 mL.

Rate of Administration

Administer IV infusion over 60 minutes.

Dosage

Pediatric Patients

Duchenne Muscular Dystrophy

IV

80 mg/kg once weekly.

If a dose is missed, administer missed dose as soon as possible.

Adults

Duchenne Muscular Dystrophy

IV

80 mg/kg once weekly.

If a dose is missed, administer missed dose as soon as possible.

Special Populations

Hepatic Impairment

No specific population dosage recommendations at this time.

Renal Impairment

Manufacturer states that no specific dosage adjustment can be recommended based on estimated glomerular filtration rate. Closely monitor patients with renal impairment.

Geriatric Patients

No specific population dosage recommendations at this time.

Cautions for Viltolarsen

Contraindications

None.

Warnings/Precautions

Kidney Toxicity

Kidney toxicity observed in animal studies, but not in clinical trials.

Other antisense oligonucleotides have caused kidney toxicity, including potentially fatal glomerulonephritis.

Monitor kidney function; S_crmay be an unreliable marker in DMD.

Obtain serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio before treatment. During treatment, check urine dipstick monthly, and serum cystatin C and urine protein-to-creatinine ratio every 3 months. Use urine collected before infusion or at least 48 hours after most recent infusion, or use a test that avoids pyrogallol red to prevent false positive urine protein results.

Immunogenicity

Potential for immunogenicity. Anti-dystrophin antibodies reported; no adverse events reported. Lack of observed immunogenicity, viltolarsen not highly immunogenic.

Specific Populations

Pregnancy

Not studied in females, and no data available on use during pregnancy.

Lactation

No data on whether viltolarsen is distributed into human milk, or if drug has any effects on breastfed infant or on milk production.

Females and Males of Reproductive Potential

Fertility studies not conducted. No effects on fertility observed in male mice when mating with untreated females.

Pediatric Use

Viltolarsen is indicated for treatment of DMD in pediatric patients who have confirmed mutation of the DMD gene that is amenable to exon 53 skipping.

Geriatric Use

No experience in the geriatric population because DMD primarily affects children and young adults.

Hepatic Impairment

Not studied; does not undergo hepatic metabolism.

Renal Impairment

Renally eliminated. Increased viltolarsen exposure expected with renal impairment, but no dosage adjustment recommended for DMD patients due to altered creatinine levels.

Common Adverse Effects

Most common adverse reactions (≥15%): upper respiratory tract infection, injection site reaction, cough, pyrexia.

Drug Interactions

Low potential for drug-drug interactions.

Does not inhibit CYP3A4/5, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT1A1, or UGT2B7. Does not induce CYP1A2, CYP2B6, or CYP3A4.

Not metabolized by CYP enzymes and not substrate of transporters BCRP, BSEP, MDR1, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K. Does not inhibit transporters tested (OATP1B1, OATP1B3, OAT3, BCRP, MDR1, BSEP, OAT1, OCT1, OCT2, MATE1, and MATE2-K).

Viltolarsen Pharmacokinetics

Absorption

Plasma Concentrations

Peak plasma concentrations achieved at end of infusion.

Distribution

Plasma Protein Binding

39-40%; not concentration dependent.

Elimination

Metabolism

No hepatic metabolism.

No metabolites detected.

Elimination Route

Mainly excreted unchanged in urine.

Half-life

2.5 hours.

Stability

Storage

Parenteral

Injection, for IV use

Store vial at 2-8°C; do not freeze.

Prepared infusion solution stable at 20-26°C for up to 6 hours (inclusive of 1 hour infusion time). If not used immediately, may store prepared solution at 2-8°C for up to 24 hours; do not freeze.

Actions

Antisense oligonucleotide of the phosphorodiamidate morpholino oligomer subclass.
Binds to exon 53 of dystrophin pre-mRNA and restores mRNA reading frame, inducing production of de novo truncated dystrophin protein.

Advice to Patients

Inform patients that nephrotoxicity has occurred with drugs similar to viltolarsen. Advise patients of the importance of monitoring for kidney toxicity by their healthcare providers during treatment with viltolarsen.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Viltolarsen is obtained through the manufacturer. Contact the manufacturer or consult the Viltepso website ([Web]) for more information.