Casimersen (Monograph)

Brand name: Amondys 45
Drug class: Antisense Oligonucleotides

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

Introduction

Antisense oligonucleotide that binds to exon 45 of dystrophin pre-messenger RNA (pre-mRNA).

Uses for Casimersen

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 45 skipping. This indication received accelerated approval based on increased 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 the use of corticosteroids. While antisense oligonucleotides such as casimersen may provide benefits when initiated in the early ambulatory stage, current guidelines do not specifically address these therapies.

Casimersen Dosage and Administration

General

Pretreatment Screening

Obtain serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio prior to initiating therapy.
Consider measuring glomerular filtration rate prior to initiating therapy.

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 proteinuria via urine dipstick every month.
Monitor serum cystatin C and urine protein-to-creatinine ratio (UPCR) every 3 months.

Administration

IV Administration

Administer by IV infusion.

Commercially available as concentrated solution for injection that requires dilution prior to IV administration.

Use a 0.2 micron in-line filter to administer the drug.

Do not administer with any other medications.

May consider application of a topical anesthetic cream to infusion site before administration.

Dilution

Calculate the dose based on patient weight to determine number of vials needed.

Use a 21-gauge or smaller non-coring needle to withdraw the required volume, changing needles periodically to prevent dulling. Dilute in 0.9% sodium chloride to 100–150 ml and gently invert to mix; do not shake. Inspect the solution and discard if cloudy, discolored, or containing unwanted particles other than trace amounts of small, white to off-white amorphous particles.

Complete the infusion within 4 hours of dilution. If immediate use is not possible, the diluted solution may be stored for up to 24 hours at 2-8°C. Do not freeze and discard any unused solution.

Rate of Administration

Administer the IV infusion over 35–60 minutes.

Dosage

Pediatric Patients

Duchenne Muscular Dystrophy

IV infusion

30 mg/kg administered as a 35-60 minute IV infusion once weekly.

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

Adults

Duchenne Muscular Dystrophy

IV infusion

30 mg/kg administered as a 35-60 minute IV infusion once weekly.

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

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations based on eGFR.

Geriatric Patients

No specific dosage recommendations.

Cautions for Casimersen

Contraindications

Serious hypersensitivity to casimersen or any of its inactive ingredients.

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions, including angioedema and anaphylaxis, reported.

Treat reactions promptly and consider slowing, interrupting, or stopping the infusion.

Kidney Toxicity

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

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

Monitor kidney function; creatinine may 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.

Specific Populations

Pregnancy

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

Lactation

No data on whether casimersen is present in breast milk or has any effects on milk production or on the breastfed infant.

Females and Males of Reproductive Potential

Fertility studies not conducted. No effects on the male reproductive system observed in animals.

Pediatric Use

Casimersen is indicated for treatment of DMD in pediatric patients who have a confirmed mutation of the DMD gene that is amenable to exon 45 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 and clearance is not expected to be affected by liver function.

Renal Impairment

Renal clearance is reduced in non-DMD adults with renal impairment, but no dosage adjustment is recommended for DMD patients due to altered creatinine levels. Closely monitor patients with renal impairment.

Common Adverse Effects

Most common adverse reactions (>20%): upper respiratory tract infection, cough, pyrexia, headache, arthralgia, oropharyngeal pain.

Drug Interactions

Low potential for clinically significant drug-drug interactions with major CYP enzymes and transporters.

Does not inhibit CYP1A2, CYP2B6, CYP2C8, or CYP2D6.

Not a substrate or strong inhibitor of key drug transporters including organic anion transporter (OAT)1, OAT3, OCT2, OAT polypeptide (OATP)1B1, OATP1B3, multidrug and toxin extrusion (MATE)1, MATE protein 2-kidney (MATE2-K), P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein (MRP)2.

Casimersen Pharmacokinetics

Absorption

Plasma Concentrations

Peak plasma concentrations achieved near end of infusion.

Distribution

Plasma Protein Binding

8.4–31.6%; not concentration dependent.

Elimination

Elimination Route

Primarily excreted unchanged in urine.

Half-life

Elimination half-life approximately 3.5 hours.

Stability

Storage

Parenteral

Injection Concentrate

Store vials at 2–8°C and in the original carton to protect from light until ready to use; do not freeze or shake.

Diluted solution: Complete infusion within 4 hours of dilution or store for up to 24 hours at 2–8°C if not used immediately.

Actions

Antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass.
Binds to exon 45 of dystrophin pre-mRNA, promoting exon skipping and enabling the production of a truncated but functional dystrophin protein in patients with exon 45 skipping mutations.

Advice to Patients

Advise patients and caregivers that hypersensitivity reactions, including angioedema and anaphylaxis, have occurred with casimersen. Instruct them to seek immediate medical care if symptoms occur.
Inform patients that nephrotoxicity has occurred with drugs similar to casimersen. Advise them on the importance of kidney function monitoring during treatment.
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 women 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.