Casimersen (Monograph)

Brand name: Amondys 45
Drug class: Antisense Oligonucleotides

Introduction

Casimersen is an antisense oligonucleotide.

Uses for Casimersen

Casimersen has the following uses:

Casimersen is indicated for the 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 is approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with casimersen. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.

Casimersen Dosage and Administration

General

Casimersen is available in the following dosage form(s) and strength(s):

Injection: 100 mg/2 mL in a single-dose vial.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Pediatric Patients

Dosage and Administration

Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio should be measured before starting casimersen.
The recommended dosage of casimersen is 30 mg/kg of body weight once weekly.
Administer as an IV infusion over 35 to 60 minutes via an in-line 0.2 micron filter.
Dilution required prior to administration.

Adults

Dosage and Administration

Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio should be measured before starting casimersen.
The recommended dosage of casimersen is 30 mg/kg of body weight once weekly.
Administer as an IV infusion over 35 to 60 minutes via an in-line 0.2 micron filter.
Dilution required prior to administration.

Cautions for Casimersen

Contraindications

None.

Warnings/Precautions

Kidney Toxicity

Kidney toxicity was observed in animals who received casimersen. Although kidney toxicity was not observed in the clinical studies with casimersen, kidney toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Kidney function should be monitored in patients taking casimersen. Because of the effect of reduced skeletal muscle mass on creatinine measurements, creatinine may not be a reliable measure of kidney function in DMD patients. Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio should be measured before starting casimersen. Consider also measuring glomerular filtration rate using an exogenous filtration marker before starting casimersen. During treatment, monitor urine dipstick every month, and serum cystatin C and urine protein-to-creatinine ratio every three months. Only urine expected to be free of excreted casimersen should be used for monitoring of urine protein. Urine obtained on the day of casimersen infusion prior to the infusion, or urine obtained at least 48 hours after the most recent infusion, may be used. Alternatively, use a laboratory test that does not use the reagent pyrogallol red, as this reagent has the potential to cross-react with any casimersen that is excreted in urine and thus lead to a false-positive result for urine protein.

If a persistent increase in serum cystatin C or proteinuria is detected, refer to a pediatric nephrologist for further evaluation.

Specific Populations

Pregnancy

There are no human or animal data available to assess the use of casimersen during pregnancy.

In the U.S. general population, major birth defects occur in 2% to 4% and miscarriage occurs in 15% to 20% of clinically recognized pregnancies.

Lactation

There are no human or animal data to assess the effect of casimersen on milk production, the presence of casimersen in milk, or the effects of casimersen on the breastfed infant.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for casimersen and any potential adverse effects on the breastfed infant from casimersen or from the underlying maternal condition.

Pediatric Use

Casimersen is indicated for the treatment of DMD in patients who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping, including pediatric patients.

Juvenile Animal Toxicity Data: IV administration of casimersen (0, 100, 300, and 900 mg/kg) to juvenile male rats once weekly for 10 weeks (postnatal days 14 to 77) resulted in renal tubular degeneration/necrosis at the highest dose tested. No effects were observed on the male reproductive system, neurobehavioral development, or immune function. At the overall no-effect dose (300 mg/kg), plasma exposure (AUC) was 4 times that in humans at the recommended human dose of 30 mg/kg/week.

Geriatric Use

DMD is largely a disease of children and young adults; therefore, there is no experience with casimersen in geriatric DMD patients.

Renal Impairment

Renal clearance of casimersen is decreased in non-DMD adults with renal impairment based on estimated glomerular filtration rate (calculated using the Modification of Diet and Renal Disease [MDRD] equation). However, because of the effect of reduced skeletal muscle mass on creatinine measurements in DMD patients, no specific dosage adjustment can be recommended for DMD patients with renal impairment based on estimated glomerular filtration rate. Patients with known renal function impairment should be closely monitored during treatment with casimersen.

Common Adverse Effects

The most common adverse reactions (incidence >20% and at least 5% higher than placebo) were upper respiratory tract infection, cough, pyrexia, headache, arthralgia, and oropharyngeal pain.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

Casimersen is designed to bind to exon 45 of dystrophin pre-mRNA resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 45 skipping. Exon 45 skipping is intended to allow for production of an internally truncated dystrophin protein in patients with genetic mutations that are amenable to exon 45 skipping.

Advice to Patients

Inform patients that nephrotoxicity has occurred with drugs similar to casimersen. Advise patients of the importance of monitoring for kidney toxicity by their healthcare providers during treatment with casimersen.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.