Eteplirsen is an antisense oligonucleotide specifically indicated for the treatment of patients with Duchenne muscular dystrophy (DMD) who have a confirmed mutation of the dystrophin gene that makes them more likely to respond to exon 51 skipping. Approximately 13% of the DMD population has this mutation. DMD is a rare, X-chromosome-linked disease characterized by progressive muscle deterioration and weakness; it affects approximately 1 in 3,500 to 5,000 male births. Affected children typically develop symptoms in early childhood that quickly progress to a loss of ambulation in adolescence and ultimately, life-threatening heart and respiratory conditions that limit life expectancy to early adulthood. Eteplirsen is the first drug to receive FDA-approval for the treatment of DMD. This approval was based on the surrogate endpoint of increased dystrophin production in skeletal muscle, which the FDA has stated is reasonably likely to predict clinical benefit (e.g., improved motor function). However, small clinical trials failed to demonstrate statistically significant clinical benefit compared to placebo, and the amount of protein produced was only a small fraction of the normal level. In one study, the median increase in truncated dystrophin was 0.1%; the average dystrophin protein level was 0.16% of normal (i.e., 0.16% of the dystrophin level in healthy subjects) before treatment and 0.44% of normal after 48 weeks of treatment. In another study, the average dystrophin protein level in muscle tissues was 0.93% of normal after 180 weeks of treatment. Nonetheless, eteplirsen offers a low-risk treatment option for patients with a rare, debilitating, and life-threatening genetic disorder. The most common adverse effects reported during clinical trials were balance disorder and vomiting. Eteplirsen was FDA-approved in September 2016.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Eteplirsen is a clear, colorless solution that may have some opalescence and contain trace amounts of small white to off-white amorphous particles. Do not use if the solution is cloudy, discolored, or contains extraneous particulate matter.
Intravenous Administration
Preparation
-Dilute prior to use.
-Allow the vials to warm to room temperature.
-Mix the contents of each vial by gently inverting 2 or 3 times. Do not shake.
-Withdraw the calculated amount of drug from the vials with a syringe fitted with a 21-gauge or smaller non-coring needle.
-Dilute the withdrawn drug with 0.9% Sodium Chloride Injection to make a total volume of 100 to 150 mL.
-Do not mix other medications with eteplirsen.
-Administer immediately after dilution. Complete the infusion within 4 hours of dilution.
-Storage: If immediate use is not possible, store the diluted infusion solution for up to 24 hours at 36 to 46 degrees F (2 to 8 degrees C). Do not freeze. Discard any unused drug.
Intermittent IV Infusion
-Topical anesthetic cream may be applied to the infusion site prior to eteplirsen administration.
-Flush the IV access line with 0.9% Sodium Chloride Injection prior to and after infusion.
-Infuse the prepared solution via an in-line 0.2-micron filter over 35 to 60 minutes.
-Do not infuse other medications concomitantly via the same IV access line.
-Eteplirsen is administered once weekly. If a dose is missed, it may be administered as soon as possible after the scheduled time.
Hypersensitivity reactions, including bronchospasm, chest pain (unspecified), cough, sinus tachycardia, and urticaria have occurred in patients treated with eteplirsen. If a hypersensitivity reaction occurs, institute appropriate medical treatment and consider slowing the infusion or interrupting eteplirsen therapy. Cough and rash were reported in more than 10% of eteplirsen-treated patients during open-label observational studies (n = 163).
Balance disorder (vertigo or similar symptoms) (38%), vomiting (38%), and contact dermatitis (25%) occurred in at least 2 eteplirsen-treated patients and at a frequency greater than the placebo group, which did not report any incidence, in a 24 week, double-blind, placebo-controlled study in which patients were randomized to receive weekly IV infusions of eteplirsen 30 mg/kg (n = 4), eteplirsen 50 mg/kg (n = 4), or placebo (n = 4). Of note, the 50 mg/kg once weekly regimen is not recommended. Based on the small number of patients studied, these represent crude frequencies and may not reflect events and frequencies observed in clinical practice. Headache and vomiting were reported in more than 10% of eteplirsen-treated patients during open-label observational studies (n = 163).
Fever, flushing, proteinuria, dehydration, cyanosis of the lips, and malaise have been reported with postmarketing use of eteplirsen.
FDA-approved labeling reports no contraindications for the use of eteplirsen in patients with a confirmed mutation of the Duchenne muscular dystrophy gene that is amenable to exon 51 skipping.
Hypersensitivity reactions have occurred with eteplirsen use; if a reaction occurs, institute appropriate medical treatment and consider slowing or interrupting therapy.
There are no human or animal data available to assess the use of eteplirsen during pregnancy.
There are no human or animal data available to assess the effect of eteplirsen on breast-feeding. This includes data in regards to milk production, the presence of the drug in milk, or the effects of the drug on the breast-fed infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Duchenne muscular dystrophy (DMD) is largely a disease of children and young adults; therefore, there is no geriatric experience with the use of eteplirsen. The drug has not been studied in the geriatric population.
For the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation of the DMD gene that is amenable to exon 51 skipping:
NOTE: Eteplirsen is designated an orphan drug by the FDA for treatment of Duchenne muscular dystrophy.
Intravenous dosage:
Adults: 30 mg/kg/dose IV once weekly.
Children and Adolescents: 30 mg/kg/dose IV once weekly.
Maximum Dosage Limits:
-Adults
30 mg/kg/dose IV once weekly.
-Geriatric
Safety and efficacy have not been established.
-Adolescents
30 mg/kg/dose IV once weekly.
-Children
30 mg/kg/dose IV once weekly.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; eteplirsen has not been studied in patients with hepatic impairment.
Patients with Renal Impairment Dosing
Renal clearance of eteplirsen is reduced in non-Duchenne muscular dystrophy (DMD) adults with renal impairment based on estimated creatinine clearance. However, because of the effect of reduced skeletal muscle mass on creatinine measurement in DMD patients, no specific dosage adjustment can be recommended for DMD patients with renal impairment.
*non-FDA-approved indication
There are no drug interactions associated with Eteplirsen products.
Eteplirsen is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) class that selectively binds to exon 51 of the dystrophin pre-messenger ribonucleic acid (pre-mRNA). This causes the exon to be skipped and prevents that part of the code from being read during mRNA processing, which restores the reading frame for the remainder of the protein and allows for a truncated but partially functional dystrophin.
The dystrophin protein is responsible for muscle cell integrity. Duchenne muscular dystrophy (DMD) is caused by various mutations, most often internal deletions, in the gene coding for dystrophin. These mutations shift the reading frame so that mRNA does not code correctly for a functional protein, leading to a lack of dystrophin which results in muscle cell membrane destabilization and, consequently, muscle deterioration and loss. Exon skipping allows for production of functional protein. During clinical trials, all eteplirsen-treated patients evaluated (n = 36) were found to produce mRNA for a truncated dystrophin protein. In one study, the median increase in truncated dystrophin was 0.1%; the average dystrophin protein level was 0.16% of normal (i.e., 0.16% of the dystrophin level in healthy subjects) before treatment and 0.44% of normal after 48 weeks of treatment. In another study, the average dystrophin protein level in muscle tissues was 0.93% of normal after 180 weeks of treatment.
Eteplirsen is administered intravenously. In vitro data suggests human plasma protein binding ranges from 6% to 17%. Mean apparent volume of distribution is 600 mL/kg after weekly infusion. Eteplirsen does not appear to be hepatically metabolized. Total clearance is 339 mL/kg/hour after 12 weeks of therapy. Renal clearance accounts for approximately two-thirds of the administered dose within 24 hours of administration. Elimination half-life is 3 to 4 hours.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: None
Based on in vitro data, eteplirsen is expected to have a low potential for drug-drug interactions. Eteplirsen does not appear to be hepatically metabolized. In vitro investigations did not reveal significant inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. In addition, eteplirsen did not induce CYP2B6 or CYP3A4, and induction of CYP1A2 was substantially less than the prototypical inducer, omeprazole. Eteplirsen was not a substrate and did not have any major inhibitory potential for the key human transporters OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, P-glycoprotein (P-gp), BRCP, MRP2, and BSEP.
-Route-Specific Pharmacokinetics
Intravenous Route
Peak plasma concentrations occur near the end of the infusion (i.e., within 1.1 to 1.2 hours) after both single and multiple IV infusions of eteplirsen. During clinical trials, inter-subject variability for eteplirsen Cmax and AUC ranged from 20% to 55%.
-Special Populations
Hepatic Impairment
Eteplirsen does not appear to be hepatically metabolized. Pharmacokinetic differences due to hepatic impairment are not known; eteplirsen has not been studied in patients with hepatic impairment.
Renal Impairment
Eteplirsen is renally excreted. The effect of renal impairment on the pharmacokinetics of eteplirsen was evaluated in non-Duchenne muscular dystrophy (DMD) adults (aged 51 to 75 years) with renal impairment. Patients with mild (CrCl 60 mL/minute to 89 mL/minute) and moderate (CrCl 30 mL/minute to 59 mL/minute) renal impairment showed higher eteplirsen exposure compared to patients with normal renal function. In patients with mild and moderate renal impairment, AUC increased approximately 1.4- and 2.4-fold, respectively. The effect of severe renal failure or end-stage renal disease on eteplirsen pharmacokinetics has not been studied. Pharmacokinetic differences due to renal impairment in non-DMD adults are not generalizable to patients with DMD.
Pediatrics
The pharmacokinetics of eteplirsen were evaluated in male pediatric patients due to the prevalence of Duchenne muscular dystrophy in this population.
Geriatric
Pharmacokinetic differences in geriatric patients are not known; eteplirsen has not been studied in geriatric patients given the prevalence of the disease in pediatric patients and young adults.
Gender Differences
Pharmacokinetic differences due to gender are not known; eteplirsen has not been studied in female patients.
Ethnic Differences
Pharmacokinetic differences due to race are not known; 89% of patients studied were Caucasian.