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    Antisense Oligonucleotides for Muscular Dystrophy

    DEA CLASS

    Rx

    DESCRIPTION

    Antisense oligonucleotide
    Used 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
    Limited evidence for clinical improvement; provides low-risk treatment option for patients with a rare, debilitating, and life-threatening disorder

    COMMON BRAND NAMES

    Exondys 51

    HOW SUPPLIED

    Exondys 51 Intravenous Inj Sol: 1mL, 50mg

    DOSAGE & INDICATIONS

    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

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; eteplirsen has not been studied in patients with hepatic impairment.

    Renal Impairment

    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.[61175]

    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.[61175]

    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.[61175]
     
    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.[61175]

    STORAGE

    Exondys 51 :
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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.

    Pregnancy

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

    Breast-feeding

    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.

    Geriatric

    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.

    ADVERSE REACTIONS

    Severe

    bronchospasm / Rapid / Incidence not known
    cyanosis / Early / Incidence not known

    Moderate

    contact dermatitis / Delayed / 25.0-25.0
    chest pain (unspecified) / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    dehydration / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known

    Mild

    vertigo / Early / 38.0-38.0
    cough / Delayed / 10.0
    rash / Early / 10.0
    vomiting / Early / 10.0
    headache / Early / 10.0
    urticaria / Rapid / Incidence not known
    fever / Early / Incidence not known
    flushing / Rapid / Incidence not known
    malaise / Early / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Eteplirsen products.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.

    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%.