Golodirsen is an injectable antisense oligonucleotide indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the dystrophin gene that is amenable to exon 53 skipping. Approximately 8% 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. FDA-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). During a small 2-part clinical study (n = 25), mean dystrophin concentrations increased from 0.1% of normal at baseline to 1.02% of normal after 48 weeks of golodirsen treatment. The most common adverse reactions reported include headache, fever, fall, abdominal pain, nasopharyngitis, cough, vomiting, and nausea. Measurement of glomerular filtration rate prior to initiation and monitoring for renal toxicity during treatment is recommended. Although not observed in clinical trials, renal toxicity has been observed in golodirsen-treated animals and in humans after administration of some antisense oligonucleotides.
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. Golodirsen is a clear to slightly opalescent, colorless liquid, and may 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 other than the trace amounts described.
-If a dose is missed, administer it as soon as possible after the scheduled dose.
Intravenous Administration
Preparation
-Allow vials to warm to room temperature.
-Mix the contents of each vial by gently inverting 2 to 3 times. Do not shake.
-Withdraw the dosage volume using a 21-gauge or smaller bore non-coring needle.
-Dilute withdrawn drug in 0.9% Sodium Chloride Injection to make a total volume of 100 to 150 mL. Gently invert 2 to 3 times to mix. Do not shake. Visually inspect for particulates.
-Administer immediately after dilution, completing the infusion with 4 hours of dilution.
-Storage: If immediate use is not possible, store diluted solution for up to 24 hours at 2 to 8 degrees C (36 to 46 degrees F). Do not freeze. Discard unused drug.
Intermittent IV Infusion
-Topical anesthetic cream may be applied to the infusion site prior to golodirsen administration.
-Flush the IV access line with 0.9% Sodium Chloride Injection prior to and after the infusion.
-Infuse the prepared solution over 35 to 60 minutes via an in-line 0.2-micron filter.
-Do not infuse other medications concomitantly via the same IV access line.
-Slow the infusion or interrupt therapy if a hypersensitivity reaction occurs.
Headache (41%), fever (41%), fall (29%), abdominal pain (27%), naso-pharyngitis (27%), cough (27%), vomiting (27%), and nausea (20%) were the most common adverse reactions reported in golodirsen-treated patients during clinical trials.
Injection site reaction (i.e., administration site pain and catheter site related reaction), back pain, pain, diarrhea, dizziness, ligament sprain, contusion, influenza, oropharyngeal pain, rhinitis, skin abrasion, ear infection, seasonal allergy, sinus tachycardia, constipation, and fracture occurred at a frequency greater than 5% in golodirsen-treated patients during clinical trials.
Hypersensitivity reactions including rash, pyrexia, pruritus, urticaria, dermatitis, and skin exfoliation (exfoliative dermatitis) have occurred in golodirsen-treated patients. If a hypersensitivity reaction occurs, institute appropriate medical management and consider slowing the infusion or interrupting therapy.
Hypersensitivity reactions have occurred in golodirsen-treated patients. If a hypersensitivity reaction occurs, institute appropriate medical management and consider slowing the infusion or interrupting therapy.
Closely monitor patients with renal disease or known renal impairment (including renal failure) during treatment with golodirsen. Measure serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio prior to initiation. Additionally, consider measuring glomerular filtration rate (GFR) using an exogenous filtration marker prior to initiation. During treatment, measure urine dipstick monthly and serum cystatin C and urine protein-to-creatinine ratio every 3 months. Only use urine expected to be free of excreted drug for monitoring urine protein; urine must be obtained on the day of infusion prior to infusion or at least 48 hours after the most recent infusion. Alternatively, use a laboratory test that does not use the reagent pyrogallol red. This reagent has the potential to cross react with any golodirsen that is excreted in the urine and may therefore lead to a false positive result for urine protein. Consult a pediatric nephrologist if a persistent increase in serum cystatin C or proteinuria is detected. Renal clearance of golodirsen is reduced in non-Duchenne muscular dystrophy (DMD) adults with renal impairment, based on estimated GFR calculated using the Modification of Diet and Renal Disease (MDRD) equation. However, creatinine may not be a reliable measure of renal function in DMD patients because of the effect of reduced skeletal muscle mass on creatinine measurements. Renal toxicity was not observed in clinical trials of golodirsen; however, toxicity has been observed in golodirsen-treated animals and in humans after administration of some antisense oligonucleotides.
There are no human or animal data available to assess the use of golodirsen during pregnancy.
There are no human or animal data available to assess the effect of golodirsen on milk production, the presence of golodirsen in milk, or the effects 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 maternal 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 golodirsen. The drug has not been studied in the geriatric population.
For the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping:
NOTE: Golodirsen 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; golodirsen has not been studied in patients with hepatic impairment.
Patients with Renal Impairment Dosing
Monitor renal function in all patients; specific guidelines for dosage adjustments in renal impairment are not available.
*non-FDA-approved indication
There are no drug interactions associated with Golodirsen products.
Golodirsen is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) class that selectively binds to exon 53 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 (n =25), mean dystrophin concentrations increased from 0.1% of normal at baseline to 1.02% of normal after 48 weeks of golodirsen treatment.
Golodirsen is administered intravenously. Mean steady-state Vd is 668 mL/kg. Protein binding ranges from 33% to 39% and is not concentration dependent. Golodirsen is metabolically stable with no metabolites. It is mostly excreted unchanged in the urine with a plasma clearance of 346 mL/kg/hour and an elimination half-life of 3.4 hours.
Affected cytochrome P450 isoenzymes and drug transporters: none
Based on in vitro data, golodirsen has a low potential for drug-drug interactions. Golodirsen is not metabolized hepatically. Golodirsen was a weak inducer of CYP1A2 in vitro.
-Route-Specific Pharmacokinetics
Intravenous Route
Golodirsen exposure increases proportionally with dose, with minimal accumulation with once-weekly dosing. Inter-subject variability (as %CV) of Cmax and AUC ranged from 38% to 72% and 34% to 44%, respectively, during clinical trials.
-Special Populations
Hepatic Impairment
Golodirsen is not hepatically metabolized. It has not been studied in patients with hepatic impairment.
Renal Impairment
Golodirsen exposure (AUC) increased approximately 1.2-fold and 1.9-fold in subjects with Stage 2 (eGFR 60 to 89 mL/minute/1.73 m2) or Stage 3 (eGFR 30 to 59 mL/minute/1.73 m2) chronic kidney disease (CKD), respectively, during pharmacokinetic evaluation in adult non-Duchenne muscular dystrophy (DMD) subjects (age range: 41 to 65 years). There was no change in the Cmax in subjects with Stage 2 CKD; in patients with Stage 3 CKD, there was a 1.2-fold increase in Cmax compared to subjects with normal renal function. The effect of Stage 4 or Stage 5 CKD on golodirsen pharmacokinetics has not been studied. Estimated GFR values derived from the Modification of Diet and Renal Disease (MDRD) and threshold definition for CKD stages are not generalizable to pediatric patients with DMD.
Pediatrics
The pharmacokinetics of golodirsen presented were evaluated in male pediatric Duchenne muscular dystrophy patients.
Geriatric
Golodirsen has not been studied in geriatric patients given the prevalence of the disease in pediatric patients and young adults.
Gender Differences
Golodirsen pharmacokinetics have not been studied in female patients.
Ethnic Differences
Pharmacokinetic differences due to race are not known; 92% of patients studied were Caucasian.