2.1 Monitoring to Assess Safety

Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio (UPCR) should be measured before starting AMONDYS 45. Consider measurement of glomerular filtration rate prior to initiation of AMONDYS 45. Monitoring for kidney toxicity during treatment is recommended. Obtain the urine sample prior to infusion of AMONDYS 45 or at least 48 hours after infusion [see Warnings and Precautions (5.2)].

2.2 Dosing Information

The recommended dosage of AMONDYS 45 is 30 milligrams per kilogram administered once weekly as a 35 to 60-minute intravenous infusion via an in-line 0.2 micron filter.

If a dose of AMONDYS 45 is missed, it may be administered as soon as possible after the scheduled dose.

2.3 Preparation Instructions

AMONDYS 45 is supplied in single-dose vials as a preservative-free concentrated solution that requires dilution prior to administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use aseptic technique.

1. Calculate the total dose of AMONDYS 45 to be administered based on the patient's weight and the recommended dose of 30 milligrams per kilogram. Determine the volume of AMONDYS 45 needed and the correct number of vials to supply the full calculated dose.
2. Allow the vials to warm to room temperature. Mix the contents of each vial by gently inverting 2 or 3 times. Do not shake.
3. Visually inspect each vial of AMONDYS 45. The solution 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 in the vials is cloudy, discolored or contains extraneous particulate matter other than trace amounts of small, white to off-white amorphous particles.
4. With a syringe fitted with a 21-gauge or smaller bore non-coring needle, withdraw the calculated volume of AMONDYS 45 from the appropriate number of vials. To avoid dulling the needle and fragmenting the stoppers, replace the needle periodically during preparation.
5. Dilute the withdrawn AMONDYS 45 in 0.9% Sodium Chloride Injection, USP, to make a total volume of 100 to 150 mL. Gently invert 2 to 3 times to mix. Do not shake. Visually inspect the diluted solution. Do not use if the solution is cloudy, discolored or contains extraneous particulate matter other than trace amounts of small, white to off-white amorphous particles.
6. Administer the diluted solution via an in-line 0.2 micron filter.
7. AMONDYS 45 contains no preservatives and should be administered immediately after dilution. Complete infusion of diluted AMONDYS 45 within 4 hours of dilution. If immediate use is not possible the diluted product may be stored for up to 24 hours at 2 °C to 8 °C (36 °F to 46 °F). Do not freeze. Discard unused AMONDYS 45.

2.4 Administration Instructions

Application of a topical anesthetic cream to the infusion site prior to administration of AMONDYS 45 may be considered.

AMONDYS 45 is administered via intravenous infusion. Flush the intravenous access line with 0.9% Sodium Chloride Injection, USP, prior to and after infusion.

Infuse the diluted AMONDYS 45 over 35 to 60 minutes via an in-line 0.2 micron filter. Do not mix other medication with AMONDYS 45 or infuse other medications concomitantly via the same intravenous access with AMONDYS 45.

If a hypersensitivity reaction occurs, consider slowing the infusion, interrupting or discontinuing the AMONDYS 45 therapy [see Warning and Precautions (5.1) and Adverse Reactions (6.2)].

5.1 Hypersensitivity Reactions

Hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients who were treated with AMONDYS 45. If a hypersensitivity reaction occurs, institute appropriate medical treatment, and consider slowing the infusion [see Dosage and Administration (2.4)], interrupting, or discontinuing the AMONDYS 45 infusion and monitor until the condition resolves [see Contraindications (4)].

5.2 Kidney Toxicity

Kidney toxicity was observed in animals who received casimersen [see Use in Specific Populations (8.4) and Nonclinical Toxicology (13.2)]. Although kidney toxicity was not observed in the clinical studies with AMONDYS 45, kidney toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Kidney function should be monitored in patients taking AMONDYS 45. 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 AMONDYS 45. Consider also measuring glomerular filtration rate using an exogenous filtration marker before starting AMONDYS 45. During treatment, monitor urine dipstick every month, and serum cystatin C and urine protein-to-creatinine ratio (UPCR) every three months. Only urine expected to be free of excreted AMONDYS 45 should be used for monitoring of urine protein. Urine obtained on the day of AMONDYS 45 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 AMONDYS 45 that is excreted in the 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.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the AMONDYS 45 clinical development program, 76 patients received at least one intravenous dose of AMONDYS 45 (30 mg/kg). All patients were male and had genetically confirmed Duchenne muscular dystrophy. Age at study entry was 7 to 20 years (mean 9.9 years). Most (88%) patients were White, and 9% were Asian.

AMONDYS 45 was studied in a double-blind, placebo-controlled study (Study 1).

Patients in ongoing Study 1 received AMONDYS 45 (n=57) 30 mg/kg or placebo (n=31) intravenously once weekly for up to 96 weeks, after which all patients received or will receive AMONDYS 45 30 mg/kg for up to 48 weeks.

Adverse reactions observed in ≥20% of patients treated with AMONDYS 45 and 5% more frequently than in the placebo group in Study 1 are shown in Table 1.

Other adverse reactions that occurred in at least 10% of patients treated with AMONDYS 45, and that were reported at a rate at least 5% more frequently in the AMONDYS 45 group than in the placebo group, were: ear pain, nausea, ear infection, post-traumatic pain, and dizziness and light-headedness.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of AMONDYS 45. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients treated with AMONDYS 45.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

AMONDYS 45 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 [see Clinical Studies (14)].

8.5 Geriatric Use

DMD is largely a disease of children and young adults; therefore, there is no experience with AMONDYS 45 in geriatric DMD patients.

8.6 Patients with 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) [see Clinical Pharmacology (12.3)]. 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 AMONDYS 45.

12.1 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 [see Clinical Studies (14)].

12.2 Pharmacodynamics

In the interim analysis of muscle biopsy tissue obtained at baseline and at Week 48 from patients in Study 1, patients who received AMONDYS 45 (n=27) demonstrated a significant increase in skipping of exon 45 (p<0.001) compared to baseline, demonstrated by reverse transcription digital droplet polymerase chain reaction (RT-ddPCR). Patients who received placebo (n=16) did not demonstrate a significant increase in exon 45 skipping (p=0.808). The level of exon skipping is positively correlated with dystrophin protein expression [see Clinical Studies (14)].

In Study 1 [see Clinical Studies (14)], dystrophin levels as assessed by the Sarepta Western blot assay increased from 0.93% (SD 1.67) of normal at baseline to 1.74% (SD 1.97) of normal after 48 weeks of treatment with AMONDYS 45. The mean change from baseline in dystrophin after 48 weeks of treatment with AMONDYS 45 was 0.81% (SD 0.70) of normal levels (p<0.001). This increase in dystrophin protein expression after treatment with AMONDYS 45 positively correlated with the level of exon skipping. The mean change from baseline in dystrophin after 48 weeks of treatment with placebo was 0.22% (SD 0.49). Patients who received AMONDYS 45 showed a significantly greater increase in dystrophin protein levels from baseline to Week 48 compared to those who received placebo (mean difference of 0.59%; p = 0.004). Dystrophin levels assessed by Western blot can be meaningfully influenced by differences in sample processing, analytical technique, reference materials, and quantitation methodologies. Therefore, comparing dystrophin results from different assay protocols will require a standardized reference material and additional bridging studies.

Correct localization of dystrophin to the sarcolemma in patients treated with AMONDYS 45 was demonstrated by immunofluorescence staining.

12.3 Pharmacokinetics

The pharmacokinetics of casimersen was evaluated in DMD patients following administration of intravenous (IV) doses ranging from 4 mg/kg/week to 30 mg/kg/week (i.e., recommended dosage). Following a single IV dose of casimersen, Cmax was reached at the end of infusion. Casimersen exposure increased in a proportional manner with dose increment. No accumulation of casimersen was observed in plasma following once weekly dosing. Inter-subject variability (as %CV) for casimersen Cmax and AUC ranged from 12% to 34% and 16% to 34%, respectively.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

Kidney toxicity was observed in studies in male mice and rats [see Warnings and Precautions (5.1)].

In male mice, casimersen was administered weekly for 12 weeks (0, 12, 120, or 960 mg/kg) or 22 weeks (0, 300, 960, or 2000 mg/kg) by intravenous injection or for 26 weeks by subcutaneous injection (0, 300, 600, or 960 mg/kg). In the 12-week study, microscopic findings in kidney (cytoplasmic basophilia and microvacuolation) were observed at the highest dose tested. In the 22- and 26-week studies, renal tubular degeneration was observed at all doses. A no-effect dose for adverse effects on kidney was not identified. Plasma exposure (AUC) at the lowest dose tested in the 26-week study (300 mg/kg) was approximately 2 times that in humans at the recommended human dose (RHD) of 30 mg/kg/week.

In male rats, intravenous administration of casimersen (0, 250, 500, 1000, or 2000 mg/kg) weekly for 13 weeks resulted in renal tubular degeneration at all doses tested; at the highest dose, the microscopic changes were accompanied by increases in blood urea nitrogen. A no-effect dose for adverse effects on kidney was not identified. Plasma exposure (AUC) at the lowest dose tested were approximately 4 times that in humans at the RHD.

16.1 How Supplied

AMONDYS 45 injection is supplied in single dose vials. The solution is a clear to slightly opalescent, colorless liquid, and may contain trace amounts of small, white to off-white amorphous particles.

• Single-dose vials containing 100 mg/2 mL (50 mg/mL) NDC 60923-227-02

16.2 Storage and Handling

Store AMONDYS 45 at 2°C to 8°C (36°F to 46°F). Do not freeze. Store in original carton until ready for use to protect from light.

Hypersensitivity Reactions

Advise patients and/or caregivers that hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients who were treated with AMONDYS 45. Instruct them to seek immediate medical care should they experience signs and symptoms of hypersensitivity [see Warnings and Precautions (5.1)].

Kidney Toxicity

Inform patients nephrotoxicity has occurred with drugs similar to AMONDYS 45. Advise patients of the importance of monitoring for kidney toxicity by their healthcare providers during treatment with AMONDYS 45 [see Warnings and Precautions (5.2)].

Manufactured for:
Sarepta Therapeutics, Inc.
Cambridge, MA 02142 USA

Sarepta and Sarepta Therapeutics are trademarks of Sarepta Therapeutics, Inc. registered in the U.S. Patent and Trademark Office and may be registered in various other jurisdictions. AMONDYS 45 and the AMONDYS 45 logo are trademarks of Sarepta Therapeutics, Inc.