BRIEF SUMMARY

CASIMERSIN-(Feb 2021)

Indn- For the treatment of Duchenne muscular dystrophy   

Comp- Injection: 100 mg/2 mL in a single-dose vial  • Administer as an intravenous (IV) infusion over 35 to 60 minutes via an in-line 0.2 micron filter 

• Dilution required prior to administration 

ADR- most common adverse reactions  were upper respiratory tract infection, cough, pyrexia, headache, arthralgia, and oropharyngeal pain

CI- None

WARNINGS-­ • Kidney Toxicity: Based on animal data, may cause kidney toxicity. Kidney function should be monitored; creatinine may not be a reliable measure of renal function in DMD patients.

Pat Inform-

 Inform patients nephrotoxicity has occurred with drugs similar  to the product

Advise patients of the importance of monitoring for kidney toxicity by their healthcare providers during treatment 

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 8

Name of the Drug-    AMONDYS 45

Active Ingredient -    Casimersen

Pharmacological Classification-   For the treatment of Duchenne muscular                                                                       dystrophy                                                                                                                                                                                                               Date of Approval-          2/25/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                                AMONDYS 45 safely and effectively.                                                                             See full prescribing information for AMONDYS 45. AMONDYS 45 (casimersen) injection, for intravenous use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE

 AMONDYS 45 is an antisense oligonucleotide 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 AMONDYS 45 

Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.

DOSAGE AND ADMINISTRATION

• Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio should be measured before starting AMONDYS 45 (2.1) • 30 milligrams per kilogram of body weight once weekly

 • Administer as an intravenous (IV) infusion over 35 to 60 minutes via an in-line 0.2 micron filter 

• Dilution required prior to administration 

ADVERSE REACTIONS

 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. 

CONTRAINDICATIONS-                                                                                                            None

WARNINGS AND PRECAUTIONS

­ • Kidney Toxicity: Based on animal data, may cause kidney toxicity. Kidney function should be monitored; creatinine may not be a reliable measure of renal function in DMD patients.

DOSAGE AND ADMINISTRATION

• Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio should be measured before starting AMONDYS 45 (2.1) • 30 milligrams per kilogram of body weight once weekly

 • Administer as an intravenous (IV) infusion over 35 to 60 minutes via an in-line 0.2 micron filter 

• Dilution required prior to administration 

DOSAGE FORMS AND STRENGTHS-

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

 PATIENT COUNSELING INFORMATION

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 

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.

 CLINICAL PHARMACOLOGY

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.

.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).

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.

Distribution-                                                                                                                      Binding of casimersen to human plasma protein was not concentration-dependent and ranged from 8.4% to 31.6%. The mean apparent volume of distribution at steady state (Vss) was 367 mL/kg (%CV = 28.9) following a 30 mg/kg dose of casimersen administered intravenously.

Elimination-                                                                                                                   The plasma clearance (CL) of casimersen was 180 mL/hr/kg at the 30 mg/kg dose. The elimination half-life (t1/2) was 3.5 hours (SD 0.4 hours). 

Metabolism-                                                                                                                 Casimersen is metabolically stable in human hepatic microsomal incubations. No metabolites were detected in plasma or urine.

Excretion-                                                                                                                       Casimersen is mostly excreted unchanged in the urine. In a clinical study with radiolabeled casimersen, more than 90% of the drug was excreted in urine, with negligible fecal excretion.

Specific Populations-                                                                                                       Age, Sex & Race The pharmacokinetics of AMONDYS 45 have been evaluated in male DMD patients 9 to 20 years of age. There is no experience with the use of AMONDYS 45 in DMD patients 65 years of age or older.

AMONDYS 45 has not been studied in female patients. The potential impact of race on the pharmacokinetics of casimersen is unknown.

Patients with Renal Impairment-                                                                                     The effect of renal impairment on the pharmacokinetics of casimersen was evaluated in 0nonDMD subjects aged 35 to 65 years with Stage 2 chronic kidney disease (CKD) (n=8, estimated glomerular filtration rate [eGFR] =60 and <90 mL/min/1.73 m2 ) or Stage 03 CKD (n=8, eGFR =30 and <60 mL/min/1.73 m2 ) and matched healthy subjects (n=9, eGFR =90 mL/min/1.73 m2 ).

 No specific dosage adjustment can be recommended for patients with renal impairment.

Patients with Hepatic Impairment-                                                                     AMONDYS 45 has not been studied in patients with hepatic impairment. However, casimersen does not undergo hepatic metabolism, and the systemic clearance of casimersen is not expected to be affected by hepatic impairment.

Drug Interaction Studies-                                                                                          Based on in vitro data, casimersen has a low potential for clinically relevant drug-drug interactions with major CYP enzymes and transporters. Casimersen did not inhibit CYP1A2, CYP2B6, CYP2C8, or CYP2D6 in vitro.                                           

 Casimersen was a potential inhibitor of CYP3A4/5, CYP2C9, and CYP2C19 in vitro; however, considering its short plasma half-life and lack of plasma accumulation with the weekly dosing regimen, clinical drug interaction with substrates for these enzymes is unlikely.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                        There are no human or animal data available to assess the use of AMONDYS 45 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.

2. Lactation Risk Summary -                                                                                       There are no human or animal data to assess the effect of AMONDYS 45 on milk production, the presence of casimersen in milk, or the effects of AMONDYS 45 on the breastfed infant.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AMONDYS 45 and any potential adverse effects on the breastfed infant from AMONDYS 45 or from the underlying maternal condition

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 

Juvenile Animal Toxicity Data Intravenous 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.

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.

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) 

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.