AMONDYS 45- casimersen_injection

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 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. The level of exon skipping is positively correlated with dystrophin protein expression [see Clinical Studies ( 14 In Study 1 [see Clinical Studies ( 14 Correct localization of dystrophin to the sarcolemma in patients treated with AMONDYS 45 was demonstrated by immunofluorescence staining. 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. , recommended dosage). Following a single IV dose of casimersen, C max max Distribution Binding of casimersen to human plasma protein was not concentration-dependent and ranged from 8. The mean apparent volume of distribution at steady state (V ss Elimination The plasma clearance (CL) of casimersen was 180 mL/hr/kg at the 30 mg/kg dose. The elimination half-life (t 1/2 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 non-DMD 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 m 2 2 2 In subjects with Stage 2 or Stage 3 CKD, exposure (AUC) increased approximately 1. 2-fold and 1. 8-fold, respectively, compared with subjects with normal renal function. The C max max max Estimated GFR values derived from MDRD equations and the threshold definitions for various CKD stages in otherwise healthy adults would not be generalizable to pediatric patients with DMD. Therefore, no specific dosage adjustment can be recommended for patients with renal impairment [see Use in Specific Populations ( 8. 6 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 Casimersen did not inhibit CYP1A2, CYP2B6, CYP2C8, or CYP2D6 in vitro in vitro.

AMONDYS 45 is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD [see Clinical Studies ( 14 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 [see Clinical Studies ( 14 1.

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 ( 2. 2 Administer as an intravenous (IV) infusion over 35 to 60 minutes via an in-line 0. 2 micron filter ( 2. 4 Dilution required prior to administration ( 2. 3 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 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. 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. 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. Allow the vials to warm to room temperature. Mix the contents of each vial by gently inverting 2 or 3 times. Do not shake. 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. 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. 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. 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. Administer the diluted solution via an in-line 0. 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. 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. 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 Contraindications ( 4 5.

The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity reactions [see Warnings and Precautions ( 5. 1 Kidney toxicity [see Warnings and Precautions ( 5. 2 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. 1 To report SUSPECTED ADVERSE REACTIONS, contact Sarepta Therapeutics, Inc. at 1-888-SAREPTA (1-888-727-3782) or FDA at 1-800-FDA-1088 or www. gov/medwatch 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. 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 Table 1. Adverse Reactions Occurring in at Least 20% of Patients Treated with AMONDYS 45 and at a Rate at Least 5% More Frequently than in the Placebo Group in Study 1 *Includes upper respiratory infection, pharyngitis, nasopharyngitis, and rhinitis. Adverse Reaction AMONDYS 45 Placebo Upper Respiratory Tract Infections* 65 55 Cough 33 26 Pyrexia 33 23 Headache 32 19 Arthralgia 21 10 Oropharyngeal Pain 21 7 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. 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. Infusion-related reactions including rash, headache, cough, abdominal pain (including upper abdominal pain), and vomiting occurred within 24 hours from the start of an infusion of AMONDYS 45. Hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients treated with AMONDYS 45.

[see Warnings and Precautions ( 5. 1 AMONDYS 45 is contraindicated in patients with serious hypersensitivity to casimersen or to any of the inactive ingredients in AMONDYS 45.

Risk Summary There are no human or animal data available to assess the use of AMONDYS 45 during pregnancy. general population, major birth defects occur in 2% to 4% and miscarriage occurs in 15% to 20% of clinically recognized pregnancies. 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. AMONDYS 45 is indicated for the treatment of DMD in patients who have a confirmed mutation of the DMD [see Clinical Studies ( 14 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. DMD is largely a disease of children and young adults; therefore, there is no experience with AMONDYS 45 in geriatric DMD patients. 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.

NONCLINICAL TOXICOLOGY
Carcinogenesis Carcinogenicity studies have not been conducted with casimersen. Mutagenesis Casimersen was negative in in vitro (bacterial reverse mutation assay and chromosomal aberration assay in CHO cells) and in vivo (mouse bone marrow micronucleus) assays. Impairment of Fertility Fertility studies in animals were not conducted with casimersen. No effects of casimersen were observed on the male reproductive system following weekly administration to male mice at subcutaneous doses up to 960 mg/kg for 26 weeks or to male monkeys at intravenous doses up to 640 mg/kg for 39 weeks. Plasma exposures at the highest doses tested in mouse and monkey were approximately 9 and 35 times, respectively, that in humans at the recommended human dose of 30 mg/kg/week. 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. Plasma exposure (AUC) at the lowest dose tested were approximately 4 times that in humans at the RHD.
CLINICAL STUDIES
The effect of AMONDYS 45 on dystrophin production was evaluated in one study in male DMD patients who have a confirmed mutation of the DMD Study 1 is an ongoing, double-blind, placebo-controlled, multicenter study designed to evaluate the safety and efficacy of AMONDYS 45 in ambulatory patients. The study is planned to enroll a total of 111 patients, age 7 to 13 years, randomized to AMONDYS 45 or placebo in a 2 to 1 ratio. Patients were required to have been on a stable dose of oral corticosteroids for at least 24 weeks prior to dosing with AMONDYS 45 or placebo. Following the 96-week double-blind period, all patients began or are to begin an additional 48 week open-label treatment period. Interim efficacy was assessed based on change from baseline in the dystrophin protein level (measured as % of the dystrophin level in healthy subjects, i.e., % of normal) at Week 48 of Study 1. Interim results from 43 evaluable patients (n = 27, AMONDYS 45; n = 16, placebo) who had a muscle biopsy at Week 48 of the double-blind period are presented in Table 2 Table 2. Dystrophin Levels (% of Normal) at Baseline and at Week 48 from Muscle Biopsy Interim Results in Study 1 Placebo AMONDYS 45 Dystrophin by Sarepta Western blot n=16 n=27 Baseline Mean (SD) 0.54 (0.79) 0.93 (1.67) Week 48 Mean (SD) 0.76 (1.15) 1.74 (1.97) Change from Baseline Mean (SD) 0.22 (0.49) 0.81 (0.70) p-value Change from Baseline to Week 48 0.09 <0.001 Between group mean difference 0.59 p-value between groups p=0.004

Sarepta Therapeutics, Inc.

• Founded in:

  2013-06-25 00:00:00

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AMONDYS 45- casimersen_injection Product manual source documgent