U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  35

ADVERSE REACTIONS

­ The most common adverse reactions (incidence =15% in patients treated with VILTEPSO) were upper respiratory tract infection, injection site reaction, cough, and pyrexia. 

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. 

 Patient Counseling Information

Kidney Toxicity-                                                                                                                        Inform patients nephrotoxicity has occurred with drugs similar to VILTEPSO.

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

Manufactured for: NS Pharma, Inc. Paramus, NJ 07652

 CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                                VILTEPSO is designed to bind to exon 53 of dystrophin pre-mRNA resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping. Exon 53 skipping is intended to allow for production of an internally truncated dystrophin protein in patients with genetic mutations that are amenable to exon 53 skipping.

2. Pharmacodynamics-                                                                                                           After treatment with VILTEPSO 80 mg/kg once weekly, all patients evaluated (N=8) were found to produce mRNA for a truncated dystrophin protein, as measured by reverse transcription polymerase chain reaction (RT-PCR), and demonstrated exon 53 skipping, as measured by DNA sequence analysis.

3. Pharmacokinetics The pharmacokinetics of viltolarsen was evaluated in DMD patients following administration of intravenous (IV) doses ranging from 1.25 mg/kg/week (0.016 times the recommended dosage) to 80 mg/kg/week (the recommended dosage).

Bioavailability is assumed to be 100%, and median Tmax was around 1 hour (end of infusion). 

Distribution-                                                                                                                               The mean viltolarsen steady-state volume of distribution was 300 mL/kg (%CV=14 at a dose of 80 mg/kg. Viltolarsen plasma protein binding ranged from 39% to 40% and is not concentration dependent.

Elimination-                                                                                                                  Metabolism-                                                                                                                                 Data from in vitro metabolism indicate that viltolarsen is metabolically stable. No metabolites were detected in plasma or urine.

Excretion-                                                                                                                         VILTEPSO is excreted mainly as an unchanged drug in the urine. Viltolarsen elimination half-life was 2.5 (%CV=8) hours, and plasma clearance was 217 mL/hr/kg (%CV=22).

Specific Populations-                                                                                                                   Age, Sex & Race The pharmacokinetics of viltolarsen have been evaluated only in male pediatric DMD patients.There is no experience with VILTEPSO in patients 65 years of age or older. No marked differences in any PK parameters were observed between White and Asian patients.

Patients with Renal or Hepatic Impairment -                                                                   VILTEPSO has not been studied in patients with renal or hepatic impairment. Viltolarsen was found to be metabolically stable, and hepatic metabolism does not contribute to the elimination of viltolarsen.

In addition, viltolarsen was mainly excreted unchanged in the urine. Viltolarsen is eliminated renally, and renal impairment is expected to result in increasing exposure of viltolarsen.

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 glomerular filtration rate estimated by serum creatinine

In Vitro Drug Interaction Studies-                                                                                  Viltolarsen did not inhibit CYP3A4/5, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT1A1, or UGT2B7.                                                         

Viltolarsen did not induce CYP1A2, CYP2B6, or CYP3A4.

Viltolarsen is not metabolized by CYP enzymes and is not a substrate of transporters BCRP, BSEP, MDR1, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K.

Viltolarsen did not inhibit the transporters tested (OATP1B1, OATP1B3, OAT3, BCRP, MDR1, BSEP, OAT1, OCT1, OCT2, MATE1, and MATE2-K).

Based on in vitro data, viltolarsen has a low potential for drug-drug interactions with major CYP enzymes and drug transporters in humans. 8 Reference ID: 4655432

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                                    There are no human or animal data available to assess the use of VILTEPSO 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 VILTEPSO on milk production, the presence of viltolarsen in milk, or the effects of VILTEPSO on the breastfed infant.

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

3.Pediatric Use-                                                                                                                     VILTEPSO is indicated for the treatment of DMD in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping, including pediatric patients.

 The no-effect dose for renal toxicity (60 mg/kg), plasma exposures were similar to that in humans at the recommended human dose of 80 mg/kg/week.

4. Geriatric Use DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with VILTEPSO.

5. Patients with Renal Impairment VILTEPSO has not been studied in patients with renal impairment. Viltolarsen is mostly excreted unchanged in the urine, and renal impairment may increase its exposure.

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 VILTEPSO.