DRUG INTERACTIONS

Avoid coadministration with drugs that are substrates of multidrug and toxin extrusion (MATE) transporters.

 DRUG INTERACTIONS- details

.1 Effect of EVRYSDI on Substrates of Multidrug and Toxin Extrusion (MATE) Protein Transporters Based on in vitro data, EVRYSDI may increase plasma concentrations of drugs eliminated via MATE1 or MATE2-K , such as metformin. 

Avoid coadministration of EVRYSDI with MATE substrates. If coadministration cannot be avoided, monitor for drug-related toxicities and consider dosage reduction of the coadministered drug (based on the labeling of that drug) if needed.

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  33

ADVERSE REACTIONS

The most common adverse reactions in later-onset SMA (incidence at least 10% of patients treated with EVRYSDI and more frequent than control) were fever, diarrhea, and rash. 

 The most common adverse reactions in infantile-onset SMA were similar to those observed in later-onset SMA patients. Additionally, adverse reactions with an incidence of at least 10% were upper respiratory tract infection, pneumonia, constipation, and vomiting. 

  CONTRAINDICATIONS                                                                                               None. 

DOSAGE AND ADMINISTRATION-

DOSAGE FORMS AND STRENGTHS

For Oral Solution: 60 mg of risdiplam as a powder for constitution to provide 0.75 mg/mL solution.

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Pregnancy and Fetal Risk- 

 Inform pregnant women and women of reproductive potential that, based on animal studies, EVRYSDI may cause fetal harm.

Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant.

Advise women of childbearing potential to use effective contraception during treatment with EVRYSDI and for at least 1 month after stopping EVRYSDI. 

Advise a female patient to immediately inform the prescriber if she is pregnant or planning to become pregnant 

Potential Effects on Male Fertility-                                                                         Advise male patients that their fertility may be compromised while on treatment with EVRYSDI 

Instructions for Preparation of Oral Solution -                                                             Advise patients to ensure that EVRYSDI is in liquid form when received from the pharmacy. Instruct patients/caregivers to take EVRYSDI after a meal or after breastfeeding at approximately the same time each day.

However, instruct caregivers to not mix EVRYSDI with formula or milk.

Instruct patients/caregivers to take EVRYSDI immediately after it is drawn up into the reusable oral syringe  EVRYSDI™ [risdiplam]

Distributed by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 EVRYSDI is a trademark of Genentech, Inc

 CLINICAL PHARMACOLOGY

1. Mechanism of Action

Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier designed to treat patients with spinal muscular atrophy (SMA) caused by mutations in chromosome 5q that lead to SMN protein deficiency.

Using in vitro assays and studies in transgenic animal models of SMA, risdiplam was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein in the brain.

In vitro and in vivo data indicate that risdiplam may cause alternative splicing of additional genes, including FOXM1 and MADD. FOXM1 and MADD are thought to be involved in cell cycle regulation and apoptosis, respectively, and have been identified as possible contributors to adverse effects seen in animals.

2. Pharmacodynamics-                                                                                                In clinical trials, EVRYSDI led to an increase in SMN protein with a greater than 2-fold median change from baseline within 4 weeks of treatment initiation.

The increase was sustained throughout the treatment period (of at least 12 months) across all SMA types.

3. Pharmacokinetics-                                                                                       Pharmacokinetics of EVRYSDI have been characterized in healthy adult subjects and in patients with SMA.

Effect of Food-                                                                                                             In the clinical efficacy studies (Study 1 and Study 2), risdiplam was administered with a morning meal or after breastfeeding.

Distribution-                                                                                                               The apparent volume of distribution at steady state is 6.3 L/kg. Risdiplam is predominantly bound to serum albumin, without any binding to alpha-1 acid glycoprotein, with a free fraction of 11%.

Elimination-                                                                                                                   The apparent clearance (CL/F) of risdiplam is 2.1 L/h for a 14.9 kg patient. The terminal elimination half-life of risdiplam was approximately 50 hours in healthy adults.

Metabolism-                                                                                                                      Risdiplam is primarily metabolized by flavin monooxygenase 1 and 3 (FMO1 and FMO3) and also by CYPs 1A1, 2J2, 3A4, and 3A7.

Parent drug was the major component found in plasma, accounting for 83% of drug-related material in circulation. The pharmacologically-inactive metabolite M1 was identified as the major circulating metabolite.

Excretion-                                                                                                                   Following a dose of 18 mg, approximately 53% of the dose (14% unchanged risdiplam) was excreted in the feces and 28% in urine (8% unchanged risdiplam).

Specific Populations-                                                                                                      There were no clinically significant differences in the pharmacokinetics of EVRYSDI based on race or gender.

Renal impairment is not expected to alter the exposures to risdiplam. 

The impact of geriatric age and hepatic impairment on the pharmacokinetics of EVRYSDI has not been studied.

Pediatric Patients-                                                                                                   Body weight and age were found to have significant effect on the pharmacokinetics of risdiplam.

The estimated exposure (mean AUC0-24h) for infantile-onset SMA patients (age 2 to 7 months at enrollment) at the recommended dose of 0.2 mg/kg once daily was 1930 ng.h/mL.

Drug Interaction Studies-                                                                                      Effect of Other Drugs on EVRYSDI Coadministration of 200 mg itraconazole (a strong CYP3A inhibitor) twice daily with a single 6 mg oral dose of risdiplam did not have a clinically relevant effect on the pharmacokinetics of risdiplam (11% increase in AUC and 9% decrease in Cmax).

Risdiplam is a weak substrate of human MDR-1 and breast cancer resistant protein (BCRP) transporters in vitro. Human MDR-1 or BCRP inhibitors are not expected to result in a clinically significant increase of risdiplam concentrations.

Effect of EVRYSDI on Other Drugs-                                                                       Risdiplam and its major circulating metabolite M1 did not induce CYP1A2, 2B6, 2C8, 2C9, 2C19, or 3A4 in vitro.

Based on physiologically-based pharmacokinetic (PBPK) modeling, a similar increase is expected in children and infants as young as 2 months of age.

I

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary                                                                                             There are no adequate data on the developmental risk associated with the use of EVRYSDI in pregnant women.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. . 

2 Lactation Risk Summary                                                                                    There are no data on the presence of risdiplam in human milk, the effects on the breastfed infant, or the effects on milk production. Risdiplam was excreted in the milk of lactating rats orally administered risdiplam. Reference ID: 4653194 The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for EVRYSDI and any potential adverse effects on the breastfed infant from EVRYSDI or from the underlying maternal condition.

3 Females and Males of Reproductive Potential-                                              Studies of risdiplam in juvenile and adult rats and in monkeys demonstrated adverse effects on the reproductive organs, including germ cells, in males at clinically-relevant plasma exposures 

Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating EVRYSDI 

Contraception-                                                                                                   EVRYSDI may cause embryofetal harm when administered to a pregnant woman  

Female Patients-                                                                                                        Advise female patients of reproductive potential to use effective contraception during treatment with EVRYSDI and for at least 1 month after her last dose.

Infertility Male                                                                                                             Patients Male fertility may be compromised by treatment with EVRYSDI 

Counsel male patients of reproductive potential receiving EVRYSDI about the potential effects on fertility. Male patients may consider sperm preservation prior to treatment.

4. Pediatric Use-                                                                                                        The safety and effectiveness of EVRYSDI in pediatric patients 2 months of age and older have been established 

Safety and effectiveness in pediatric patients below the age of 2 months have not been established