DRUG INTERACTIONS-(summary)

 • Moderate or Strong CYP3A4 Inhibitors: Avoid concomitant use. Consider SKYCLARYS dosage reduction with monitoring if use is unavoidable.

 • Moderate or Strong CYP3A4 Inducers: Avoid concomitant use.

DRUG INTERACTIONS (details)

1 Effect of Other Drugs on SKYCLARY'S -                                                           CYP3A4 Inhibitors Omaveloxolone is a CYP3A4 substrate. Concomitant use of SKYCLARYS with moderate or strong CYP3A4 inhibitors is expected to result in clinically significant increased exposure of omaveloxolone , which may increase the risk of adverse reactions.

Avoid concomitant use of SKYCLARYS with moderate or strong CYP3A4 inhibitors. If use cannot be avoided, dosage modifications are recommended..

CYP3A4 Inducers- Omaveloxolone is a CYP3A4 substrate. Concomitant use of SKYCLARYS with moderate or strong CYP3A4 inducers may significantly decrease exposure of omaveloxolone , which may reduce the effectiveness of SKYCLARYS.

Avoid concomitant use of SKYCLARYS with moderate or strong CYP3A4 inducers. 

2 Effect of SKYCLARYS on Other Drugs -                                                          CYP3A4 and CYP2C8 Substrates Omaveloxolone is a weak inducer of CYP3A4 and CYP2C8. Concomitant use with SKYCLARYS can reduce the exposure of CYP3A4 and CYP2C8 substrates which may reduce the activity of these substrates.                         

 Refer to the prescribing information of substrates of CYP3A4 and CYP2C8 for dosing instructions if used concomitantly with SKYCLARYS and monitor for lack of efficacy of the concomitant treatment.

Hormonal Contraceptives- Omaveloxolone is a weak CYP3A4 inducer.  Concomitant use with SKYCLARYS may reduce the efficacy of hormonal contraceptives.

Advise patients to avoid concomitant use with combined hormonal contraceptives (e.g., pill, patch, ring), implants, and progestin only pills .

BRIEF SUMMARY

OMVAELOXONE-(Feb 2023)

Indn- To  treat Friedrich's Ataxia    

Dosage- • Recommended dosage is 150 mg (3 capsules) taken orally once daily.

  Administer  on an empty stomach at least 1 hour before eating. Swallow capsules whole.   Moderate and Severe Hepatic Impairment: The recommended dosage  is 100 mg once daily for patients with moderate hepatic impairment

ADR-  Most common adverse reactions (incidence =20% and greater than placebo) are elevated liver enzymes (AST/ALT), headache, nausea, abdominal pain, fatigue, diarrhea, and musculoskeletal pain.

CI- None

WARNINGS-   Elevation of Aminotransferases: Monitor ALT, AST, and total bilirubin prior to initiation

Pat inform- inform patients that elevation in aminotransferases have occurred in patients treated .. Liver function tests will be performed prior to initiation , every month for the first 3 months of treatment, and periodically thereafter as needed .

 Inform patients that elevations in BNP, a marker of cardiac function, have occurred in patients treated with the dug

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 8

Name-        SKYCLARYS

Acive  Ingredient -  Omvaeloxone

 Pharmacological clssificiation-        To  treat Friedrich's Ataxia                                                                                                                                                                                           Date of Approval-         2/28/2023 

HIGHLIGHTS OF PRESCRIBING INFORMATION -

These highlights do not include all the information needed to use SKYCLARYS safely and effectively.                                                                                                               See full prescribing information for SKYCLARYS. SKYCLARYS™ (omaveloxolone) capsules, for oral use

Initial U.S. Approval: 2023

INDICATIONS AND USAGE-

 SKYCLARYS is indicated for the treatment of Friedreich’s ataxia in adults and adolescents aged 16 years and older.

ADVERSE REACTIONS-

 Most common adverse reactions (incidence =20% and greater than placebo) are elevated liver enzymes (AST/ALT), headache, nausea, abdominal pain, fatigue, diarrhea, and musculoskeletal pain.

CONTRAINDICATIONS-

 None

WARNINGS AND PRECAUTIONS-

 • Elevation of Aminotransferases: Monitor ALT, AST, and total bilirubin prior to initiation, every month for the first 3 months of treatment, and periodically thereafter.

 • Elevation of B-type Natriuretic Peptide (BNP): Advise patients of signs and symptoms of fluid overload.

 • Lipid Abnormalities: Monitor cholesterol periodically during treatment.

DOSAGE AND ADMINISTRATION-

 • Obtain alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, B-type natriuretic peptide (BNP), and lipid parameters prior to initiating SKYCLARYS and during treatment.

 • Recommended dosage is 150 mg (3 capsules) taken orally once daily.

 • Administer SKYCLARYS on an empty stomach at least 1 hour before eating.

 • Swallow SKYCLARYS capsules whole. Do not open, crush or chew.

 • Moderate and Severe Hepatic Impairment: The recommended dosage of SKYCLARYS is 100 mg once daily for patients with moderate hepatic impairment. If adverse reactions emerge, further reduce the dosage to 50 mg once daily. Avoid use in patients with severe hepatic impairment.

DOSAGE FORMS AND STRENGTHS-

 Capsules: 50 mg 

PATIENT COUNSELING INFORMATION-

 Advise the patient to read the FDA-approved patient labeling (Patient Information).

Elevation of Aminotransferases -                                                                              Inform patients that elevation in aminotransferases have occurred in patients treated with SKYCLARYS. Liver function tests will be performed prior to initiating SKYCLARYS, every month for the first 3 months of treatment, and periodically thereafter as needed .

Fluid Overload-                                                                                                                 Inform patients that elevations in BNP, a marker of cardiac function, have occurred in patients treated with SKYCLARYS.

BNP will be performed prior to initiating SKYCLARYS and if signs and symptoms of fluid overload occur, such as sudden weight gain, peripheral edema, palpitations, and shortness of breath.

Advise patients to contact their healthcare provider if signs and symptoms of fluid overload develop.

Lipid Abnormalities-                                                                                                  Inform patients that treatment with SKYCLARYS has been associated with increases in LDL cholesterol and decreases in HDL cholesterol.

Cholesterol will be assessed prior to starting SKYCLARYS and monitored periodically during treatment

Advise patients to discuss all medications they are taking, including other prescription medications, non-prescription medications, or herbal products (e.g., St. John’s Wort) with their healthcare provider.

Pregnancy -                                                                                                                Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during SKYCLARYS therapy

Females of Reproductive Potential-                                                                           Counsel females using hormonal contraceptives to use an alternative contraceptive method (e.g., non-hormonal intrauterine system) or additional non-hormonal contraceptive (e.g., condoms) during concomitant use and for 28 days after discontinuation of SKYCLARYS.

Administration-                                                                                                         Advise patients to take SKYCLARYS on an empty stomach at least 1 hour before eating.

Swallow SKYCLARYS capsules whole. Do not open, crush, or chew.

Advise patients that if a dose of SKYCLARYS is missed to not to double their dose or take more than the prescribed dose.

Advise patients to avoid grapefruit juice and grapefruit while they are taking SKYCLARYS . .

Manufactured for Reata Pharmaceuticals, Inc., Plano, TX 75024 USA SKYCLARYS is a trademark of Reata Pharmaceuticals Holdings, LLC, used under license by Reata Pharmaceuticals, Inc., Plano, TX 75024 USA Copyright© 2023, Reata Pharmaceuticals, Inc., Plano, TX 75024 USA All rights reserve

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                              The precise mechanism by which omaveloxolone exerts its therapeutic effect in patients with Friedreich’s ataxia is unknown.

Omaveloxolone have been shown to activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans.

2. Pharmacodynamics-                                                                                                 Potential to Prolong the QT Interval The effect of omaveloxolone on the QTc interval has not been adequately characterized.

3. Pharmacokinetics-                                                                                                  Absorption- The median (range) time to achieve peak plasma concentration was 7 to 14 (1 to 24) hours.

The total plasma omaveloxolone exposure based on area under the concentration-time curve (AUC) increased in a dose-dependent and dose proportional manner over a dose range of 50 mg (0.33 times the recommended dosage) to 150 mg, but maximum omaveloxolone plasma concentration (Cmax) increased in a less than dose proportional manner over the dose range in healthy fasted subjects.

Effect of Food-                                                                                                      Omaveloxolone Cmax and AUC0-inf increased by approximately 350% and 15%, respectively, with a high-fat meal (800-1000 calories, approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively) compared to fasted conditions.

Distribution-                                                                                                                  The mean apparent volume of distribution of omaveloxolone is 7361 L (105 L/kg for a 70 kg person). Protein binding of omaveloxolone is 97%.

Elimination-                                                                                                                   The mean (range) terminal half-life of omaveloxolone is 57 hours (32 to 90 hours). The mean apparent plasma clearance of omaveloxolone is 109 L/hr.

Metabolism-                                                                                                           Omaveloxolone is primarily metabolized by CYP3A with minor metabolism by CYP2C8 and CYP2J2

Excretion-                                                                                                                      Following administration of a single oral dose of radiolabeled omaveloxolone 150 mg to healthy subjects, approximately 92% of the dose was recovered in feces (approximately 91% within 96 hours after administration) and 0.1% in urine.

Specific Populations-                                                                                               There were no clinically significant differences in the pharmacokinetics of omaveloxolone based on age (16 to 71 years of age), sex, race, or body weight (41 to 128 kg).

The effect of renal impairment on the pharmacokinetics of omaveloxolone is unknown.

Patients with Hepatic Impairment -                                                                           There were no clinically significant differences in the pharmacokinetics of omaveloxolone in subjects with mild hepatic impairment (Child-Pugh Class A).

In subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C), omaveloxolone clearance was reduced, resulting in higher plasma exposure of omaveloxolone.

The omaveloxolone AUC increased up to 1.65-fold and Cmax increased up to 1.83-fold in subjects with moderate hepatic impairment.

The omaveloxolone AUC increased up to 2.17-fold in subjects with severe hepatic impairment; however, this change was variable..

Drug Interaction Studies- Clinical Studies -Strong CYP3A Inhibitors:                 Omaveloxolone Cmax increased 3-fold and AUC 4-fold following concomitant use with itraconazole (strong CYP3A inhibitor).

Moderate CYP3A Inhibitors:                                                                               Omaveloxolone Cmax and AUC increased approximately 1.25-fold following concomitant use with verapamil (moderate CYP3A4 and P-gp inhibitor) ..

Strong and Moderate CYP3A Inducers:                                                                     The effect of concomitant use with moderate and strong CYP3A4 inducers is unknown; however, a significant reduction in omaveloxolone exposure is likely following concomitant use based on its metabolic pathway.

Certain CYP450 Enzymes or Transporter Substrates:                                   Omaveloxolone decreased the AUC of midazolam (CYP3A4 substrate) by approximately 45%, AUC of repaglinide (CYP2C8 substrate) by approximately 35%, and AUC of rosuvastatin (BCRP and OATP1B1 substrate) by approximately 30%.

There were no clinically significant differences in the pharmacokinetics of digoxin (P-gp substrate) or metformin [(organic cation transporter (OCT)1 substrate] when coadministered with omaveloxolone.

Other Drugs:                                                                                                                   No clinically significant differences in the pharmacokinetics of omaveloxolone are expected following concomitant use with weak CYP3A4 inhibitors or strong CYP2C8 inhibitors.

In Vitro Studies CYP Enzymes                                                                            Omaveloxolone is not an inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP2D6. Omaveloxolone is not an inducer of CYP1A2 and CYP2B6.

Drug Transporters:                                                                                                 Omaveloxolone is not an inhibitor of BCRP, BSEP, OAT3, OATP1B1, OATP1B3, OCT2, MATE1, and MATE2-K. Omaveloxolone inhibited the renal transporter OAT1.

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Risk Summary

There are no adequate data on the developmental risks associated with the use of SKYCLARYS in pregnant women.

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

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

.2.Laction Summary-                                                                                                  There are no data on the presence of omaveloxolone or its metabolites in human milk. The effects on milk production and the breastfed infant are unknown.

3 Females and Males of Reproductive Potential-                                                    SKYCLARYS may decrease the efficacy of hormonal contraceptives.

Advise patients to avoid concomitant use with combined hormonal contraceptives (e.g., pill, patch, ring), implants, and progestin only pills.

Counsel females using hormonal contraceptives to use an alternative contraceptive method (e.g., non-hormonal intrauterine system) or additional non-hormonal contraceptive (e.g., condoms) during concomitant use and for 28 days after discontinuation of SKYCLARYS.

4. Pediatric Use-                                                                                                             The safety and effectiveness of SKYCLARYS for the treatment of Friedreich's ataxia have been established in pediatric patients aged 16 years and older.

Use of SKYCLARYS for this indication is supported by evidence from one adequate and well-controlled study (Study 1) in adults and in pediatric patients aged 16 years and older ..

Safety and effectiveness of SKYCLARYS have not been established in pediatric patients less than 16 years of age.

5. Geriatric Use-                                                                                                              Clinical studies of SKYCLARYS in Friedreich’s ataxia did not include patients aged 65 and over. No data are available to determine whether they respond differently than younger adult patients.

6. Hepatic Impairment-                                                                                       Omaveloxolone plasma exposure is increased in patients with moderate or severe hepatic impairment (Child-Pugh Class B and C) .

Avoid treatment with SKYCLARYS in patients with severe hepatic impairment, including those who develop severe hepatic impairment. If hepatic function improves to moderate impairment, mild impairment, or normal function,

Initiation of SKYCLARYS treatment at the approved recommended dosage may be considered.

For patients with moderate hepatic impairment, a reduced dosage is recommended with close monitoring for adverse reactions .

For patients with mild hepatic impairment (Child-Pugh Class A), no dose adjustments are recommended.