DRUG INTERACTIONS-(summary)

 • Strong or moderate CYP3A inhibitors: Avoid concomitant use.

• Strong or moderate CYP3A inducers: Avoid concomitant use.

• Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors and H2-receptor antagonists. If concomitant use cannot be avoided, OGSIVEO administration can be staggered with antacids.

DRUG INTERACTIONS-(details)

1 Effects of Other Drugs on OGSIVEO-

. Effects of Other Drugs on OGSIVEO Strong or Moderate CYP3A Inhibitors Clinical Effect Nirogacestat is a CYP3A substrate.

Strong or moderate CYP3A inhibitors increase nirogacestat exposure], which may increase the risk of OGSIVEO adverse reactions.

Prevention or Management-                                                                                       Avoid concomitant use of OGSIVEO with strong or moderate CYP3A inhibitors including grapefruit products, Seville oranges, and starfruit.

Strong or Moderate CYP3A Inducers Clinical Effect -Nirogacestat is a CYP3A substrate. Strong or moderate CYP3A inducers decrease serum nirogacestat exposure , which may reduce the effectiveness of OGSIVEO.

Prevention or Management- Avoid concomitant use of OGSIVEO with strong or moderate CYP3A inducers.

Gastric Acid Reducing Agents Clinical Effect-                                                            Nirogacestat is poorly soluble at pH = 6. Gastric acid reducing agents may decrease serum nirogacestat exposure , which may reduce the effectiveness of OGSIVEO.

Prevention or Management-                                                                                               Avoid concomitant use with proton pump inhibitors and H2 blockers.

If concomitant use cannot be avoided, OGSIVEO can be staggered with antacids (e.g., administer OGSIVEO 2 hours before or 2 hours after antacid use).

2. Effects of OGSIVEO on Other Drugs

Clinical Effect- Nirogacestat increases exposure of CYP3A substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates.

Prevention or Management -                                                                                           Avoid concomitant use with CYP3A substrates where minimal concentration changes may lead to serious adverse reactions. Certain CYP2C19 Substrates Clinical

Effect- Nirogacestat decreases exposure of CYP2C19 substrates , which may decrease efficacy of these substrates

 Prevention or Management-                                                                                      Avoid concomitant use with OGSIVEO where decreased concentrations of CYP2C19 substrates may lead to significant decreases in efficacy of the CYP2C19 substrate unless otherwise recommended in the Prescribing Information for the CYP2C19 substrate.

BRIEF SUMMARY

NIROGACESTAT- (Nov 2023)

Indn-   To treat adults with processing desmoid tumors who require  systemic treatment

Comp-    Tablets: 50 mg.  • The recommended dosage is 150 mg orally twice daily until disease progression or unacceptable toxicity.

ADR-    The most common (> 15 %) adverse reactions are diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection and dyspnea.

 The most common laboratory abnormalities (=15%) are decreased phosphate, increased urine glucose, increased urine protein, increased AST, increased ALT, and decreased potassium.

CI-    None. 

WARNINGS AND PRECAUTIONS-

 • Diarrhea: Severe diarrhea can occur. Monitor and dose modify for Grade 3-4 diarrhea.

 • Ovarian Toxicity: Female reproductive function and fertility may be impaired. Advise females of reproductive potential of the potential risk prior to treatment and monitor routinely.

Pat Infm-

Diarrhea-                                                                                                                         Advise patients that OGSIVEO can cause diarrhea, which may be severe, and to contact their healthcare provider for sustained diarrhea that does not respond to supportive care 

Ovarian Toxicity-                                                                                                               Advise females of reproductive potential that OGSIVEO can cause ovarian toxicity and impair fertility, and that these effects may continue following discontinuation of OGSIVEO

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 52

Name-          OGSIUEO

Active ingedient-       Nirgogacesant      

Indication              To treat adults with processing desmoid tumors who require                                       systemic treatment

Date  of approval       11/27/2023 

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use                        OGSIVEO safely and effectively.

See full prescribing information for OGSIVEO. OGSIVEOTM (nirogacestat) tablets, for oral use

Initial U.S. Approval: 2023

INDICATIONS AND USAGE-

 OGSIVEO is a gamma secretase inhibitor indicated for adult patients with progressing desmoid tumors who require systemic treatment. 

ADVERSE REACTIONS-

 The most common (> 15 %) adverse reactions are diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection and dyspnea.

 The most common laboratory abnormalities (=15%) are decreased phosphate, increased urine glucose, increased urine protein, increased AST, increased ALT, and decreased potassium.

CONTRAINDICATIONS-

 None. 

WARNINGS AND PRECAUTIONS-

 • Diarrhea: Severe diarrhea can occur. Monitor and dose modify for Grade 3-4 diarrhea.

 • Ovarian Toxicity: Female reproductive function and fertility may be impaired. Advise females of reproductive potential of the potential risk prior to treatment and monitor routinely.

 • Hepatotoxicity: Elevated AST and ALT can occur. Monitor AST and ALT regularly and modify dose as recommended.

 • Non-Melanoma Skin Cancers: Perform dermatologic examination prior to initiation of OGSIVEO and routinely during treatment.

 • Electrolyte Abnormalities: Monitor phosphate and potassium regularly and modify dose as recommended.

 • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential 

-------------------------------ADVERSE REACTIONS------------------------------ The most common (> 15 %) adverse reactions are diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection and dyspnea. (6.1) The most common laboratory abnormalities (=15%) are decreased phosphate, increased urine glucose, increased urine protein, increased AST, increased ALT, and decreased potassium. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact SpringWorks Therapeutics Inc. at 1-888-400-7989 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

------------------------------DRUG INTERACTIONS------------------------------- • Strong or moderate CYP3A inhibitors: Avoid concomitant use. (7.1) • Strong or moderate CYP3A inducers: Avoid concomitant use. (7.1) • Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors and H2-receptor antagonists. If concomitant use cannot be avoided, OGSIVEO administration can be staggered with antacids. (7.1) -------------------------USE IN SPECIFIC POPULATIONS--------------------- • Lactation: Advise not to breastfeed. (8.2)

DOSAGE AND ADMINISTRATION-

 • The recommended dosage is 150 mg orally twice daily until disease progression or unacceptable toxicity.

 • See Full Prescribing Information for dosage modifications due to adverse reactions. -

DOSAGE FORMS AND STRENGTHS--

 Tablets: 50 mg. 

PATIENT COUNSELING INFORMATION -

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

Diarrhea-                                                                                                                         Advise patients that OGSIVEO can cause diarrhea, which may be severe, and to contact their healthcare provider for sustained diarrhea that does not respond to supportive care 

Ovarian Toxicity-                                                                                                               Advise females of reproductive potential that OGSIVEO can cause ovarian toxicity and impair fertility, and that these effects may continue following discontinuation of OGSIVEO

. Advise patients to tell their healthcare provider if they experience symptoms of ovarian toxicity, including hot flashes or menstrual irregularities

 Liver Toxicity-                                                                                                           Advise patients that OGSIVEO can cause ALT or AST elevations, and that their healthcare provider should monitor liver transaminase levels regularly

Non-Melanoma Skin Cancers -                                                                                 Advise patients that OGSIVEO can cause new non-melanoma skin cancers, that they will be monitored for these, and to contact their healthcare provider for any new or changing lesions on their skin].

Electrolyte Abnormalities-                                                                                        Advise patients that OGSIVEO can cause hypophosphatemia and/or hypokalemia which may require phosphate and/or potassium supplementation.

Advise patients that they will be monitored for these and to contact their healthcare provider if they experience muscle pain or weakness

Embryo-Fetal Toxicity-                                                                                                  Advise pregnant women and females of reproductive potential of the potential harm to a fetus.

Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy, and to stop taking OGSIVEO if they become pregnant. Also, advise females of reproductive potential to use effective contraception during treatment with OGSIVEO and for 1 week after the last dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment with OGSIVEO and for 1 week after the last dose

Lactation-                                                                                                                       Advise women not to breastfeed during treatment with OGSIVEO and for 1 week after the last dose 

Drug Interactions-                                                                                                      Advise patients to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid starfruit, Seville oranges, grapefruit, and juice from any of these fruits when taking OGSIVEO [

Manufactured for: SpringWorks Therapeutics, Inc. Stamford, CT 06902 OGSIVEOTM is a trademark of SpringWorks Therapeutics, Inc. ©2023 SpringWorks Therapeutics, Inc.

CLINICAL PHARMACOLOGY

1. Mechanism of Action -

Nirogacestat is a gamma secretase inhibitor that blocks proteolytic activation of the Notch receptor. When dysregulated, Notch can activate pathways that contribute to tumor growth.

2. Pharmacodynamics-                                                                                                  Exposure-Response Relationships There is an exposure-response relationship between nirogacestat exposure and Grade 3 hypophosphatemia with a higher risk of Grade 3 hypophosphatemia at higher exposure.

Cardiac Electrophysiology-                                                                                               At the recommended dosage, a mean increase in the QTc interval > 20 ms was not observed.

3. Pharmacokinetics Nirogacestat pharmacokinetic parameters in patients with desmoid tumors are summarized 

Pharmacokinetic Parameters and Characteristics of Nirogacestat General Information Steady state exposure [Mean (%CV)] Cmax 508 (62) ng/mL AUC0-tau 3370 (58) ng·h/mL Time to steady-state Approximately 6 days Accumulation ratio [Median (Min, Max)] 1.6 (1.3, 4.6)

Absorption Tmax [Median (Min, Max)] 1.5 (0.5, 6.5) hours Absolute bioavailability 19%

Food effect [dose-normalized GMR% (90% CI)] Cmax 93 % (55%, 166%) AUC 114% (76%, 171%)

Distribution Protein Binding* Serum protein binding 99.6% Human serum albumin 94.6% a-1 acid glycoprotein 97.9%

Apparent volume of distribution (Vz/F) [Mean (%CV)] 1430 (65) L

Elimination Apparent Systemic Clearance (CL/F) [Mean (%CV)] 45 (58) L/hr Terminal elimination half-life (t1/2) [Mean (%CV)] 23 (37) hr

Metabolism Primary pathway N-dealkylation via CYP3A4 (85%) Secondary pathways Metabolism by CYP 3A4, 2C19, 2C9, and 2D6

Excretion Feces 38% Urine 17% (<1% unchanged) Expired air 9.7% * Protein binding values reflect results from separate assays. Abbreviations: AUC0-tau = area under the time concentration curve to the dosing interval; Cmax = maximum plasma concentration; Tmax = time to reach Cmax; GMR = geometric mean ratio 11 Reference ID: 5283221

Specific Populations-                                                                                                      No clinically significant differences in the pharmacokinetics of nirogacestat were observed based on age (18 to 80 years), sex, race (Asian, Black or African American, and White), or mild or moderate renal impairment (eGFR =41 mL/min/1.73m2 ).

Effects of Hepatic Impairment The mean AUC increased by up to 16% and the mean Cmax decreased by up to 39% in subjects with moderate hepatic impairment identified by Child-Pugh Class B or NCI-ODWG Group C criteria compared to that of subjects with normal hepatic function. Insufficient data are available to characterize nirogacestat PK in patients with severe hepatic impairment.

Drug Interaction Studies Clinical Studies and Model-Informed Approaches Strong CYP3A inhibitors: Nirogacestat Cmax increased by 2.5-fold and AUC by 8.2-fold following coadministration of a single dose of OGSIVEO (100 mg) with itraconazole (a strong CYP3A inhibitor).

USE IN SPECIFIC POPULATIONS

1 Pregnancy Risk Summary-

Based on findings from animal studies and its mechanism of action, OGSIVEO can cause fetal harm or loss of pregnancy when administered to a pregnant woman .

Oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity and embryo-fetal death at maternal exposures below the human exposure at the recommended dose of 150 mg twice daily 

There are no available data on the use of OGSIVEO in pregnant women.

Advise pregnant women of the potential risk to a fetus

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.

2. Lactation Risk Summary-                                                                                        There are no data on the presence of nirogacestat or its metabolites in human milk or the effects of nirogacestat on a breastfed child or milk production.

Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with OGSIVEO and for 1 week after the last dose

3 Females and Males of Reproductive Potential-                                                        OGSIVEO can cause fetal harm when administered to a pregnant woman

Pregnancy Testing-                                                                                                           Verify the pregnancy status of females of reproductive potential prior to initiating OGSIVEO

Contraception-                                                                                                              Females -Advise females of reproductive potential to use effective contraception during treatment with OGSIVEO and for 1 week after the last dose.

Males- Advise males with female partners of reproductive potential to use effective contraception during treatment with OGSIVEO and for 1 week after the last dose. Infertility

Based on findings in animal studies, OGSIVEO can impair female and male fertility. OGSIVEO has been shown to interfere with folliculogenesis and spermatogenesis in nonclinical studies resulting in changes that included ovarian atrophy

4. Pediatric Use-                                                                                                             The safety and effectiveness of OGSIVEO have not been established in pediatric patients. Epiphyseal disorder, manifesting as a widening of the epiphyseal growth plate, has been reported in pediatric patients with open growth plates treated with OGSIVEO.

5, Geriatric Use-                                                                                                                Of the total number of OGSIVEO-treated patients in the DeFi study, 3 (4%) were 65 years of age and older and none were 75 years of age and older.

Clinical studies of OGSIVEO did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than younger adult patients.

OVERDOSAGE-

Due to the high level of protein binding, OGSIVEO is not expected to be dialyzable [see Clinical Pharmacology (12.3)].