ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling:Diarrhea see Warnings and Precautions 5.1 )] Ovarian Toxicity see Warnings and Precautions 5.2 )] Hepatotoxicity [see Warnings and Precautions 5.3 )] Non-Melanoma Skin Cancers [see Warnings and Precautions 5.4 )] Electrolyte Abnormalities see Warnings and Precautions 5.5 )] Diarrhea see Warnings and Precautions 5.1 )] Ovarian Toxicity see Warnings and Precautions 5.2 )] Hepatotoxicity [see Warnings and Precautions 5.3 )] Non-Melanoma Skin Cancers [see Warnings and Precautions 5.4 )] Electrolyte Abnormalities see Warnings and Precautions 5.5 )] 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 at 1-888-400-7989 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of OGSIVEO was evaluated in 69 patients enrolled in DeFi with progressing desmoid tumor [see Clinical Studies 14 ]. Patients received OGSIVEO 150 mg orally twice daily or placebo orally twice daily until disease progression or unacceptable toxicity. The median duration of exposure to OGSIVEO was 20.6 months (range: 0.3 to 33.6). Serious adverse reactions occurred in 20% of patients who received OGSIVEO. Serious adverse reactions occurring in >= 2% of patients were ovarian toxicity (4%).Permanent discontinuation of OGSIVEO due to an adverse reaction occurred in 20% of patients. Adverse reactions which resulted in permanent discontinuation of OGSIVEO in >= 2% of patients were diarrhea, ovarian toxicity, increased ALT, and increased AST. Dosage interruptions of OGSIVEO due to an adverse reaction occurred in 51% of patients. Adverse reactions which required dosage interruption in >= 2% of patients included diarrhea, rash, stomatitis, hypophosphatemia, fatigue, folliculitis, nausea, and ovarian toxicity.Dose reductions of OGSIVEO due to an adverse reaction occurred in 42% of patients. Adverse reactions which required dose reductions in >= 2% of patients included diarrhea, rash, stomatitis, hypophosphatemia, folliculitis, hidradenitis, and ovarian toxicity. The most common (>= 15% with difference between arms of >= 5% compared to placebo) adverse reactions that occurred in patients receiving OGSIVEO were diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection and dyspnea.Table summarizes the adverse reactions that occurred in DeFi.Table 2. Adverse Reactions (>= 15%) in Patients with Desmoid Tumor Who Received OGSIVEO with Difference Between Arms of >= 5% Compared to Placebo on DeFiAdverse ReactionOGSIVEO(N 69)Placebo(N 72)All Grades(%)Grade 3(%)All Grades(%)Grade 3(%)GastrointestinalDiarrhea8416351.4Nausea541.4390Stomatitis 39440Abdominal Pain 221.4141.4Reproductive SystemOvarian toxicity , 75c 000Skin and Subcutaneous TissueRash a686140Alopecia1901.40GeneralFatigue 542.9380Nervous SystemHeadache 300150RespiratoryCough 20060Dyspnea16060InfectionsUpper respiratory tract infection 1702.80a Includes multiple related composite terms. Investigator assessment of ovarian toxicity included ovarian failure, premature menopause, amenorrhea, and menopause The number of females of reproductive potential in each arm is used as the denominator (OGSIVEO = 36, Placebo = 37)Clinically relevant adverse reactions occurring in 15% of patients receiving OGSIVEO in DeFi included non-melanoma skin cancers, epistaxis, hidradenitis suppurativa, folliculitis, and influenza-like illness.Table summarizes laboratory abnormalities in DeFi.Table 3. Laboratory Abnormalities (>=15%) that Worsened from Baseline in Patients with Desmoid Tumor Who Received OGSIVEO in DeFiLaboratory Abnormality OGSIVEO Placebo All Grades (%) Grade or (%) All Grades (%) Grade or (%) ChemistryDecreased phosphate ,b 65Not Applicable11Not ApplicableIncreased urine glucose ,d 51Not Applicable0Not Applicable Increased urine protein 400250Increased aspartate aminotransferase 332.9181.4Increased alanine aminotransferase 306211.4Decreased potassium 221.44.20a The denominator used to calculate the rate was 69 for nirogacestat and 72 for placebo based on the number of patients with baseline value and at least one post-treatment value.b CTCAE Version 5.0 does not include numeric thresholds for grading of hypophosphatemia; all grades represent patients with lab value Lower Limit of Normal (LLN).c The denominator used to calculate the rate was 68 for nirogacestat and 69 for placebo based on the number of patients with baseline value and at least one post-treatment value.d CTCAE Version 5.0 does not include numeric thresholds for grading of increased urine glucose.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Nirogacestat is gamma secretase inhibitor that blocks proteolytic activation of the Notch receptor. When dysregulated, Notch can activate pathways that contribute to tumor growth. 12.2 Pharmacodynamics Exposure-Response RelationshipsThere is an exposure-response relationship between nirogacestat exposure and Grade hypophosphatemia with higher risk of Grade hypophosphatemia at higher exposure. Cardiac ElectrophysiologyAt the recommended dosage, mean increase in the QTc interval 20 ms was not observed.. 12.3 Pharmacokinetics Nirogacestat pharmacokinetic parameters in patients with desmoid tumors are summarized in Table 6. Table 6. Pharmacokinetic Parameters and Characteristics of Nirogacestat General InformationSteady state exposure[Mean (%CV)]Cmax 508 (62) ng/mLAUC0- tau 3370 (58) ng.h/mLTime to steady-stateApproximately daysAccumulation ratio [Median (Min, Max)]1.6 (1.3, 4.6)AbsorptionTmax [Median (Min, Max)]1.5 (0.5, 6.5) hoursAbsolute bioavailability19%Food effect [dose-normalized GMR% (90% CI)]Cmax 93 (55%, 166%)AUC114% (76%, 171%)DistributionSerum protein binding99.6% Protein BindingHuman serum albumin94.6% -1 acid glycoprotein97.9% Apparent volume of distribution (Vz/F)[Mean (%CV)]1430 (65) LEliminationApparent Systemic Clearance (CL/F)[Mean (%CV)]45 (58) L/hrTerminal elimination half-life (t1/2)[Mean (%CV)]23 (37) hrMetabolismPrimary pathwayN-dealkylation via CYP3A4 (85%) Secondary pathwaysMetabolism by CYP 3A4, 2C19, 2C9, and 2D6ExcretionFeces38%Urine17% (<1% unchanged)Expired air9.7% 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 ratioSpecific PopulationsNo 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 ImpairmentThe 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 or NCI-ODWG Group 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 StudiesClinical Studies and Model-Informed ApproachesStrong CYP3A inhibitors: Nirogacestat Cmax increased by 2.5-fold and AUC by 8.2-fold following coadministration of single dose of OGSIVEO (100 mg) with itraconazole (a strong CYP3A inhibitor). Nirogacestat AUC is predicted to increase by 6.33-, 5.19-, and 3.46-fold following coadministration of multiple doses of OGSIVEO (150 mg BID) with itraconazole, ketoconazole and clarithromycin (strong CYP3A inhibitors), respectively. Moderate CYP3A inhibitors: Nirogacestat AUC is predicted to increase by 2.73- and 3.18-fold following coadministration of multiple doses of OGSIVEO (150 mg BID) with erythromycin (moderate CYP3A inhibitor) and fluconazole (moderate CYP3A inhibitor), respectively.Strong CYP3A inducers: Nirogacestat AUC is predicted to decrease by 85% following coadministration of multiple doses of OGSIVEO (150 mg BID) with rifampin (strong CYP3A inducer).Moderate CYP3A inducers: Nirogacestat AUC is predicted to decrease by 67% following coadministration of multiple doses of OGSIVEO (150 mg BID) with efavirenz (moderate CYP3A inducer).CYP3A substrates: Midazolam (CYP3A substrate) Cmax is predicted to increase by 1.77-fold and AUC by 2.07-fold following concomitant use with multiple doses of OGSIVEO (150 mg BID).CYP2C19 substrates: Concomitant use of multiple doses of OGSIVEO (150 mg BID) with drug that is sensitive substrate of CYP2C19 decreases the plasma concentrations of these substrates. P-gp substrates: Exposure to dabigatran (P-gp substrate) Cmax and AUC were not affected by concomitant use with nirogacestat.Drugs that increase gastric pH: Concomitant administration of proton pump inhibitors (e.g., omeprazole), histamine type (H2)-receptor antagonists (e.g., famotidine), or antacids (e.g., calcium) is expected to reduce concentrations of nirogacestat. Other Drugs:No clinically significant differences in nirogacestat pharmacokinetics were predicted when used concomitantly with cimetidine (weak CYP3A inhibitor).No clinically significant differences were predicted in the pharmacokinetics of the following drugs when used concomitantly with nirogacestat: rosiglitazone (CYP2C8 substrate) or S-warfarin (CYP2C9 substrate).In Vitro StudiesNirogacestat does not inhibit CYP 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6. Nirogacestat is an inducer of CYP2B6, CYP2C8, CYP2C9, and CYP2C19, but does not induce CYP 1A2.Transporter systems: Nirogacestat is P-gp substrate, but not substrate of BCRP, OATP1B1, and OATP1B3. Nirogacestat is P-gp inhibitor, but not an inhibitor of BCRP, MATE1, MATE2-K, OATP1B1, OATP1B3, OAT1, OAT2 and OAT3.

CLINICAL STUDIES SECTION.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of OGSIVEO was evaluated in 69 patients enrolled in DeFi with progressing desmoid tumor [see Clinical Studies 14 ]. Patients received OGSIVEO 150 mg orally twice daily or placebo orally twice daily until disease progression or unacceptable toxicity. The median duration of exposure to OGSIVEO was 20.6 months (range: 0.3 to 33.6). Serious adverse reactions occurred in 20% of patients who received OGSIVEO. Serious adverse reactions occurring in >= 2% of patients were ovarian toxicity (4%).Permanent discontinuation of OGSIVEO due to an adverse reaction occurred in 20% of patients. Adverse reactions which resulted in permanent discontinuation of OGSIVEO in >= 2% of patients were diarrhea, ovarian toxicity, increased ALT, and increased AST. Dosage interruptions of OGSIVEO due to an adverse reaction occurred in 51% of patients. Adverse reactions which required dosage interruption in >= 2% of patients included diarrhea, rash, stomatitis, hypophosphatemia, fatigue, folliculitis, nausea, and ovarian toxicity.Dose reductions of OGSIVEO due to an adverse reaction occurred in 42% of patients. Adverse reactions which required dose reductions in >= 2% of patients included diarrhea, rash, stomatitis, hypophosphatemia, folliculitis, hidradenitis, and ovarian toxicity. The most common (>= 15% with difference between arms of >= 5% compared to placebo) adverse reactions that occurred in patients receiving OGSIVEO were diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection and dyspnea.Table summarizes the adverse reactions that occurred in DeFi.Table 2. Adverse Reactions (>= 15%) in Patients with Desmoid Tumor Who Received OGSIVEO with Difference Between Arms of >= 5% Compared to Placebo on DeFiAdverse ReactionOGSIVEO(N 69)Placebo(N 72)All Grades(%)Grade 3(%)All Grades(%)Grade 3(%)GastrointestinalDiarrhea8416351.4Nausea541.4390Stomatitis 39440Abdominal Pain 221.4141.4Reproductive SystemOvarian toxicity , 75c 000Skin and Subcutaneous TissueRash a686140Alopecia1901.40GeneralFatigue 542.9380Nervous SystemHeadache 300150RespiratoryCough 20060Dyspnea16060InfectionsUpper respiratory tract infection 1702.80a Includes multiple related composite terms. Investigator assessment of ovarian toxicity included ovarian failure, premature menopause, amenorrhea, and menopause The number of females of reproductive potential in each arm is used as the denominator (OGSIVEO = 36, Placebo = 37)Clinically relevant adverse reactions occurring in 15% of patients receiving OGSIVEO in DeFi included non-melanoma skin cancers, epistaxis, hidradenitis suppurativa, folliculitis, and influenza-like illness.Table summarizes laboratory abnormalities in DeFi.Table 3. Laboratory Abnormalities (>=15%) that Worsened from Baseline in Patients with Desmoid Tumor Who Received OGSIVEO in DeFiLaboratory Abnormality OGSIVEO Placebo All Grades (%) Grade or (%) All Grades (%) Grade or (%) ChemistryDecreased phosphate ,b 65Not Applicable11Not ApplicableIncreased urine glucose ,d 51Not Applicable0Not Applicable Increased urine protein 400250Increased aspartate aminotransferase 332.9181.4Increased alanine aminotransferase 306211.4Decreased potassium 221.44.20a The denominator used to calculate the rate was 69 for nirogacestat and 72 for placebo based on the number of patients with baseline value and at least one post-treatment value.b CTCAE Version 5.0 does not include numeric thresholds for grading of hypophosphatemia; all grades represent patients with lab value Lower Limit of Normal (LLN).c The denominator used to calculate the rate was 68 for nirogacestat and 69 for placebo based on the number of patients with baseline value and at least one post-treatment value.d CTCAE Version 5.0 does not include numeric thresholds for grading of increased urine glucose.

DESCRIPTION SECTION.

11 DESCRIPTION OGSIVEO oral tablets contain nirogacestat (as nirogacestat hydrobromide), gamma () secretase inhibitor. Nirogacestat hydrobromide is chemically known as (S)-2-(((S)-6,8-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl) pentanamide dihydrobromide. The empirical formula is C27H43Br2F2N5O and the molecular weight is 651.48 g/mol. Nirogacestat hydrobromide is white to off white powder with an aqueous solubility of 11.4 mg/mL and pH of 4.4 in water at 25C. Nirogacestat dihydrobromide is highly soluble at low pH, however the solubility significantly decreases at pH 6.0. The molecule has pKas of 5.77 and 7.13. The structural formula for nirogacestat hydrobromide is: OGSIVEO (nirogacestat) tablets are immediate release (IR), film-coated tablets intended for oral administration. Each 50 mg tablet contains 50 mg nirogacestat as 66.525 mg nirogacestat hydrobromide. OGSIVEO 50 mg tablets are round, biconvex with an approximate diameter of mm. They are film coated, orange in color, and debossed with 50 on one face and plain on the other face. Each 100 mg tablet contains 100 mg nirogacestat as 133.050 mg nirogacestat hydrobromide. OGSIVEO 100 mg tablets are round, biconvex with an approximate diameter of 10 mm. They are film coated, light orange in color, and debossed with 100 on one face and plain on the other face. Each 150 mg tablet contains 150 mg nirogacestat as 199.574 mg nirogacestat hydrobromide. OGSIVEO 150 mg tablets are oval, biconvex with approximate dimensions of 8.5 17.5mm. They are film coated, orange yellow in color, and debossed with 150 on one face and plain on the other face.OGSIVEO tablets contain the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate type A. The tablets are finished with Opadry(R) QX orange film coating consisting of the following ingredients: FD&C yellow 6/sunset yellow FCF aluminum lake, glycerol monocaprylocaprate type 1/mono/diglycerides, iron oxide yellow, macrogol (PEG) polyvinyl alcohol graft copolymer, polyvinyl alcohol partially hydrolyzed, talc, and titanium dioxide. The structural formula for nirogacestat hydrobromide is: OGSIVEO oral tablets contain nirogacestat (as nirogacestat hydrobromide), gamma () secretase inhibitor. Nirogacestat hydrobromide is chemically known as (S)-2-(((S)-6,8-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl) pentanamide dihydrobromide. The empirical formula is C27H43Br2F2N5O and the molecular weight is 651.48 g/mol. Nirogacestat hydrobromide is white to off white powder with an aqueous solubility of 11.4 mg/mL and pH of 4.4 in water at 25C. Nirogacestat dihydrobromide is highly soluble at low pH, however the solubility significantly decreases at pH 6.0. The molecule has pKas of 5.77 and 7.13.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION The recommended dosage is 150 mg orally twice daily until disease progression or unacceptable toxicity. (2.1) See Full Prescribing Information for dosage modifications due to adverse reactions. (2.2) The recommended dosage is 150 mg orally twice daily until disease progression or unacceptable toxicity. (2.1) See Full Prescribing Information for dosage modifications due to adverse reactions. (2.2) 2.1 Recommended Dosage The recommended dosage of OGSIVEO is 150 mg administered orally twice daily until disease progression or unacceptable toxicity. Each 150 mg dose of OGSIVEO consists of three 50 mg tablets or one 150 mg tablet. OGSIVEO may be taken with or without food.Instruct patients to swallow OGSIVEO tablets whole and not to break, crush, or chew prior to swallowing. If patient vomits or misses dose, instruct the patient to take the next dose at its scheduled time. 2.2 Dos ag Modifications for Adverse Reactions The recommended dose modifications for OGSIVEO for selected severe adverse reactions are summarized in Table [ see Warnings and Precautions 5 , Adverse Reactions 6 ]. For other severe adverse reactions, life-threatening adverse reactions, or persistent intolerable Grade adverse events, withhold drug until resolved to Grade <= or baseline. Only restart at dose of 100 mg twice daily after considering the potential benefit and likelihood of recurrence of the adverse reaction. Permanently discontinue OGSIVEO for recurrence of severe or life-threatening adverse reaction upon rechallenge at the reduced dose. Table 1. Recommended Dose Modifications for Adverse ReactionsAdverse ReactionSeverityOGSIVEO Dosage ModificationsDiarrhea persisting for >= days despite maximal medical therapy see Warnings and Precautions 5.1 ] Grades or 4Withhold OGSIVEO until resolved to Grade <= or baseline, then restart at dose of 100 mg twice daily.ALT or AST increased [see Warnings and Precautions 5.3 ] Grade 2(>= to x ULN)Withhold OGSIVEO until ALT, AST, or both are resolved to 3 ULN or baseline, then restart at dose of 100 mg twice daily.Grades or 4(> x ULN)Permanently discontinue.Hypophosphatemia persisting for >= days despite maximal replacement therapy [see Warnings and Precautions 5.5 ] Grades or 4Withhold OGSIVEO until resolved to Grade <= or baseline, then restart at dose of 100 mg twice daily.Hypokalemia despite maximal replacement therapy [see Warnings and Precautions 5.5 ] Grades or 4Withhold OGSIVEO until resolved to Grade <= or baseline, then restart at dose of 100 mg twice daily.

DRUG INTERACTIONS SECTION.

7 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). 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). 7.1 Effect of Other Drugs on OGSIVEO Table 4. Effects of Other Drugs on OGSIVEOStrong or Moderate CYP3A InhibitorsClinical EffectNirogacestat is CYP3A substrate. Strong or moderate CYP3A inhibitors increase nirogacestat exposure see Clinical Pharmacology 12.3 )] which may increase the risk of OGSIVEO adverse reactions.Prevention or ManagementAvoid concomitant use of OGSIVEO with strong or moderate CYP3A inhibitors including grapefruit products, Seville oranges, and starfruit. Strong or Moderate CYP3A InducersClinical EffectNirogacestat is CYP3A substrate. Strong or moderate CYP3A inducers decrease serum nirogacestat exposure see Clinical Pharmacology 12.3 )] which may reduce the effectiveness of OGSIVEO.Prevention or ManagementAvoid concomitant use of OGSIVEO with strong or moderate CYP3A inducers. Gastric Acid Reducing AgentsClinical EffectNirogacestat is poorly soluble at pH >= 6. Gastric acid reducing agents may decrease serum nirogacestat exposure [see Clinical Pharmacology 12.3 )], which may reduce the effectiveness of OGSIVEO.Prevention or ManagementAvoid 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 hours before or hours after antacid use).. 7.2 Effects of OGSIVEO on Other Drugs Table 5. Effects of OGSIVEO on Other DrugsCertain CYP3ASubstratesClinical EffectNirogacestat increases exposure of CYP3A substrates see Clinical Pharmacology 12.3 )] which may increase the risk of adverse reactions related to these substrates.Prevention or ManagementAvoid concomitant use with CYP3A substrates where minimal concentration changes may lead to serious adverse reactions.Certain CYP2C19 SubstratesClinical EffectNirogacestat decreases exposure of CYP2C19 substrates [see Clinical Pharmacology 12.3 )], which may decrease efficacy of these substrates.Prevention or ManagementAvoid 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).DiarrheaAdvise 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 see Dosage and Administration 2.2 , Warnings and Precautions 5.1 ]. Ovarian ToxicityAdvise 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 see Warnings and Precautions 5.2 ]. Liver ToxicityAdvise patients that OGSIVEO can cause ALT or AST elevations, and that their healthcare provider should monitor liver transaminase levels regularly see Dosage and Administration 2.2 , Warnings and Precautions 5.3 ]. Non-Melanoma Skin CancersAdvise 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 [see Warnings and Precautions 5.4 ] Electrolyte AbnormalitiesAdvise 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 see Dosage and Administration 2.2 ), Warnings and Precautions 5.5 ]. Embryo-Fetal ToxicityAdvise pregnant women and females of reproductive potential of the potential harm to fetus. Advise females of reproductive potential to inform their healthcare provider of 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 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with OGSIVEO and for week after the last dose see Warnings and Precautions 5.6 , Use in Specific Populations 8.3 ]. LactationAdvise women not to breastfeed during treatment with OGSIVEO and for week after the last dose see Use in Specific Populations 8.2 ] Drug InteractionsAdvise 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 [see Drug Interactions 7 ]. Manufactured for: SpringWorks Therapeutics, Inc. Stamford, CT 06902 OGSIVEO(R) is trademark of SpringWorks Therapeutics, Inc. (C)2024 SpringWorks Therapeutics, Inc.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Nirogacestat pharmacokinetic parameters in patients with desmoid tumors are summarized in Table 6. Table 6. Pharmacokinetic Parameters and Characteristics of Nirogacestat General InformationSteady state exposure[Mean (%CV)]Cmax 508 (62) ng/mLAUC0- tau 3370 (58) ng.h/mLTime to steady-stateApproximately daysAccumulation ratio [Median (Min, Max)]1.6 (1.3, 4.6)AbsorptionTmax [Median (Min, Max)]1.5 (0.5, 6.5) hoursAbsolute bioavailability19%Food effect [dose-normalized GMR% (90% CI)]Cmax 93 (55%, 166%)AUC114% (76%, 171%)DistributionSerum protein binding99.6% Protein BindingHuman serum albumin94.6% -1 acid glycoprotein97.9% Apparent volume of distribution (Vz/F)[Mean (%CV)]1430 (65) LEliminationApparent Systemic Clearance (CL/F)[Mean (%CV)]45 (58) L/hrTerminal elimination half-life (t1/2)[Mean (%CV)]23 (37) hrMetabolismPrimary pathwayN-dealkylation via CYP3A4 (85%) Secondary pathwaysMetabolism by CYP 3A4, 2C19, 2C9, and 2D6ExcretionFeces38%Urine17% (<1% unchanged)Expired air9.7% 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 ratioSpecific PopulationsNo 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 ImpairmentThe 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 or NCI-ODWG Group 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 StudiesClinical Studies and Model-Informed ApproachesStrong CYP3A inhibitors: Nirogacestat Cmax increased by 2.5-fold and AUC by 8.2-fold following coadministration of single dose of OGSIVEO (100 mg) with itraconazole (a strong CYP3A inhibitor). Nirogacestat AUC is predicted to increase by 6.33-, 5.19-, and 3.46-fold following coadministration of multiple doses of OGSIVEO (150 mg BID) with itraconazole, ketoconazole and clarithromycin (strong CYP3A inhibitors), respectively. Moderate CYP3A inhibitors: Nirogacestat AUC is predicted to increase by 2.73- and 3.18-fold following coadministration of multiple doses of OGSIVEO (150 mg BID) with erythromycin (moderate CYP3A inhibitor) and fluconazole (moderate CYP3A inhibitor), respectively.Strong CYP3A inducers: Nirogacestat AUC is predicted to decrease by 85% following coadministration of multiple doses of OGSIVEO (150 mg BID) with rifampin (strong CYP3A inducer).Moderate CYP3A inducers: Nirogacestat AUC is predicted to decrease by 67% following coadministration of multiple doses of OGSIVEO (150 mg BID) with efavirenz (moderate CYP3A inducer).CYP3A substrates: Midazolam (CYP3A substrate) Cmax is predicted to increase by 1.77-fold and AUC by 2.07-fold following concomitant use with multiple doses of OGSIVEO (150 mg BID).CYP2C19 substrates: Concomitant use of multiple doses of OGSIVEO (150 mg BID) with drug that is sensitive substrate of CYP2C19 decreases the plasma concentrations of these substrates. P-gp substrates: Exposure to dabigatran (P-gp substrate) Cmax and AUC were not affected by concomitant use with nirogacestat.Drugs that increase gastric pH: Concomitant administration of proton pump inhibitors (e.g., omeprazole), histamine type (H2)-receptor antagonists (e.g., famotidine), or antacids (e.g., calcium) is expected to reduce concentrations of nirogacestat. Other Drugs:No clinically significant differences in nirogacestat pharmacokinetics were predicted when used concomitantly with cimetidine (weak CYP3A inhibitor).No clinically significant differences were predicted in the pharmacokinetics of the following drugs when used concomitantly with nirogacestat: rosiglitazone (CYP2C8 substrate) or S-warfarin (CYP2C9 substrate).In Vitro StudiesNirogacestat does not inhibit CYP 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6. Nirogacestat is an inducer of CYP2B6, CYP2C8, CYP2C9, and CYP2C19, but does not induce CYP 1A2.Transporter systems: Nirogacestat is P-gp substrate, but not substrate of BCRP, OATP1B1, and OATP1B3. Nirogacestat is P-gp inhibitor, but not an inhibitor of BCRP, MATE1, MATE2-K, OATP1B1, OATP1B3, OAT1, OAT2 and OAT3.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONOGSIVEO (og-SIH-vee-oh)(nirogacestat)tabletsWhat is OGSIVEOOGSIVEO is prescription medication used to treat adults with progressing desmoid tumors who require medicine by mouth or injection (systemic therapy).It is not known if OGSIVEO is safe and effective in children.Before taking OGSIVEO tell your healthcare provider about all of your medical conditions, including if you:have liver problems. are pregnant or plan to become pregnant. OGSIVEO can harm your unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with OGSIVEO. Females who are able to become pregnant: Your healthcare provider will give you pregnancy test before you start treatment with OGSIVEO. You should use effective birth control (contraception) during treatment with OGSIVEO and for week after the last dose. Talk to your healthcare provider about birth control methods that may be right for you. Stop taking OGSIVEO and tell your healthcare provider right away if you become pregnant. Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with OGSIVEO and for week after the last dose. are breastfeeding or plan to breastfeed. It is not known if OGSIVEO passes into your breast milk. Do not breastfeed during treatment with OGSIVEO and for week after the last dose.Tell your healthcare provider about all the medicines you take, including prescription and over-the counter medicines, vitamins, and herbal supplements.You should avoid taking proton pump inhibitors (PPIs) and H2 blockers during treatment with OGSIVEO. Ask your healthcare provider if you are not sure if you take one of these medicines. How should take OGSIVEOTake OGSIVEO exactly as your healthcare provider tells you to take it. Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with OGSIVEO if you develop side effects. Take OGSIVEO times day with or without food. Swallow OGSIVEO tablets whole. Do not break, crush or chew tablets. If you take an antacid medicine, take OGSIVEO hours before or hours after taking the antacid. If you vomit after taking dose or miss dose of OGSIVEO, take your next dose at your regular time. Do not take doses of OGSIVEO to make up the dose.What should avoid while taking OGSIVEOAvoid eating or drinking grapefruit products, Seville oranges, and starfruit during treatment with OGSIVEO. What are the possible side effects of OGSIVEOOGSIVEO can cause serious side effects, including: Diarrhea. Diarrhea is common during treatment with OGSIVEO and may sometimes be severe. Your healthcare provider may tell you to drink more fluids or may tell you to take antidiarrheal medicines. Tell your healthcare provider right away if you have diarrhea that lasts longer than few days and does not get better after taking antidiarrheal medicines. Ovarian problems. Females who are able to become pregnant may have ovarian problems and changes in their menstrual cycle during treatment with OGSIVEO. OGSIVEO may affect fertility which may affect your ability to have child. Tell your healthcare provider if you have any changes in your menstrual cycle or any hot flashes, night sweats or vaginal dryness during treatment with OGSIVEO. Liver problems. OGSIVEO can cause an increase in liver enzymes. Your healthcare provider will do blood tests to check your liver function before you start and during your treatment with OGSIVEO. New Non-Melanoma Skin Cancers. Your healthcare provider will do skin exams before and during treatment with OGSIVEO if you are at risk for skin cancer. Tell your healthcare provider if you have any new or changing skin lesions. Electrolyte (salt) problems. Your healthcare provider will do blood tests to check your phosphate and potassium levels during treatment with OGSIVEO and may give you medicines to treat low phosphate or low potassium if needed. Tell your healthcare provider if you develop any muscle pain or weakness. The most common side effects of OGSIVEO are:rashstomach (abdominal) painnauseacoughtirednesshair lossmouth soresupper respiratory infectionheadacheshortness of breathOGSIVEO can affect fertility in females and males, which may affect your ability to have child. Talk to your healthcare provider if this is concern for you. These are not all of the possible side effects of OGSIVEO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How do store OGSIVEOStore OGSIVEO tablets at room temperature between 68F to 77F (20C to 25C). Keep OGSIVEO and all medicines out of reach of children.General information about safe and effective use of OGSIVEO.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use OGSIVEO for condition for which it is not prescribed. Do not give OGSIVEO to other people even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about OGSIVEO that is written for health professionals.What are the ingredients in OGSIVEOActive ingredient: nirogacestat Inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate type A. Film Coating ingredients: FD&C yellow 6/sunset yellow FCF aluminum lake, glycerol monocaprylocaprate type 1/mono/diglycerides, iron oxide yellow, macrogol (PEG) polyvinyl alcohol graft copolymer, polyvinyl alcohol partially hydrolyzed, talc, and titanium dioxide.Manufactured for SpringWorks Therapeutics, Inc. Stamford, CT 06902. OGSIVEO(R) is trademark of SpringWorks Therapeutics, Inc. (C)2024 SpringWorks Therapeutics, Inc.. have liver problems. are pregnant or plan to become pregnant. OGSIVEO can harm your unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with OGSIVEO. Females who are able to become pregnant: Your healthcare provider will give you pregnancy test before you start treatment with OGSIVEO. You should use effective birth control (contraception) during treatment with OGSIVEO and for week after the last dose. Talk to your healthcare provider about birth control methods that may be right for you. Stop taking OGSIVEO and tell your healthcare provider right away if you become pregnant. Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with OGSIVEO and for week after the last dose. are breastfeeding or plan to breastfeed. It is not known if OGSIVEO passes into your breast milk. Do not breastfeed during treatment with OGSIVEO and for week after the last dose.. Take OGSIVEO exactly as your healthcare provider tells you to take it. Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with OGSIVEO if you develop side effects. Take OGSIVEO times day with or without food. Swallow OGSIVEO tablets whole. Do not break, crush or chew tablets. If you take an antacid medicine, take OGSIVEO hours before or hours after taking the antacid. If you vomit after taking dose or miss dose of OGSIVEO, take your next dose at your regular time. Do not take doses of OGSIVEO to make up the dose.. Diarrhea. Diarrhea is common during treatment with OGSIVEO and may sometimes be severe. Your healthcare provider may tell you to drink more fluids or may tell you to take antidiarrheal medicines. Tell your healthcare provider right away if you have diarrhea that lasts longer than few days and does not get better after taking antidiarrheal medicines. Ovarian problems. Females who are able to become pregnant may have ovarian problems and changes in their menstrual cycle during treatment with OGSIVEO. OGSIVEO may affect fertility which may affect your ability to have child. Tell your healthcare provider if you have any changes in your menstrual cycle or any hot flashes, night sweats or vaginal dryness during treatment with OGSIVEO. Liver problems. OGSIVEO can cause an increase in liver enzymes. Your healthcare provider will do blood tests to check your liver function before you start and during your treatment with OGSIVEO. New Non-Melanoma Skin Cancers. Your healthcare provider will do skin exams before and during treatment with OGSIVEO if you are at risk for skin cancer. Tell your healthcare provider if you have any new or changing skin lesions. Electrolyte (salt) problems. Your healthcare provider will do blood tests to check your phosphate and potassium levels during treatment with OGSIVEO and may give you medicines to treat low phosphate or low potassium if needed. Tell your healthcare provider if you develop any muscle pain or weakness. rash. stomach (abdominal) pain. nausea. cough. tiredness. hair loss. mouth sores. upper respiratory infection. headache. shortness of breath. Store OGSIVEO tablets at room temperature between 68F to 77F (20C to 25C).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. (8.2). Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy Risk SummaryBased on findings from animal studies and its mechanism of action, OGSIVEO can cause fetal harm or loss of pregnancy when administered to pregnant woman see linical Pharmacology 12.1 ] 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 [see Data ]. There are no available data on the use of OGSIVEO in pregnant women. Advise pregnant women of the potential risk to 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.Data Animal DataDaily oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in decreased fetal body weights, pre- and post-implantation loss, and fetal subcutis edema at doses >= 20 mg/kg/day (approximately 0.85 times the recommended dose of 150 mg twice daily based on area under the curve). 8.2 Lactation Risk SummaryThere are no data on the presence of nirogacestat or its metabolites in human milk or the effects of nirogacestat on 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 week after the last dose.. 8.3 Females and Males of Reproductive Potential OGSIVEO can cause fetal harm when administered to pregnant woman (see Use in Specific Populations 8.1 ]. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating OGSIVEO see Use in Specific Populations 8.1 ]. ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with OGSIVEO and for week after the last dose.MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with OGSIVEO and for week after the last dose.InfertilityBased 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 see Nonclinical Toxicology 13.1 ]. 8.4 Pediatric Use The safety and effectiveness of OGSIVEO have not been established in pediatric patients. Epiphyseal disorder, manifesting as widening of the epiphyseal growth plate, has been reported in pediatric patients with open growth plates treated with OGSIVEO. 8.5 Geriatric Use Of the total number of OGSIVEO-treated patients in the DeFi study, (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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS Diarrhea: Severe diarrhea can occur. Monitor and dose modify for Grade 3-4 diarrhea. (5.1) 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. (5.2) Hepatotoxicity: Elevated AST and ALT can occur. Monitor AST and ALT regularly and modify dose as recommended. (5.3) Non-Melanoma Skin Cancers: Perform dermatologic examination prior to initiation of OGSIVEO and routinely during treatment. (5.4) Electrolyte Abnormalities: Monitor phosphate and potassium regularly and modify dose as recommended. (5.5) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to fetus and to use effective contraception. (5.6, 8.1, 8.3). Diarrhea: Severe diarrhea can occur. Monitor and dose modify for Grade 3-4 diarrhea. (5.1) 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. (5.2) Hepatotoxicity: Elevated AST and ALT can occur. Monitor AST and ALT regularly and modify dose as recommended. (5.3) Non-Melanoma Skin Cancers: Perform dermatologic examination prior to initiation of OGSIVEO and routinely during treatment. (5.4) Electrolyte Abnormalities: Monitor phosphate and potassium regularly and modify dose as recommended. (5.5) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to fetus and to use effective contraception. (5.6, 8.1, 8.3). 5.1 Diarrhea Diarrhea, sometimes severe, can occur in patients treated with OGSIVEO [see Adverse Reactions 6.1 ].In DeFi, diarrhea occurred in 84% of patients treated with OGSIVEO, and included Grade events in 16% of patients. Median time to first diarrhea event for patients treated with OGSIVEO was days (range: to 434 days). Monitor patients and manage using antidiarrheal medications. Modify dose as recommended see Dosage and Administration 2.2 ]. 5.2 Ovarian Toxicity Female reproductive function and fertility may be impaired in patients being treated with OGSIVEO. Impact on fertility may depend on factors including the duration of therapy and the state of gonadal function at the time of treatment. The long-term effects of OGSIVEO on fertility have not been established. Advise patients on the potential risks for ovarian toxicity before initiating treatment with OGSIVEO see Use in Specific Populations 8.3 ]. Monitor patients for changes in menstrual cycle regularity or the development of symptoms of estrogen deficiency, including hot flashes, night sweats, and vaginal dryness.. 5.3 Hepatotoxicity ALT or AST elevations occurred in 30% and 33% of patients who received OGSIVEO in DeFi, respectively. Grade ALT or AST elevations (> x ULN) occurred in 6% and 2.9% of patients, respectively [see Adverse Reactions 6.1 ]. Monitor liver function tests regularly and modify dose as recommended [see Dosage and Administration 2.2 ].. 5.4 Non-Melanoma Skin Cancers New non-melanoma skin cancers can occur in patients treated with OGSIVEO. In DeFi, cutaneous squamous cell carcinoma and basal cell carcinoma occurred in 2.9% and 1.4% of patients, respectively [see Adverse Reactions 6.1 ]. Perform dermatologic evaluations prior to initiation of OGSIVEO and routinely during treatment. 5.5 Electrolyte Abnormalities Electrolyte abnormalities can occur in patients treated with OGSIVEO. In DeFi, these included decreased phosphate (65%) and decreased potassium (22%). Phosphate <2 mg/dL occurred in 20% of patients who received OGSIVEO. Grade decreased potassium occurred in 1.4% of patients see dverse Reactions 6.1 ]. Monitor phosphate and potassium levels regularly and supplement as necessary. Modify dose as recommended [see Dosage and Administration 2.2 ]. 5.6 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, OGSIVEO can cause fetal harm when administered to pregnant women. Oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity and death at maternal exposures below the human exposure at the recommended dose of 150 mg twice daily. Advise pregnant women of the potential risk to fetus. Advise females and males of reproductive potential to use effective contraception during treatment with OGSIVEO and for week after the last dose see Use in Specific Populations 8.1 8.3 ].