daraxonrasib

7 DRUG INTERACTIONS Strong CYP3A Inhibitors with P-gp Inhibition : Avoid concomitant use. ( 7.1 ) Strong CYP3A Inhibitors without P-gp Inhibition : Reduce RASONQUE dosage. ( 2.4 ) Moderate CYP3A Inhibitors with or without P-gp Inhibition : Reduce RASONQUE dosage. ( 2.4 ) P-gp Inhibitors : Reduce RASONQUE dosage. ( 2.4 ) Cyclosporine A : Avoid concomitant use. ( 7.1 ) Strong CYP3A Inducers : Avoid concomitant use. Increase RASONQUE dosage if concomitant use cannot be avoided. ( 2.4 , 7.1 ) Moderate CYP3A Inducers : Increase RASONQUE dosage. ( 2.4 ) P-gp Substrates : Take at least 4 hours apart from RASONQUE. ( 7.2 ) 7.1 Effects of Other Drugs on RASONQUE Table 5: Effects of Other Drugs on RASONQUE Strong or Moderate CYP3A Inhibitors with or without P-gp Inhibition Prevention or Management Strong CYP3A inhibitors with P-glycoprotein (P-gp) inhibition : Avoid concomitant use. Strong CYP3A inhibitors without P-gp inhibition : Reduce RASONQUE dosage to 150 mg once daily [see Dosage and Administration (2.4) ] . Moderate CYP3A inhibitors with P-gp inhibition : Reduce RASONQUE dosage to 100 mg once daily [see Dosage and Administration (2.4) ] . Moderate CYP3A inhibitors without P-gp inhibition : Reduce RASONQUE dosage to 200 mg once daily [see Dosage and Administration (2.4) ] . Mechanism and Clinical Effect Daraxonrasib is a CYP3A and P-gp substrate. Moderate or strong CYP3A inhibitors with or without P-gp inhibition increase daraxonrasib exposure [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions. P-gp Inhibitors Prevention or Management Reduce RASONQUE dosage to 150 mg once daily [see Dosage and Administration (2.4) ] . Mechanism and Clinical Effect Daraxonrasib is a P-gp substrate. P-gp inhibitors increase daraxonrasib exposure [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions. Cyclosporine A Prevention or Management Avoid concomitant use of RASONQUE with systemic cyclosporine A or its derivatives. Mechanism and Clinical Effect Cyclosporine A or its derivatives and daraxonrasib bind to cyclophilin A. Coadministration of systemic cyclosporine A or its derivatives and RASONQUE may have the potential to alter daraxonrasib pharmacokinetics, efficacy, and safety. Strong or Moderate CYP3A Inducers Prevention or Management Strong CYP3A inducers : Avoid concomitant use. If concomitant use cannot be avoided, increase RASONQUE dosage to 400 mg once daily [see Dosage and Administration (2.4) ] . Moderate CYP3A inducers : Increase RASONQUE dosage to 400 mg once daily [see Dosage and Administration (2.4) ] . Mechanism and Clinical Effect Daraxonrasib is a CYP3A substrate. Strong CYP3A inducers reduce daraxonrasib exposure [see Clinical Pharmacology (12.3) ] , which may reduce the effectiveness of RASONQUE. 7.2 Effects of RASONQUE on Other Drugs P-gp Substrates Take a P-gp substrate at least 4 hours apart from RASONQUE. Daraxonrasib is a P-gp inhibitor. Coadministration with RASONQUE increases exposure of P-gp substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates.

1 INDICATIONS AND USAGE RASONQUE is indicated for the treatment of adult patients with metastatic pancreatic adenocarcinoma who have received at least one prior systemic therapy or who are not candidates for multiagent systemic therapy. RASONQUE is an inhibitor of the RAS GTPase family, indicated for the treatment of adult patients with metastatic pancreatic adenocarcinoma who have received at least one prior systemic therapy or who are not candidates for multiagent systemic therapy. ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended dosage: 300 mg orally once daily. ( 2.2 ) Swallow tablets whole with or without food. ( 2.2 ) Administer prophylactic and concomitant medications to reduce the risk of dermatologic reactions. ( 2.1 ) 2.1 Prophylactic and Concomitant Medication When initiating RASONQUE and throughout treatment, prophylactic and concomitant medications are recommended to reduce the risk of dermatologic reactions [see Warnings and Precautions (5.1) ] : administer a topical corticosteroid (applied to the face and chest) and emollient creams advise patients to limit sun exposure and use broad-spectrum sunscreen (SPF 30 or higher) consider prophylactic oral antibiotics (e.g., doxycycline or minocycline) 2.2 Recommended Dosage The recommended dosage of RASONQUE is 300 mg orally once daily until disease progression or unacceptable toxicity. Take RASONQUE at the same time each day with or without food. Swallow tablets whole. Do not chew, crush, or split tablets. If a dose is missed for more than 4 hours, skip the missed dose, and take the next dose at the next regularly scheduled time. If vomiting occurs after taking the dose, do not take an additional dose. Resume dosing at the next regularly scheduled time. 2.3 Dosage Modifications for Adverse Reactions Recommended dosage reductions for adverse reactions are provided in Table 1 . Permanently discontinue RASONQUE in patients who are unable to tolerate 150 mg orally once daily. Table 1: Recommended Dosage Reductions for Adverse Reactions Dose Reduction Level Dosage First dose reduction 200 mg once daily Second dose reduction 150 mg once daily Recommended dosage modifications for adverse reactions are provided in Table 2 . Table 2: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity Graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. Dosage Modification Dermatologic Toxicity (rash) [see Warnings and Precautions (5.1) ] Grade 2 Consider withholding RASONQUE until recovery to ≤ Grade 1. Initiate supportive measures, as necessary. Resume RASONQUE at the same dose level or the next lower dose level. Grade 3 Withhold RASONQUE until recovery to ≤ Grade 1. Initiate supportive measures, as necessary, and consider consultation with a dermatologist. Resume RASONQUE at the next lower dose level. Grade 4 Permanently discontinue. Stomatitis [see Warnings and Precautions (5.2) ] Grade 2 Consider withholding RASONQUE until recovery to ≤ Grade 1. Initiate supportive measures, as necessary. Resume RASONQUE at the same dose level or the next lower dose level. Grade 3 Withhold RASONQUE until recovery to ≤ Grade 1. Initiate supportive measures, as necessary. Resume RASONQUE at the next lower dose level. Grade 4 Permanently discontinue. Diarrhea [see Warnings and Precautions (5.3) ] Grade 2 Consider withholding RASONQUE until recovery to ≤ Grade 1. Initiate antidiarrheal treatment. Resume RASONQUE at the same dose level or the next lower dose level. Grade 3 Withhold RASONQUE until recovery to ≤ Grade 1. Initiate antidiarrheal treatment. Resume RASONQUE at the next lower dose level. Grade 4 Permanently discontinue. Gastrointestinal Perforation [see Warnings and Precautions (5.4) ] Grade 3 Withhold RASONQUE until recovery to ≤ Grade 1. If appropriate, resume RASONQUE at the next lower dose level. Grade 4 Permanently discontinue. Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.5) ] Grade 2 Withhold RASONQUE until recovery to ≤ Grade 1. If appropriate, resume RASONQUE at the next lower dose level. Recurrent Grade 2, or Grade 3-4 Permanently discontinue. Nausea or Vomiting [see Adverse Reactions (6.1) ] Grade 3 Withhold RASONQUE until recovery to ≤ Grade 1. Initiate or modify anti-emetic regimen. Resume RASONQUE at the next lower dose level. Grade 4 Permanently discontinue. Other Adverse Reactions [see Adverse Reactions (6.1) ] Grade 3 Withhold RASONQUE until recovery to ≤ Grade 1 or baseline. Resume RASONQUE at the next lower dose level. Grade 4 Permanently discontinue. 2.4 Dosage Modifications for Drug Interactions Strong CYP3A Inhibitors without P-gp Inhibition Reduce the dosage of RASONQUE from 300 mg once daily to 150 mg once daily when used concomitantly with a strong CYP3A inhibitor without P-gp inhibition [see Drug Interactions (7.1) ] . After the strong CYP3A inhibitor without P-gp inhibition has been discontinued for 5 days or 3 to 5 half-lives, whichever is longer, resume the RASONQUE dosage taken prior to initiating the inhibitor. Moderate CYP3A Inhibitors with P-gp Inhibition Reduce the dosage of RASONQUE from 300 mg once daily to 100 mg once daily when used concomitantly with a moderate CYP3A inhibitor with P-gp inhibition [see Drug Interactions (7.1) ] . After the moderate CYP3A inhibitor with P-gp inhibition has been discontinued for 3 to 5 half-lives, resume the RASONQUE dosage taken prior to initiating the inhibitor. Moderate CYP3A Inhibitors without P-gp Inhibition Reduce the dosage of RASONQUE from 300 mg once daily to 200 mg once daily when used concomitantly with a moderate CYP3A inhibitor without P-gp inhibition [see Drug Interactions (7.1) ] . After the moderate CYP3A inhibitor without P-gp inhibition has been discontinued for 3 to 5 half-lives, resume the RASONQUE dosage taken prior to initiating the inhibitor. P-gp Inhibitors Reduce the dosage of RASONQUE from 300 mg once daily to 150 mg once daily when used concomitantly with a P-gp inhibitor [see Drug Interactions (7.1) ] . After the P-gp inhibitor has been discontinued, resume the RASONQUE dosage taken prior to initiating the inhibitor. Strong CYP3A Inducers If a strong CYP3A inducer cannot be avoided, increase the dosage of RASONQUE from 300 mg once daily to 400 mg once daily when used concomitantly with a strong CYP3A inducer [see Drug Interactions (7.1) ] . After discontinuing use of the strong CYP3A inducer, resume RASONQUE dosage (7 to 14 days after discontinuing the strong CYP3A inducer) that was taken prior to initiating the inducer. Moderate CYP3A Inducers Increase the dosage of RASONQUE from 300 mg once daily to 400 mg once daily when used concomitantly with a moderate CYP3A inducer [see Drug Interactions (7.1) ] . After discontinuing use of the moderate CYP3A inducer, resume RASONQUE dosage (7 to 14 days after discontinuing the moderate CYP3A inducer) that was taken prior to initiating the inducer.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Dermatologic and Soft Tissue Toxicity [see Warnings and Precautions (5.1) ] Stomatitis and Oral Disorders [see Warnings and Precautions (5.2) ] Diarrhea [see Warnings and Precautions (5.3) ] Gastrointestinal Perforation [see Warnings and Precautions (5.4) ] Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.5 )] Most common adverse reactions (≥ 20%) were rash, diarrhea, stomatitis, nausea, fatigue, vomiting, abdominal pain, edema, decreased appetite, and hemorrhage. ( 6.1 ) Most common laboratory abnormalities (≥ 20%) were decreased albumin, decreased calcium, decreased hemoglobin, increased aspartate aminotransferase, decreased lymphocytes, decreased platelets, increased alanine aminotransferase, decreased sodium, decreased white blood cells, decreased magnesium, increased alkaline phosphatase, increased creatinine, and decreased potassium. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Revolution Medicines, Inc. at 1-844-2-REVMED (1-844-273-8633) 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 a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population of RASONQUE described in the WARNINGS AND PRECAUTIONS section reflects exposure to RASONQUE 300 mg once daily in 241 patients with pancreatic adenocarcinoma enrolled in RASolute 302 and 184 patients with pancreatic adenocarcinoma enrolled in the open-label trial RMC-6236-001. Metastatic Pancreatic Adenocarcinoma The safety of RASONQUE was evaluated in RASolute 302 [see Clinical Studies (14) ] . Patients with metastatic pancreatic adenocarcinoma received either RASONQUE 300 mg once daily (N = 241) or physician’s choice of standard of care (SOC) chemotherapy regimens (N = 214). Among patients who received RASONQUE, 52% were exposed for 6 months or longer and 2% were exposed for greater than one year. Serious adverse reactions occurred in 30% of patients treated with RASONQUE. Serious adverse reactions occurring in ≥ 2% of patients treated with RASONQUE were diarrhea (3.7%), pyrexia (3.3%), sepsis (2.9%), fatigue (2.1%), and hemorrhage (2.1%). Adverse reactions leading to permanent discontinuation of RASONQUE occurred in 2.9% of patients, including two patients who discontinued due to rash (0.8%). Adverse reactions leading to dose interruptions occurred in 69% of patients who received RASONQUE. Adverse reactions which required dose interruptions in ≥ 5% of patients were rash (27%), stomatitis (20%), fatigue (9%), diarrhea (8%), vomiting (8%), nausea (7%), and pyrexia (6%). Adverse reactions leading to dose reductions occurred in 37% of patients who received RASONQUE. Adverse reactions which required dose reductions in ≥ 5% of patients were rash (18%), stomatitis (8%), and diarrhea (5%). The most common (≥ 20%) adverse reactions in patients treated with RASONQUE were rash, diarrhea, stomatitis, nausea, fatigue, vomiting, abdominal pain, edema, decreased appetite, and hemorrhage. Table 3 and Table 4 summarize adverse reactions and laboratory abnormalities in RASolute 302, respectively. Table 3: Adverse Reactions (≥ 10%) in Patients Who Received RASONQUE in RASolute 302 Adverse Reaction Graded per NCI CTCAE Version 5.0. RASONQUE N = 241 Physician’s Choice SOC Chemotherapy Regimens Chemotherapy: mFOLFIRINOX, gemcitabine and nab-paclitaxel, FOLFOX, or nal-IRI+5-FU/LV. N = 214 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Skin and subcutaneous tissue disorders Rash Includes multiple related terms. 87 13 9 0 Dry skin 14 0 3 0 Pruritus 11 0.4 4 0 Gastrointestinal disorders Diarrhea 67 7 44 8 Stomatitis 56 12 19 3 Nausea 52 3 42 2 Vomiting 42 1 25 1 Abdominal pain 27 2 26 2 Constipation 16 0.4 21 0.5 General disorders and administration site conditions Fatigue 47 5 61 10 Edema 25 0.8 22 0 Pyrexia 19 1 23 0.9 Metabolism and nutrition disorders Decreased appetite 24 2 27 0.9 Vascular disorders Hemorrhage 22 3 12 4 Musculoskeletal and connective tissue disorders Musculoskeletal pain 19 0.8 27 1 Infections and infestations Paronychia 17 0 0 0 Nervous system disorders Neuropathy peripheral 10 0 29 4 Other clinically important adverse reactions occurring in less than 10% of patients who received RASONQUE in RASolute 302 included renal-limited thrombotic microangiopathy (0.4%). Table 4: Select Laboratory Abnormalities (≥ 20%) that Worsened from Baseline in Patients Who Received RASONQUE in RASolute 302 The denominator used to calculate the percentage varied from 234 to 237 in the RASONQUE arm and from 207 to 208 in the SOC chemotherapy arm, based on the number of patients with a baseline value and at least one post-baseline value. Laboratory Abnormality Graded per NCI CTCAE Version 5.0. RASONQUE Physician’s Choice SOC Chemotherapy Regimens All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Chemistry Albumin decreased 71 3 51 1 Calcium (corrected) decreased 64 2 47 3 Aspartate aminotransferase increased 51 3 36 2 Alanine aminotransferase increased 36 4 39 0.5 Sodium decreased 36 6 30 5 Magnesium decreased 34 1 22 1 Alkaline phosphatase increased 29 2 24 0.5 Creatinine increased 24 0.8 9 0 Potassium decreased 20 3 33 7 Hematology Hemoglobin decreased 52 10 68 20 Lymphocyte cell count decreased 49 11 56 19 Platelet count decreased 45 3 58 10 White blood cell count decreased 35 3 58 17