warnings and cautions
5 WARNINGS AND PRECAUTIONS Dermatologic and Soft Tissue Toxicity : RASONQUE can cause dermatologic or soft tissue toxicities, including rash, pruritus, and dry skin. Advise patients to limit sun exposure, use sunscreen, and use emollient creams. Withhold, reduce the dose, or permanently discontinue based on severity. ( 2.3 , 5.1 ) Stomatitis and Oral Disorders : RASONQUE can cause stomatitis, including mouth ulcers and oral mucositis. Withhold, reduce the dose, or permanently discontinue based on severity. ( 2.3 , 5.2 ) Diarrhea : RASONQUE can cause diarrhea. Withhold, reduce the dose, or permanently discontinue based on severity. ( 2.3 , 5.3 ) Gastrointestinal Perforation : Monitor for gastrointestinal perforation. Withhold if suspected. If appropriate, reduce the dose or permanently discontinue if no other potential causes of gastrointestinal perforation are identified. ( 2.3 , 5.4 ) Interstitial Lung Disease (ILD)/Pneumonitis : Monitor for new or worsening pulmonary symptoms. Withhold if suspected. If appropriate, reduce the dose or permanently discontinue if no other potential causes of ILD/pneumonitis are identified. ( 2.3 , 5.5 ) Embryo-Fetal Toxicity : RASONQUE can cause fetal harm. Advise of the potential risk to the fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 Dermatologic and Soft Tissue Toxicity RASONQUE can cause dermatologic toxicity, which may be severe. Clinical manifestations included, but were not limited to, rash, pruritus, paronychia, dry skin, and skin fissures. In clinical trials of patients with pancreatic adenocarcinoma, dermatologic toxicity occurred in 86% of patients treated with RASONQUE, of which 10% were Grade 3. The median time to first onset was 13 days (range: 1 to 106 days). The median time to improvement from Grade 3 to Grade 1 or resolution was 16 days (range: 8 to 218 days). Dermatologic toxicity led to interruption of RASONQUE in 24% of patients, dose reduction in 16% of patients, and dose discontinuation in 0.5% of patients. Monitor patients who develop dermatologic or soft tissue toxicities while receiving RASONQUE. Initiate prophylactic measures (e.g., topical corticosteroids, emollient creams, sunscreen, oral antibiotics) prior to the first dose of RASONQUE to reduce the risk of moderate to severe dermatologic reactions. Advise patients to limit sun exposure while taking RASONQUE. Initiate supportive measures (e.g., oral corticosteroids) as clinically indicated, and consider dermatologic consultation. Withhold, reduce the dose, or permanently discontinue RASONQUE based on severity [see Dosage and Administration (2.3) ]. 5.2 Stomatitis and Oral Disorders RASONQUE can cause stomatitis, including mouth ulcers and oral mucositis. In clinical trials of patients with pancreatic adenocarcinoma, stomatitis occurred in 57% of patients, of which 9% were Grade 3. The median time to first onset was 22 days (range: 1 to 343 days). The median time to improvement from Grade 3 to Grade 1 or resolution was 12 days (range: 1 to 127 days). Stomatitis led to interruption of RASONQUE in 17% of patients and dose reduction in 8% of patients. Monitor patients for signs and symptoms of stomatitis while receiving RASONQUE. Initiate a steroid-containing mouthwash for treatment of stomatitis and administer other topical treatments (e.g., chlorhexidine mouthwash, 2% lidocaine viscous) as clinically indicated. Withhold, reduce the dose, or permanently discontinue RASONQUE based on severity [see Dosage and Administration (2.3) ]. 5.3 Diarrhea RASONQUE can cause diarrhea. In clinical trials of patients with pancreatic adenocarcinoma, diarrhea occurred in 63% of patients, of which 6% were Grade 3. The median time to first onset was 3 days (range: 1 to 260 days). The median time to improvement from Grade 3 to Grade 1 or resolution was 3 days (range: 1 to 21 days). Diarrhea led to interruption of RASONQUE in 8% of patients and dose reduction in 4% of patients. If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Withhold, reduce the dose, or permanently discontinue RASONQUE based on severity [see Dosage and Administration (2.3) ]. 5.4 Gastrointestinal Perforation RASONQUE can cause gastrointestinal perforation. In clinical trials of patients with pancreatic adenocarcinoma, gastrointestinal perforation occurred in 0.9% of patients treated with RASONQUE, of which 0.5% were Grade 3, one event was Grade 4, and one event was fatal. The median time to first onset was 134 days (range: 17 to 254 days). The median time to improvement from Grade ≥ 3 to resolution was 8 days (range: 7 to 9 days). Monitor patients for gastrointestinal perforation. Withhold RASONQUE if gastrointestinal perforation is suspected. Reduce the dose or permanently discontinue RASONQUE if no other potential causes of gastrointestinal perforation are identified [see Dosage and Administration (2.3) ]. 5.5 Interstitial Lung Disease (ILD)/Pneumonitis RASONQUE can cause interstitial lung disease or pneumonitis. In clinical trials of patients with pancreatic adenocarcinoma, ILD/pneumonitis occurred in 2.4% of patients treated with RASONQUE, of which 0.9% were Grade 3, and one event was fatal. The median time to first onset was 111 days (range: 22 to 242 days). The median time to improvement from Grade 3 to resolution was 12 days (range: 12 to 47 days). Monitor patients for new or worsening pulmonary symptoms. Withhold RASONQUE if ILD/pneumonitis is suspected. Reduce the dose or permanently discontinue RASONQUE if no other potential causes of ILD/pneumonitis are identified [see Dosage and Administration (2.3) ] . 5.6 Embryo-Fetal Toxicity Based on findings in animals, RASONQUE can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of daraxonrasib to pregnant female mice during the period of organogenesis resulted in adverse developmental outcomes including mortality, alterations to growth, and structural abnormalities at exposures ≥ 2.5 times the recommended dose based on area under the curve (AUC). Advise females of reproductive potential to use effective contraception during treatment with RASONQUE and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with RASONQUE and for 1 week after the last dose [see Use in Specific Populations (8.1) , (8.3) ] .