RASONQUE Film-coated tablet Ref.[116904] Active ingredients:

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)].

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)]

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:

^* Graded per NCI CTCAE Version 5.0.
^† Chemotherapy: mFOLFIRINOX, gemcitabine and nab-paclitaxel, FOLFOX, or nal-IRI+5-FU/LV.
^‡ Includes multiple related terms.

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*:

7.1 Effects of Other Drugs on RASONQUE

Table 5: Effects of Other Drugs on 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.

Risk Summary

Based on findings in animals, RASONQUE can cause fetal harm when administered to pregnant women. There are no available data on RASONQUE use in pregnant women to inform a drug-associated risk. 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 AUC (see Data). 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.

Data

Animal Data

Daraxonrasib was administered orally to pregnant female mice during the period of organogenesis at doses of 25, 50, and 75 mg/kg/day. Daraxonrasib at a dose of ≥ 50 mg/kg/day (≥ 2.5 times the exposure at the recommended dose based on AUC) was associated with post-implantation loss, reduced number of live fetuses, decreased fetal body weights, and malformations including eyes, limbs, palate, gonads, great vessels, kidneys, and bones.

Risk Summary

There are no data on the presence of daraxonrasib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with RASONQUE and for 1 week after the last dose.

RASONQUE can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating RASONQUE.

Contraception

Females

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

Males

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

The safety and effectiveness of RASONQUE have not been established in pediatric patients.

Of the 248 patients with pancreatic adenocarcinoma randomized to the RASONQUE arm in the RASolute 302 study, 54% (134 patients) were ≥ 65 years of age and 18% (45 patients) were ≥ 75 years of age. No overall differences in safety or efficacy were observed between patients who were ≥ 65 years of age and younger patients.