Pralsetinib

1 INDICATIONS AND USAGE GAVRETO is a kinase inhibitor indicated for treatment of: Adult patients with metastatic rearranged during transfection (RET ) fusion-positive non-small cell lung cancer as detected by an FDA approved test (NSCLC). ( 1.1 ) Adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). ( 1.2 ) 1.1 Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer GAVRETO is indicated for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test. 1.2 RET Fusion-Positive Thyroid Cancer GAVRETO is indicated for the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.2) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

2 DOSAGE AND ADMINISTRATION Select patients for treatment with GAVRETO based on the presence of a RET gene fusion. ( 2.1 , 14 ) The recommended dosage in adults and pediatric patients 12 years and older is 400 mg orally once daily on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO). ( 2.2 ) 2.1 Patient Selection Select patients for treatment with GAVRETO based on the presence of a RET gene fusion (NSCLC or thyroid cancer) [see Clinical Studies (14) ] . Information on FDA-approved tests for RET gene fusion (NSCLC) is available at http://www.fda.gov/CompanionDiagnostics. An FDA-approved test for the detection of RET gene fusion (thyroid cancer) is not currently available. 2.2 Recommended Dosage The recommended dosage of GAVRETO is 400 mg orally once daily on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO ) [see Clinical Pharmacology (12.3) ] . Continue treatment until disease progression or until unacceptable toxicity. If a dose of GAVRETO is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for GAVRETO the next day. Do not take an additional dose if vomiting occurs after GAVRETO but continue with the next dose as scheduled. 2.3 Dosage Modifications for Adverse Reactions The recommended dose reductions and dosage modifications for adverse reactions are provided in Table 1 and Table 2 . Table 1: Recommended Dose Reductions for GAVRETO for Adverse Reactions Dose Reduction Recommended Dosage First 300 mg once daily Second 200 mg once daily Third 100 mg once daily Permanently discontinue GAVRETO in patients who are unable to tolerate 100 mg taken orally once daily. The recommended dosage modifications for adverse reactions are provided in Table 2 . Table 2: Recommended Dosage Modifications for GAVRETO for Adverse Reactions Adverse Reactions Severity Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 Dosage Modification Serious Infections, Including Opportunistic Infections [see Warnings and Precautions (5.1) ] Grade 2 or 3 Withhold GAVRETO until resolution. Resume at a reduced dose ( Table 1 ). Grade 4 Permanently discontinue GAVRETO. ILD/Pneumonitis [see Warnings and Precautions (5.2) ] Grade 1 or 2 Withhold GAVRETO until resolution. Resume by reducing the dose as shown in Table 1 . Permanently discontinue GAVRETO for recurrent ILD/pneumonitis. Grade 4 Permanently discontinue GAVRETO. Hypertension [see Warnings and Precautions (5.3) ] Grade 3 Withhold GAVRETO for Grade 3 hypertension that persists despite optimal antihypertensive therapy. Resume at a reduced dose when hypertension is controlled. Grade 4 Discontinue GAVRETO. Hepatotoxicity [see Warnings and Precautions (5.4) ] Grade 3 or 4 Withhold GAVRETO and monitor AST/ALT once weekly until resolution to Grade 1 or baseline. Resume at reduced dose ( Table 1 ). For recurrent events at Grade 3 or higher, discontinue GAVRETO. Hemorrhagic Events [see Warnings and Precautions (5.5) ] Grade 3 or 4 Withhold GAVRETO until recovery to baseline or Grade 0 or 1. Discontinue GAVRETO for severe or life-threatening hemorrhagic events. Other Adverse Reactions [see Adverse Reactions (6.1) ] Grade 3 or 4 Withhold GAVRETO until improvement to ≤ Grade 2. Resume at reduced dose ( Table 1 ). Permanently discontinue for recurrent Grade 4 adverse reactions. 2.4 Dose Modification for Use with CYP3A and/or P-glycoprotein (P-gp) Inhibitors Avoid coadministration of GAVRETO with any of the following: Strong CYP3A inhibitors Moderate CYP3A inhibitors P-gp inhibitors Combined P-gp and strong CYP3A inhibitors Combined P-gp and moderate CYP3A inhibitors If coadministration with any of the above inhibitors cannot be avoided, reduce the current dose of GAVRETO as recommended in Table 3 . After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume GAVRETO at the dose taken prior to initiating the inhibitor [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . Table 3: Recommended Dosage Modifications for GAVRETO for Coadministration with CYP3A and/or P-gp Inhibitors Current GAVRETO Dosage Recommended GAVRETO Dosage when Coadministered with: Combined P-gp and Strong CYP3A Inhibitors Strong CYP3A Inhibitors; Moderate CYP3A Inhibitors; P-gp Inhibitors; Combined P-gp and Moderate CYP3A Inhibitors 400 mg orally once daily 200 mg orally once daily 300 mg orally once daily 300 mg orally once daily 200 mg orally once daily 200 mg orally once daily 200 mg orally once daily 100 mg orally once daily 100 mg orally once daily 2.5 Dose Modification for Use with CYP3A Inducers Avoid coadministration of GAVRETO with any of the following: Strong CYP3A inducers Moderate CYP3A inducers If coadministration with any of the above inducers cannot be avoided, increase the starting dose of GAVRETO as recommended in Table 4 starting on Day 7 of coadministration of GAVRETO with the inducer. After the inducer has been discontinued for at least 14 days, resume GAVRETO at the dose taken prior to initiating the inducer [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . Table 4: Recommended Dosage Modifications for GAVRETO for Coadministration with CYP3A Inducers Current GAVRETO Dosage Recommended GAVRETO Dosage when Coadministered with: Strong CYP3A Inducers Moderate CYP3A Inducers 400 mg orally once daily 800 mg orally once daily 600 mg orally once daily 300 mg orally once daily 600 mg orally once daily 500 mg orally once daily 200 mg orally once daily 400 mg orally once daily 300 mg orally once daily

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections, Including Opportunistic Infections [see Warnings and Precautions (5.1) ] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2) ] Hypertension [see Warnings and Precautions (5.3) ] Hepatotoxicity [see Warnings and Precautions (5.4) ] Hemorrhagic Events [see Warnings and Precautions (5.5) ] Tumor Lysis Syndrome [see Warnings and Precautions (5.6) ] Risk of Impaired Wound Healing [see Warnings and Precautions (5.7) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.8) ] The most common adverse reactions (≥ 25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia and cough. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased leukocytes, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium (corrected), decreased platelets, increased alkaline phosphatase, increased potassium, decreased potassium and increased bilirubin. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Rigel Pharmaceuticals, Inc. at 1-800-983-1329 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 in the WARNINGS AND PRECAUTIONS reflect exposure to GAVRETO as a single agent at 400 mg orally once daily in 540 patients in ARROW [see Clinical Studies (14) ]. Among 540 patients who received GAVRETO, 71% were exposed for 6 months or longer and 57% were exposed for greater than one year. The most common adverse reactions (≥ 25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia, and cough. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased leukocytes, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium (corrected), decreased platelets, increased alkaline phosphatase, increased potassium, decreased potassium and increased bilirubin. In addition to the 540 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to GAVRETO as a single agent in a randomized, open-label study, AcceleRET-Lung (NCT04222972), which enrolled 223 patients with RET-fusion positive locally advanced unresectable or metastatic NSCLC. RET Fusion-Positive Non-Small Cell Lung Cancer The safety of GAVRETO was evaluated as a single agent at 400 mg orally once daily in 281 patients with metastatic rearranged during transfection ( RET fusion-positive) non-small cell lung cancer (NSCLC) in ARROW [see Clinical Studies (14.1) ]. Among the 281 patients who received GAVRETO, 72% were exposed for 6 months or longer and 56% were exposed for ≥1 year. The median age was 60 years (range: 26 to 87 years); 54% were female, 46% were White, 46% were Asian, and 4% were Hispanic/Latino. Serious adverse reactions occurred in 65% of patients who received GAVRETO. The most frequent serious adverse reactions (in ≥ 2% of patients) were pneumonia, anemia, pneumonitis, pyrexia, sepsis, urinary tract infection, coronavirus infection, pleural effusion, dyspnea, musculoskeletal pain, pulmonary embolism, and seizure. Fatal adverse reactions occurred in 7% of patients; fatal adverse reactions which occurred in > 1 patient included pneumonia (n=8), sepsis (n=3) and COVID (n=3). Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received GAVRETO. Adverse reactions resulting in permanent discontinuation which occurred in ≥ 2% of patients included pneumonitis (3.2%), and pneumonia (2.8%). Dosage interruptions due to an adverse reaction occurred in 73% of patients who received GAVRETO. Adverse reactions requiring dosage interruption in ≥ 2% of patients included anemia, pneumonia, pneumonitis, neutropenia, hypertension, increased blood creatine phosphokinase, fatigue, pyrexia, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), coronavirus infection, diarrhea, hypophosphatemia, musculoskeletal pain, thrombocytopenia, dyspnea, hemorrhage, leukopenia, lymphopenia, edema, sepsis, and vomiting. Dose reductions due to adverse reactions occurred in 51% of patients who received GAVRETO. Adverse reactions requiring dosage reductions in ≥ 2% of patients included anemia, neutropenia, pneumonitis, increased blood creatine phosphokinase, leukopenia, hypertension, fatigue, pneumonia, and lymphopenia. Table 5 summarizes the adverse reactions in patients with NSCLC in ARROW. Table 5: Adverse Reactions (≥ 15%) in RET Fusion-Positive NSCLC Patients Who Received GAVRETO in ARROW Adverse reaction GAVRETO N = 281 Grades 1 - 4 (%) Grades 3 or 4 (%) Gastrointestinal disorders Constipation 45 0.7 Diarrhea 30 2.5 Nausea 19 0 Dry mouth 17 0 General Disorders and Administration Site Conditions Edema Includes the preferred terms: Edema, Swelling face, Peripheral swelling, Generalized oedema, Edema peripheral, Face edema, Periorbital edema, Eyelid edema, Swelling, Localized edema 44 0 Fatigue Includes the preferred terms: Fatigue, Asthenia 42 2.5 Pyrexia 29 0.7 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Includes the preferred terms: Myalgia, Arthralgia, Pain in extremity, Neck pain, Musculoskeletal pain, Back pain, Musculoskeletal chest pain, Bone pain, Musculoskeletal stiffness 44 2.5 Increased Blood Creatine Phosphokinase 19 9 Vascular Hypertension Includes the preferred terms: Hypertension, Blood pressure increased 38 18 Respiratory, thoracic and mediastinal disorders Cough Includes the preferred terms: Cough, Productive Cough, Upper-airway cough syndrome 36 0.4 Dyspnea 21 2.1 Infection and Infestations Pneumonia Includes the preferred terms: Pneumonia, Pneumocystis jirovecii pneumonia, Pneumonia cytomegaloviral, Atypical pneumonia, Lung infection, Pneumonia bacterial, Pneumonia hemophilus, Pneumonia influenzal, Pneumonia streptococcal, Pneumonia viral, Pneumonia pseudomonal 24 13 Urinary tract infection 16 3.6 Metabolism and Nutrition Disorders Decreased appetite 18 1.1 Nervous system disorders Taste disorder Includes the preferred terms: Dysgeusia, Ageusia 17 0 Headache Includes the preferred terms: Headache, Tension Headache 15 1.1 Skin and subcutaneous tissue disorders Rash Includes the preferred terms: Rash, Rash maculo-papular, Dermatitis acneiform, Erythema, Rash generalized, Rash papular, Rash macular, Rash erythematous 17 0 Clinically relevant adverse reactions occurring in < 15% of patients included pneumonitis (14%), vomiting (14%), abdominal pain (14%), and stomatitis (6%). Table 6 summarizes the laboratory abnormalities in ARROW. Table 6: Select Laboratory Abnormalities (≥ 20%) Worsening from Baseline in RET Fusion-Positive NSCLC Patients Who Received GAVRETO in ARROW Laboratory Abnormality GAVRETO N=281 Grades 1-4 (%) Grades 3-4 (%) Chemistry Increased AST 80 3.2 Increased ALT 58 3.9 Decreased albumin 52 0 Decreased calcium (corrected) 50 1.8 Decreased phosphate 50 17 Increased creatinine 45 1.4 Increased alkaline phosphatase 43 2.5 Decreased sodium 42 10 Decreased Potassium 27 4.6 Increased Potassium 27 1.8 Decreased Magnesium 25 0 Increased Bilirubin 20 1.8 Hematology Decreased leukocytes 79 11 Decreased hemoglobin 78 18 Decreased lymphocytes 73 32 Decreased neutrophils 70 21 Decreased platelets 33 5 Clinically relevant laboratory abnormalities occurring in < 20% of patients who received GAVRETO included increased magnesium (14%). RET -altered Thyroid Cancer The safety of GAVRETO was evaluated as a single agent at 400 mg orally once daily in 138 patients with RET -altered Thyroid Cancer (including 19 patients with RET fusion-positive thyroid cancer) in ARROW [see Clinical Studies (14.2) ]. Among the 138 patients who received GAVRETO, 68% were exposed for 6 months or longer, and 40% were exposed for greater than one year. The median age was 59 years (range: 18 to 83 years); 36% were female, 74% were White, 17% were Asian, and 6% were Hispanic/Latino. Serious adverse reactions occurred in 39% of patients who received GAVRETO. The most frequent serious adverse reactions (in ≥ 2% of patients) were pneumonia, pneumonitis, urinary tract infection, pyrexia, fatigue, diarrhea, dizziness, anemia, hyponatremia, and ascites. Fatal adverse reaction occurred in 2.2% of patients; fatal adverse reactions that occurred in > 1 patient included pneumonia (n=2). Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received GAVRETO. Adverse reactions resulting in permanent discontinuation which occurred in > 1 patient included fatigue, pneumonia and anemia. Dosage interruptions due to an adverse reaction occurred in 67% of patients who received GAVRETO. Adverse reactions requiring dosage interruption in ≥ 2% of patients included neutropenia, hypertension, diarrhea, fatigue, pneumonitis, anemia, increased blood creatine phosphokinase, pneumonia, urinary tract infection, musculoskeletal pain, vomiting, pyrexia, increased AST, dyspnea, hypocalcemia, cough, thrombocytopenia, abdominal pain, increased blood creatinine, dizziness, headache, decreased lymphocyte count, stomatitis, and syncope. Dose reductions due to adverse reactions occurred in 44% of patients who received GAVRETO. Adverse reactions requiring dosage reductions in ≥ 2% of patients included neutropenia, anemia, hypertension, increased blood creatine phosphokinase, decreased lymphocyte count, pneumonitis, fatigue and thrombocytopenia. Table 7 summarizes the adverse reactions occurring in RET -altered Thyroid Cancer Patients in ARROW. Table 7: Adverse Reactions (≥ 15%) in RET-altered Thyroid Cancer Patients Who Received GAVRETO in ARROW Adverse Reactions GAVRETO N=138 Grades 1-4 (%) Grades 3-4 (%) Musculoskeletal Musculoskeletal Pain Musculoskeletal Pain includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, spinal pain 42 0.7 Only includes a Grade 3 adverse reaction Gastrointestinal Constipation 41 0.7 Diarrhea Diarrhea includes colitis, diarrhea 34 5 Abdominal Pain Abdominal Pain includes abdominal discomfort, abdominal pain, abdominal pain upper, abdominal tenderness, epigastric discomfort 17 0.7 Dry mouth 17 0 Stomatitis Stomatitis includes mucosal inflammation, stomatitis, tongue ulceration 17 0.7 Nausea 17 0.7 Vascular Hypertension 40 21 General Fatigue Fatigue includes asthenia, fatigue 38 6 Edema Edema includes eyelid edema, face edema, edema, edema peripheral, periorbital edema 29 0 Pyrexia 22 2.2 Respiratory Cough Cough includes cough, productive cough, upper-airway cough syndrome 27 1.4 Dyspnea Dyspnea includes dyspnea, dyspnea exertional 22 2.2 Nervous System Headache Headache includes headache, migraine 24 0 Peripheral Neuropathy Peripheral neuropathy includes dysaesthesia, hyperaesthesia, hypoaesthesia, neuralgia, neuropathy peripheral, paraesthesia, peripheral sensory neuropathy, polyneuropathy 20 0 Dizziness Dizziness includes dizziness, dizziness postural, vertigo 19 0.7 Dysgeusia Dysgeusia includes ageusia, dysgeusia 17 0 Skin and Subcutaneous Rash Rash includes dermatitis, dermatitis acneiform, eczema, palmar-plantar, erythrodysaesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular 24 0 Metabolism and Nutrition Decreased Appetite 15 0 Clinically relevant adverse reactions in < 15% of patients who received GAVRETO included tumor lysis syndrome and increased creatine phosphokinase. Table 8 summarizes the laboratory abnormalities occurring in RET -altered Thyroid Cancer Patients in ARROW. Table 8: Select Laboratory Abnormalities (≥ 20%) Worsening from Baseline in RET-altered Thyroid Cancer Patients Who Received GAVRETO in ARROW Laboratory Abnormality GAVRETO N=138 Grades 1-4 (%) Grades 3-4 (%) Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available, which ranged from 135 to 138 patients. Chemistry Decreased calcium (corrected) 70 9 Increased AST 69 4.3 Increased ALT 43 3.6 Increased creatinine 41 0 Decreased albumin 41 1.5 Decreased sodium 28 2.2 Decreased phosphate 28 8 Decreased magnesium 27 0.7 Increased potassium 26 1.4 Increased bilirubin 24 1.4 Increased alkaline phosphatase 22 1.4 Hematology Decreased lymphocytes 67 27 Decreased hemoglobin 63 13 Decreased neutrophils 59 16 Decreased platelets 31 2.9 Clinically relevant laboratory abnormalities in patients who received GAVRETO included increased phosphate (40%). Other Clinical Trials Experience AcceleRET-Lung trial (NCT04222972) In AcceleRET-Lung trial (NCT04222972), single agent GAVRETO (n=108) was compared to chemotherapy/immunotherapy (n=104) in patients with RET fusion-positive NSCLC. Adverse reactions were infections (72% vs.52%), including pneumonia (29% vs. 6%), urinary tract infection (22% vs. 8%), and opportunistic infections (20% vs. 6%). Opportunistic infections included pneumocystis jirovecii pneumonia, fungal infections, legionella pneumonia, cytomegalovirus infection, and herpes simplex.

12.3 Pharmacokinetics At 400 mg GAVRETO once daily under fasting conditions, the steady state mean [% coefficient of variation (CV%)] of maximum observed plasma concentration (C max ) and area under the concentration-time curve (AUC 0-24h ) of pralsetinib was 2,470 (55%) ng/mL and 36,700 (66%) h•ng/mL, respectively. Pralsetinib C max and AUC increased inconsistently over the dose range of 60 mg to 600 mg once daily (0.15 to 1.5 times the recommended dose). Pralsetinib plasma concentrations reached steady state by 3 to 5 days. The mean accumulation ratio was approximately 2-fold after once-daily oral administration. Absorption The median time to peak concentration (T max ) ranged from 2 to 4 hours following single doses of pralsetinib 60 mg to 600 mg. Food Effect Following administration of a single dose of 200 mg with a high-fat meal, (approximately 800 to 1000 calories with 50 to 60% of calories from fat), the mean C max of pralsetinib was increased by 2.0-fold, the mean AUC 0-INF was increased by 2.2-fold, and the median T max was delayed from 4 to 8.5 hours, compared to the fasted state. Distribution The mean (CV%) apparent volume of distribution (Vd/F) of pralsetinib is 303 L (68%). Protein binding of pralsetinib is 97% and is independent of concentration. The blood-to-plasma ratio is 0.6 to 0.7. Elimination The mean (±standard deviation) plasma elimination half-life (T ½ ) of pralsetinib is 16 hours (10) following single doses and 20 hours (12) following multiple doses of pralsetinib. The mean (CV%) apparent oral clearance (CL/F) of pralsetinib is 11 L/h (66%) at steady state. Metabolism Pralsetinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2, in vitro. Following a single oral dose of 310 mg of radiolabeled pralsetinib, pralsetinib metabolites from oxidation and glucuronidation were detected as 5% or less. Excretion Approximately 73% (66% as unchanged) of the total administered radioactive dose [ 14 C] pralsetinib was recovered in feces and 6% (4.8% as unchanged) was recovered in urine. Specific Populations No clinically significant differences in the PK of pralsetinib were observed based on age (19 to 87 years), sex, race (White, Black, or Asian), and body weight (32 to 128 kg). Mild and moderate renal impairment (CLcr 30 - 89 mL/min) had no effect on the exposure of pralsetinib. Pralsetinib has not been studied in patients with severe renal impairment (CLcr < 15 mL/min). Drug Interaction Studies Clinical Studies and Model-Informed Approach CYP3A Inhibitors: Coadministration of multiple doses of CYP3A inhibitors increases pralsetinib C max and AUC. Table 9: Observed or Predicted Increase in Pralsetinib Exposure after Coadministration of CYP3A Inhibitors Type of inhibitor Coadministered CYP3A Inhibitor Increase in pralsetinib C max Increase in pralsetinib AUC Observed P-gp and Strong CYP3A Inhibitor Itraconazole (200 mg twice daily on Day 1, followed by 200 mg once daily) 1.8-fold 3.5-fold Predicted Strong CYP3A Inhibitors Voriconazole (400 mg twice daily on Day 1, followed by 200 mg twice daily) 1.2-fold 2.2-fold Combined P-gp and Moderate CYP3A Inhibitors Verapamil (80 mg three times daily) 1.6-fold 2.1-fold Moderate CYP3A Inhibitors Fluconazole (400 mg once daily) 1.2-fold 1.7-fold P-gp Inhibitors: Coadministration of cyclosporine (single 600 mg dose) with a single 200 mg dose of pralsetinib in healthy subjects increased pralsetinib AUC 0-inf by 1.8-fold and C max by 1.5-fold, relative to a 200 mg dose of pralsetinib administered alone. Strong CYP3A Inducers: Coadministration of rifampin 600 mg once daily with a single GAVRETO 400 mg dose decreased pralsetinib AUC 0-INF by 68% and C max by 30%. Moderate CYP3A Inducers: Coadministration of multiple doses of efavirenz (600 mg once daily) is predicted to decrease the pralsetinib AUC by 45% and C max by 18%. Mild CYP3A Inducers: No clinically significant differences in the PK of pralsetinib were identified when GAVRETO was coadministered with mild CYP3A inducers. Acid-Reducing Agents: No clinically significant differences in the PK of pralsetinib were observed when GAVRETO was coadministered with gastric acid reducing agents. In Vitro Studies Cytochrome P450 (CYP) Enzymes : Pralsetinib is a time-dependent inhibitor of CYP3A and an inhibitor of CYP2C8, CYP2C9, and CYP3A, but not an inhibitor of CYP1A2, CYP2B6, CYP2C19 or CYP2D6 at clinically relevant concentrations. Pralsetinib is an inducer of CYP2C8, CYP2C9, and CYP3A, but not an inducer of CYP1A2, CYP2B6, or CYP2C19 at clinically relevant concentrations. Transporter Systems: Pralsetinib is a substrate of P-gp and BCRP, but not a substrate of BSEP, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, OAT1, or OAT3. Pralsetinib is an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, MATE1, MATE2-K, and BSEP, but not an inhibitor of OCT1, OCT2, and OAT1A3 at clinically relevant concentrations.