Can Paltusotine cause abdominal discomfort?

ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions ( 5.1 )] Hyperglycemia and Hypoglycemia [see Warnings and Precautions ( 5.2 )] Cardiovascular Abnormalities [see Warnings and Precautions ( 5.3 )] Thyroid Function Abnormalities [see Warnings and Precautions ( 5.4 )] Steatorrhea and Malabsorption of Dietary Fats [see Warnings and Precautions ( 5.5 )] Changes in Vitamin B 12 Levels [see Warnings and Precautions ( 5.6 )] Most common adverse reactions (≥5%) are diarrhea, abdominal pain, nausea, decreased appetite, sinus bradycardia, hyperglycemia, palpitations, and gastroenteritis ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Crinetics Pharmaceuticals, Inc. at toll-free phone 1-833-CRN-INFO 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 safety of PALSONIFY was evaluated in adults with acromegaly in two randomized, double-blind, placebo-controlled Phase 3 studies. Study 1 was a 24-week, randomized, placebo-controlled study in 111 adults who were naive or previously treated on a somatostatin analog and biochemically uncontrolled at randomization. Participants in Study 1 had a mean age of 47 years (range: 18 to 80 years) and were randomized to PALSONIFY (n=54) or placebo (n=57) [see Clinical Studies ( 14.1 )] . Study 2 was a 36-week, randomized, placebo-controlled study in 58 adults who were biochemically controlled on injectable depot formulations of octreotide or lanreotide. Participants in Study 2 had a mean age of 55 years (range: 29 to 84 years) and were randomized to PALSONIFY (n=30) or placebo (n=28) [see Clinical Studies ( 14.2 )] . Adverse Reactions Adverse reactions that occurred in ≥5% of PALSONIFY-treated participants and 5% greater incidence than placebo in the randomized-controlled phase of Study 1 and Study 2 are presented in Table 1 and Table 2 , respectively. Adverse reactions presented in Table 1 and Table 2 exclude events which occurred after a participant received rescue therapy (Study 1 PALSONIFY n=1, placebo n=13; Study 2 PALSONIFY n=1, placebo n=17). Table 1. Adverse Reactions Occurring in ≥5% of PALSONIFY-Treated Participants and 5% Greater Incidence than Placebo-Treated Participants During the Randomized Controlled Period of Study 1 a Abdominal pain also includes abdominal discomfort. b Hyperglycemia also includes impaired fasting glucose and diabetes mellitus. Adverse Reaction PALSONIFY N=54 n (%) Placebo N=57 n (%) Diarrhea 18 (33) 8 (14) Abdominal pain a 10 (19) 3 (5) Nausea 5 (9) 1 (2) Sinus bradycardia 4 (7) 0 Hyperglycemia b 4 (7) 1 (2) Table 2. Adverse Reactions Occurring in ≥5% of PALSONIFY-Treated Participants and 5% Greater Incidence than Placebo-Treated Participants During the Randomized Controlled Period of Study 2 a Decreased appetite also includes early satiety. Adverse Reaction PALSONIFY N=30 n (%) Placebo N=28 n (%) Diarrhea 7 (23) 3 (11) Nausea 4 (13) 1 (4) Decreased appetite a 3 (10) 0 Palpitations 2 (7) 0 Gastroenteritis 2 (7) 0 Gastrointestinal Gastrointestinal adverse reactions, including diarrhea, nausea, and abdominal pain were reported in participants from Studies 1 and 2 (see Table 1 and Table 2 ). Most gastrointestinal adverse reactions occurred within the first two months of PALSONIFY treatment initiation and had a median duration ranging between 6 to 18 days. Other Adverse Reactions from Studies 1 and 2 Cholelithiasis and its Complications Cholelithiasis and its complications were reported in 10/173 (6%) participants during Studies 1 and 2 as follows: cholelithiasis (n=8), acute cholecystitis, biliary colic, and bile duct stone (one participant each). The majority of the events occurred within the first nine months of treatment. One PALSONIFY-treated participant who experienced obstructive pancreatitis required cholecystectomy [see Warnings and Precautions ( 5.1 )] . Glucose Metabolism Hyperglycemia During Study 1, an increase from baseline to Week 24 in mean fasting plasma glucose (FPG) of 6.9 mg/dL and hemoglobin A1c (HbA1c) of 0.26% was observed in the PALSONIFY arm, and an increase in mean FPG of 1.5 mg/dL and HbA1c of 0.04% was observed in the placebo arm. Of the 34 PALSONIFY-treated participants who had normal baseline FPG, 25 (74%) developed at least one glucose value ≥100 mg/dL. Of the 31 placebo-treated participants who had a normal baseline FPG, 9 (29%) developed at least one elevated glucose value. All participants in Study 2 were previously treated with other somatostatin analog products known to increase glucose levels. During Study 2, a decrease from baseline to Week 36 in mean FPG of 1.8 mg/dL and HbA1c of 0.05% was observed in the PALSONIFY arm, and a decrease in mean FPG of 11.7 mg/dL and HbA1c of 0.25% was observed in the placebo arm. Of the 5 PALSONIFY-treated participants who had normal baseline FPG, 4 (80%) developed at least one glucose value ≥100 mg/dL. Of the 11 placebo-treated participants who had a normal baseline FPG, 2 (18%) developed at least one elevated glucose value. Hypoglycemia During PALSONIFY clinical development program, 5 participants in the open-label extension phase reported hypoglycemia. Most participants had a history of diabetes at baseline and were treated with antidiabetic medications, such as insulin and sulfonylureas. Cardiac Bradycardia was reported in 4 (7%) participants in the paltusotine arm versus none in placebo in Study 1, and in 1 (3%) participant in the paltusotine arm versus none in placebo in Study 2. Bradycardia was asymptomatic and occurred within the first three months of treatment. During the PALSONIFY clinical development program, 3 PALSONIFY-treated participants with preexisting cardiovascular comorbidities experienced serious cardiac adverse events during the open-label extension phase: sinus arrest (2 participants) and complete atrioventricular block (one participant). Ocular Findings of ocular phototoxicity were observed in a nonclinical study [see Nonclinical Toxicology ( 13.2 )] . Due to these findings, ocular assessments were conducted during the open-label period of Studies 1 and 2. The following retinal observations were noted: drusen; dry age-related macular degeneration, early stage; retinal pigment epithelium changes; epiretinal membrane; diabetic retinopathy; retinoschisis; and hypertensive retinopathy. Baseline assessments were not available for comparison.

WARNINGS AND PRECAUTIONS Cholelithiasis and its Complications: Monitor periodically. If complications of cholelithiasis occur, discontinue PALSONIFY and treat appropriately ( 5.1 ). Hyperglycemia and Hypoglycemia: Monitor glucose and adjust antidiabetic treatment as needed ( 5.2 ). Cardiovascular Abnormalities: Bradycardia or conduction abnormalities may occur. Dosage adjustments of concomitantly used drugs with bradycardia effects may be necessary ( 5.3 ). Thyroid Function Abnormalities: Hypothyroidism may occur. Assess thyroid function periodically ( 5.4 ). Steatorrhea and Malabsorption of Dietary Fats: New onset steatorrhea, stool discoloration, loose stools, abdominal bloating, and weight loss may occur. If new occurrence or worsening of these symptoms are reported, evaluate for potential pancreatic exocrine insufficiency ( 5.5 ). Vitamin B 12 Deficiency: Monitor vitamin B 12 levels during treatment if indicated ( 5.6 ). 5.1 Cholelithiasis and its Complications PALSONIFY may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder stones or sludge. Cholelithiasis was reported in participants treated with PALSONIFY in clinical trials. Complications of cholelithiasis, such as acute cholecystitis and pancreatitis, have also been reported with the use of PALSONIFY [see Adverse Reactions ( 6.1 )] . Monitor patients periodically. If complications of cholelithiasis occur, discontinue PALSONIFY and treat appropriately. 5.2 Hyperglycemia and Hypoglycemia PALSONIFY may alter the balance between the counter-regulatory hormones, insulin, glucagon, and growth hormone, which may result in hypoglycemia, hyperglycemia, or diabetes mellitus. Hyperglycemia was reported in participants treated with PALSONIFY in clinical trials [see Adverse Reactions ( 6.1 )] . Monitor blood glucose levels when PALSONIFY treatment is initiated or when the dose is altered. Adjust antidiabetic treatment accordingly. 5.3 Cardiovascular Abnormalities Cardiac conduction abnormalities and other ECG changes such as PR interval prolongation have occurred during treatment with PALSONIFY. Bradycardia, sinus arrest, and atrioventricular block were reported in participants treated with PALSONIFY in clinical trials [see Adverse Reactions ( 6.1 )] . These ECG changes may occur in patients with acromegaly. Dosage adjustments of concomitantly used drugs that have bradycardia effects (e.g., beta-blockers) may be necessary. 5.4 Thyroid Function Abnormalities Somatostatin analogs may suppress the secretion of thyroid-stimulating hormone, which may result in hypothyroidism. Periodic assessment of thyroid function (TSH, total, and/or free T 4 ) is recommended during treatment with PALSONIFY. 5.5 Steatorrhea and Malabsorption of Dietary Fats New onset steatorrhea, stool discoloration and loose stools have been reported in patients receiving somatostatin analogs. Somatostatin analogs reversibly inhibit secretion of pancreatic enzymes and bile acids, which may result in malabsorption of dietary fats and subsequent symptoms of steatorrhea, loose stools, abdominal bloating, and weight loss. If new occurrence or worsening of these symptoms are reported in patients receiving PALSONIFY, evaluate patients for potential pancreatic exocrine insufficiency and manage accordingly. 5.6 Vitamin B 12 Deficiency Decreased vitamin B 12 levels have been observed in patients treated with somatostatin analogs, including PALSONIFY. Monitor vitamin B 12 levels during treatment with PALSONIFY if clinically indicated.