Palsonify Drug Information

is indicated for the treatment of adults with acromegaly who had an inadequate response to surgery and/or for whom surgery is not an option. PALSONIFY is a somatostatin receptor agonist indicated for the treatment of adults with acromegaly who had an inadequate response to surgery and/or for whom surgery is not an option.

Important

Administration Instructions Take PALSONIFY orally once daily with water on an empty stomach, at least 6 hours after a meal (e.g., after overnight fasting) and at least 1 hour before the next meal .

Recommended Dosage, Titration, and Monitoring

The recommended initial dosage of PALSONIFY is 40 mg once daily. During initiation period, PALSONIFY may be temporarily reduced to 20 mg once daily if needed, based on tolerability . Once adverse reactions have resolved, resume PALSONIFY 40 mg once daily. After 2 to 4 weeks on PALSONIFY 40 mg once daily, based on IGF-1 levels, titrate to a PALSONIFY dosage of 60 mg once daily.

Dosage Modifications for Drug Interactions

Concomitant Use with Strong CYP3A4 Inducers Patients taking strong CYP3A4 inducers may require an increased dosage of PALSONIFY. Do not exceed three-fold the PALSONIFY dosage prior to concomitant use or 120 mg daily, whichever is less . Concomitant Use with Moderate CYP3A4 Inducers Patients taking moderate CYP3A4 inducers may require an increased dosage of PALSONIFY. Do not exceed two-fold the PALSONIFY dosage prior to concomitant use or 120 mg daily, whichever is less . Concomitant Use with Proton Pump Inhibitors Patients taking proton pump inhibitors may require an increased dosage of PALSONIFY. Avoid concomitant use of proton pump inhibitors in patients who are already on PALSONIFY 60 mg .

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) . 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) . 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 8 Abdominal pain a 10 3 Nausea 5 1 Sinus bradycardia 4 0 Hyperglycemia b 4 1 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 3 Nausea 4 1 Decreased appetite a 3 0 Palpitations 2 0 Gastroenteritis 2 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 . 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 . 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.

Effect of Other Drugs on

PALSONIFY Table 3. Clinically Significant Interactions Affecting PALSONIFY Strong CYP3A4 Inducers Intervention Concomitant use of PALSONIFY with strong CYP3A4 inducers may require an increased dosage of PALSONIFY, not to exceed three-fold the dose prior to concomitant use or 120 mg daily, whichever is less. Clinical Impact Concomitant use of PALSONIFY with strong CYP3A4 inducers reduced paltusotine exposure and may affect therapeutic response. Moderate CYP3A4 Inducers Intervention Concomitant use of PALSONIFY with moderate CYP3A4 inducers may require an increased dosage of PALSONIFY, not to exceed two-fold the dose prior to concomitant use or 120 mg daily, whichever is less.

Clinical Impact Concomitant use of PALSONIFY with moderate CYP3A4 inducers resulted in a decrease in paltusotine exposure. Proton Pump Inhibitors Intervention Concomitant use of PALSONIFY with PPIs may require an increased dosage of PALSONIFY. Patients who are already on PALSONIFY 60 mg should avoid concomitant use with proton pump inhibitors. Clinical Impact Concomitant use of PALSONIFY with proton pump inhibitors demonstrated a dose-dependent decrease in paltusotine exposure.

Effect of

PALSONIFY on Other Drugs Table 4. Clinically Significant Interactions Affecting Other Drugs Cyclosporine Intervention Adjustment of cyclosporine dose to maintain therapeutic levels may be necessary. Follow recommended therapeutic drug monitoring for cyclosporine. Clinical Impact Concomitant use of PALSONIFY with cyclosporine resulted in a decrease in cyclosporine bioavailability.

Pregnancy Risk Summary The available data with PALSONIFY use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, no malformations were observed with oral administration of paltusotine to pregnant rats and rabbits during organogenesis at exposures 11 and 3 times the human exposure at the maximum recommended human dose (MRHD) of 60 mg once daily, respectively (see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal development study in pregnant rats, paltusotine was administered orally at 25, 75, and 500 mg/kg/day during the period of organogenesis from gestation Day 7 to 17. The NOAEL for maternal and embryo-fetal developmental toxicity was 500 mg/kg/day, as no paltusotine-related effects were observed on any ovarian, uterine or litter parameters (approximately 11 times the MRHD based on AUC). In an embryo-fetal development study in pregnant rabbits, paltusotine was administered orally at 10, 25, and 75 mg/kg/day during the period of organogenesis from gestation Day 7 to 19. Maternal findings included an increased incidence of spontaneous abortions at 75 mg/kg/day, with decreased body weight gain, body weights, and food consumption. No fetal abnormalities were observed at any dose.

Lower fetal body weight was noted at 75 mg/kg/day. The NOAEL for maternal and embryo-fetal developmental toxicity was 25 mg/kg/day (approximately 3 times the MRHD based on AUC). In a pre- and postnatal development study, pregnant rats were given paltusotine orally at the doses of 25, 75, and 500 mg/kg/day from gestation Day 6 to lactation Day 20. Paltusotine had no effect on the growth and development of offspring up to the highest tested dose of 500 mg/kg (5 times MRHD based on AUC). In a single dose pharmacokinetic study, oral administration of paltusotine at 25 mg/kg or 500 mg/kg paltusotine to pregnant rats showed measurable paltusotine concentrations in embryos and fetuses, demonstrating placental transfer. Overall, the embryo and fetal concentrations were generally low when compared to maternal concentrations.

Pediatric Use The safety and efficacy of PALSONIFY have not been established in pediatric patients.

Overdose with somatostatin analogs may result in hyperglycemia or hypoglycemia, bradycardia, arrhythmia, diarrhea, vomiting, and other gastrointestinal symptoms. If overdose is suspected, initiate supportive treatment as dictated by patient's clinical status.