PALSONIFY Film-coated tablet Ref.[116079] Active ingredients: Paltusotine

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 T₄) 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 B12 Deficiency

Decreased vitamin B₁₂ levels have been observed in patients treated with somatostatin analogs, including PALSONIFY. Monitor vitamin B₁₂ levels during treatment with PALSONIFY if clinically indicated.

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 B₁₂ Levels [see Warnings and Precautions (5.6)]

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.

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.

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.

7.1 Effect of Other Drugs on PALSONIFY

Table 3. Clinically Significant Interactions Affecting PALSONIFY:

7.2 Effect of PALSONIFY on Other Drugs

Table 4. Clinically Significant Interactions Affecting Other Drugs:

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.

Risk Summary

There is no information available on the presence of paltusotine in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Paltusotine is present in animal milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PALSONIFY and any potential adverse effects on the breastfed infant from PALSONIFY or from the underlying maternal condition.

Data

Paltusotine concentrations were elevated 2.4- to 3.8-fold in rat milk compared to plasma during animal studies. Paltusotine concentrations in plasma and maternal milk suggest that rat pups were likely exposed in utero and/or via lactational transfer. The concentration of paltusotine in animal milk does not necessarily predict the concentration of paltusotine in human milk.

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

In the Phase 3 studies 17/84 (20.2%) PALSONIFY-treated participants were ≥65 years of age. No overall differences in safety or effectiveness of PALSONIFY have been observed between participants 65 years of age and older and younger adult participants. No dose adjustments are required based on age [see Clinical Pharmacology (12.3)].

No dosage adjustment of PALSONIFY is recommended for patients with hepatic impairment. In a clinical pharmacology study in participants with varying degrees of hepatic impairment, exposures of paltusotine were similar across all hepatic impairment groups when compared with participants with normal hepatic function [see Clinical Pharmacology (12.3)].