SIGNIFOR is a somatostatin analog indicated for the treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative ( 1 )
1.1Cushing's Disease
SIGNIFOR is indicated for the treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative.
Contraindications
None. None ( 4 )
Warnings and precautions
Hypocortisolism : Decreases in circulating levels of cortisol may occur resulting in biochemical and/or clinical hypocortisolism. SIGNIFOR dose reduction or interruption and/or adding a low-dose short-term glucocorticoid may be necessary ( 5.1 ) Hyperglycemia and Diabetes (occurs with initiation) : Intensive glucose monitoring is recommended and may require initiation or adjustment of anti-diabetic treatment per standard of care ( 5.2 ) Bradycardia and QT Prolongation : Use with caution in at-risk patients; ECG testing prior to dosing and on treatment ( 5.3 , 7.1 ) Liver Test Elevations : Evaluate liver tests prior to and during treatment ( 5.4 ) Cholelithiasis and Complications of Cholelithiasis : Monitor periodically.
Discontinue if complications of cholelithiasis are suspected ( 5.5 ) 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 ( 5.7 )
5.1Hypocortisolism Treatment with
SIGNIFOR leads to suppression of adrenocorticotropic hormone (ACTH) secretion in Cushing's disease. Suppression of ACTH may lead to a decrease in circulating levels of cortisol and potentially hypocortisolism. Monitor and instruct patients on the signs and symptoms associated with hypocortisolism (e.g., weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyponatremia, or hypoglycemia). If hypocortisolism occurs, consider temporary dose reduction or interruption of treatment with SIGNIFOR, as well as temporary, exogenous glucocorticoid replacement therapy.
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Blood glucose elevations have been seen in healthy volunteers and patients treated with SIGNIFOR. In the clinical study [see Clinical Studies (14)] , patients developed pre-diabetes and diabetes. Nearly all patients in the study, including those with normal glucose status at baseline, pre-diabetes, and diabetes, developed worsening glycemia in the first two weeks of treatment. Cushing's disease patients with poor glycemic control (HbA1c > 8%) may be at a higher risk of developing severe hyperglycemia and associated complications, e.g., ketoacidosis.
Assess the patient's glycemic status prior to starting treatment with SIGNIFOR. In patients with uncontrolled diabetes mellitus, optimize anti-diabetic therapy prior to SIGNIFOR initiation. Glycemic monitoring should be done every week for the first two to three months and periodically thereafter, as well as over the first two to four weeks after any dose increase. If hyperglycemia develops, initiate or adjust anti-diabetic treatment per standard of care.
If uncontrolled hyperglycemia persists despite appropriate treatment, reduce the dose or discontinue SIGNIFOR and perform glycemic monitoring according to clinical practice. Patients who were initiated on anti-diabetic treatment as a result of SIGNIFOR require closer monitoring after discontinuation of SIGNIFOR, especially if the anti-diabetic therapy has a risk of causing hypoglycemia.
5.3Bradycardia and QT Prolongation Bradycardia
Bradycardia has been reported with the use of SIGNIFOR [see Adverse Reactions (6)] . Patients with cardiac disease and/or risk factors for bradycardia, such as history of clinically significant bradycardia, high-grade heart block, or concomitant use of drugs associated with bradycardia, should be carefully monitored. Dose adjustments of beta-blockers, calcium channel blockers, or correction of electrolyte disturbances may be necessary.
QT Prolongation SIGNIFOR is associated with QT prolongation. In two thorough QT studies with SIGNIFOR, QT prolongation occurred at therapeutic and supra-therapeutic doses. SIGNIFOR should be used with caution in patients who are at significant risk of developing prolongation of QTc, such as those: with congenital long QT prolongation. with uncontrolled or significant cardiac disease, including recent myocardial infarction, congestive heart failure, unstable angina, or clinically significant bradycardia. on anti-arrhythmic therapy or other substances that are known to lead to QT prolongation. with hypokalemia and/or hypomagnesemia.
A baseline ECG is recommended prior to initiating therapy with SIGNIFOR and monitoring for an effect on the QTc interval is advisable. Hypokalemia and hypomagnesemia must be corrected prior to SIGNIFOR administration and should be monitored periodically during therapy.
5.4Liver Test Elevations In the Phase
III trial, 5% of patients had an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level greater than 3 times the upper limit of normal (ULN). In the entire clinical development program of SIGNIFOR, there were 4 cases of concurrent elevations in ALT greater than 3 x ULN and bilirubin greater than 2 x ULN: one patient with Cushing's disease and 3 healthy volunteers [see Adverse Reactions (6)] . In these cases, total bilirubin elevations were seen either concomitantly or preceding the transaminase elevation.
Monitoring of liver tests should be done after 1- to 2 weeks on treatment, then monthly for 3 months, and every 6 months thereafter. If ALT is normal at baseline and elevations of ALT of 3-5 times the ULN are observed on treatment, repeat the test within a week or within 48 hours if exceeding 5 times ULN. If ALT is abnormal at baseline and elevations of ALT of 3 to 5 times the baseline values are observed on treatment, repeat the test within a week or sooner if exceeding 5 times ULN.
Tests should be done in a laboratory that can provide same-day results. If the values are confirmed or rising, interrupt SIGNIFOR treatment and investigate for probable cause of the findings, which may or may not be SIGNIFOR-related. Serial measures of ALT, AST, alkaline phosphatase, and total bilirubin, should be done weekly, or more frequently, if any value exceeds 5 times the baseline value in case of abnormal baselines, or 5 times the ULN in case of normal baselines.
If resolution of abnormalities to normal or near normal occurs, resuming treatment with SIGNIFOR may be done cautiously, with close observation, and only if some other likely cause has been found.
5.5Cholelithiasis and Complications of Cholelithiasis
Cholelithiasis has been frequently reported in clinical studies with SIGNIFOR [see Adverse Reactions (6)] . There have been postmarketing reports of cholelithiasis (gallstones) resulting in complications, including cholecystitis or cholangitis and requiring cholecystectomy in patients taking SIGNIFOR. Ultrasonic examination of the gallbladder before, and periodically during SIGNIFOR therapy is recommended. If complications of cholelithiasis are suspected, discontinue SIGNIFOR and treat appropriately.
5.6 Monitoring for Deficiency of Pituitary Hormones As the pharmacological activity of SIGNIFOR mimics that of somatostatin, inhibition of pituitary hormones, other than ACTH, may occur. Monitoring of pituitary function [e.g., thyroid-stimulating harmone (TSH)/free T 4 , GH/IGF-1] should occur prior to initiation of therapy with SIGNIFOR and periodically during treatment should be considered as clinically appropriate. Patients who have undergone transsphenoidal surgery and pituitary irradiation are particularly at increased risk for deficiency of pituitary hormones.
5.7Steatorrhea and Malabsorption of Dietary Fats
New onset steatorrhea, stool discoloration and loose stools have been reported in patients receiving somatostatin analogs, including pasireotide products. 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 SIGNIFOR, evaluate patients for potential pancreatic exocrine insufficie
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Interactions
Drugs that Prolong QT : Use with caution in patients who are at significant risk of developing QTc prolongation ( 5.3 , 7.1 ) Cyclosporine : Consider additional monitoring ( 7.2 ) Bromocriptine : Consider bromocriptine dose reduction ( 7.2 )
7.1Effects of Other Drugs on
SIGNIFOR Drugs That Prolong QT Coadministration of drugs that prolong the QT interval with SIGNIFOR may have additive effects on the prolongation of the QT interval. Caution is required when coadministering SIGNIFOR with drugs that may prolong the QT interval [see Warnings and Precautions (5.3)] .
7.2Effects of
SIGNIFOR on Other Drugs Cyclosporine Concomitant administration of cyclosporine with pasireotide may decrease the relative bioavailability of cyclosporine and, therefore, dose adjustment of cyclosporine to maintain therapeutic levels may be necessary. Bromocriptine Coadministration of somatostatin analogues with bromocriptine may increase the blood levels of bromocriptine. Dose reduction of bromocriptine may be necessary.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
The limited data with SIGNIFOR in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In embryo-fetal development studies in rabbits, findings indicating developmental delay were observed with subcutaneous administration of pasireotide during organogenesis at doses less than the exposure in humans at the highest recommended dose; maternal toxicity was not observed at this dose (see Data) .
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data Animal Data In embryo-fetal development studies in rats given 1, 5, and 10 mg/kg/day subcutaneously throughout organogenesis, maternal toxicity was observed at all doses, including the lowest dose tested which had exposures 4 times higher than that at the maximum therapeutic dose based on area under the curve (AUC) comparisons across species.
An increased incidence of early/total resorptions and malrotated limbs was observed in rats at 10 mg/kg/day. At 10 mg/kg/day in rats, the maternal systemic exposure (AUC) was 42179 ng*hr/mL, approximately 144 times the exposure in humans at the highest recommended dose of 900 mcg SIGNIFOR administered as a subcutaneous injection twice a day. In embryo-fetal development studies in rabbits given 0.05, 1, and 5 mg/kg/day subcutaneously through organogenesis, maternal toxicity was observed at 1 mg/kg/day, at a maternal systemic exposure (AUC) of 1906 ng*hr/mL, approximately 7 times higher than the maximum human therapeutic exposure.
An increased incidence of unossified forepaw phalanx, indicative of a developmental retardation, was observed in rabbits at 0.05 mg/kg/day, with maternal systemic exposures less than the systemic exposure in humans at the highest recommended dose. In pre- and post-natal developmental studies in rats given subcutaneous doses of 2, 5, and 10 mg/kg/day during gestation through lactation and weaning, maternal toxicity was observed at all doses, including the lowest dose (12 times higher than the maximum therapeutic dose based on surface area comparisons across species).
Retardation of physiological growth, attributed to GH inhibition was observed at 2 mg/kg/day during a pre- and post-natal study in rats. After weaning, body weight gains in the rat pups (F1 generation) exposed to pasireotide were comparable to controls, showing reversibility of this developmental delay.
Adverse reactions
Clinically significant adverse reactions that appear in other sections of the labeling include: Hypocortisolism [see Warnings and Precautions (5.1)] Hyperglycemia and Diabetes [see Warnings and Precautions (5.2)] Bradycardia and QT prolongation [see Warnings and Precautions (5.3)] Liver Test Elevations [see Warnings and Precautions (5.4)] Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions (5.5)] Pituitary Hormone Deficiency [see Warnings and Precautions (5.6)] Steatorrhea and Malabsorption of Dietary Fats [see Warnings and Precautions (5.7) ] Most common adverse reactions occurring in ≥ 20% of patients are diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes mellitus ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases at 1-888-575-8344 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. A total of 162 Cushing's disease patients were exposed to SIGNIFOR in the Phase III study [see Clinical Studies (14)] . At study entry, patients were randomized to receive twice a day doses of either 0.6 mg or 0.9 mg of SIGNIFOR given subcutaneously.
The mean age of patients was approximately 40 years old with a predominance of female patients (78%). The majority of the patients had persistent or recurrent Cushing's disease (83%) and few patients (≤ 5%) in either treatment group had received previous pituitary irradiation. The median exposure to the treatment was 10.4 months (0.03-37.8) with 68% of patients having at least 6-months exposure. In the Phase III trial, adverse reactions were reported in 98% of patients.
The most common adverse reactions (frequency ≥ 20% in either group) were diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes mellitus. There were no deaths during the study. Serious adverse events were reported in 25% of patients. Adverse events leading to study discontinuation were reported in 17% of patients. Adverse reactions with an overall frequency higher than 5% are presented in Table 1 by randomized dose group and overall.
Gastrointestinal Disorders Gastrointestinal disorders, predominantly diarrhea, nausea, abdominal pain, and vomiting were reported frequently in the Phase III trial (see Table 1). These events began to develop primarily during the first month of treatment with SIGNIFOR and required no intervention. Hyperglycemia and Diabetes Hyperglycemia-related terms were reported frequently in the Phase III trial. For all patients, these terms included: hyperglycemia (40%), diabetes mellitus (18%), increased HbA1c (11%), type 2 diabetes mellitus (9%).
In general, increases in FPG and HbA1c were seen soon after initiation of SIGNIFOR and were sustained during the treatment period. In the SIGNIFOR 0.6 mg group, mean FPG levels increased from 98.6 mg/dL at baseline to 125.1 mg/dL at Month 6. In the SIGNIFOR 0.9 mg group, mean fasting FPG levels increased from 97.0 mg/dL at baseline to 128.0 mg/dL at Month 6. In the SIGNIFOR 0.6 mg group, HbA1c increased from 5.8% at baseline to 7.2% at Month 6.
In the SIGNIFOR 0.9 mg group, HbA1c increased from 5.8% at baseline to 7.3% at Month 6 [see Warnings and Precautions (5.2)] . At one-month follow-up visits, following discontinuation of SIGNIFOR, mean FPG and HbA1c levels decreased but remained above baseline values. Long-term follow-up data are not available. Elevated Liver Tests In the Phase III trial, there were transient mean elevations in aminotransferase values in patients treated with SIGNIFOR.
Mean values returned to baseline levels by Month 4 of treatment. The elevations were not associated with clinical symptoms of hepatic disease. In the clinical development program of SIGNIFOR, there were 4 patients with concurrent elevations in ALT greater than 3 x ULN and bilirubin greater than 2 x ULN: one patient with Cushing's disease and 3 healthy volunteers [see Warnings and Precautions (5.4)] . In all 4 cases, the elevations were noted within the first 10 days of treatment.
In all of these cases, total bilirubin elevations were seen either concomitantly or preceding the transaminase elevation. The patient with Cushing's disease developed jaundice. All 4 cases had resolution of the laboratory abnormalities with discontinuation of SIGNIFOR. Hypocortisolism Cases of hypocortisolism were reported in the Phase III study in Cushing's disease patients [see Adverse Reactions (6), Clinical Studies (14)] .
The majority of cases were manageable by reducing the dose of SIGNIFOR and/or adding low-dose, short-term glucocorticoid therapy [see Warnings and Precautions (5.1)] . Injection-Site Reactions Injection-site reactions were reported in 17% of patients enrolled in the Phase III trial in Cushing's disease. The events were most frequently reported as local pain, erythema, hematoma, hemorrhage, and pruritus. These events resolved spontaneously and required no intervention.
Thyroid Function Hypothyroidism, with the use of SIGNIFOR, was reported for seven patients participating in the Phase III study in Cushing's disease. All seven patients presented with a TSH close to or below the lower limit at study entry, which precludes establishing a conclusive relationship between the adverse event and the use of SIGNIFOR. Other Abnormal Laboratory Findings Asymptomatic and reversible elevations in lipase and amylase were observed in patients receiving SIGNIFOR in clinical studies.
Pancreatitis is a potential adverse reaction associated with the use of somatostatin analogs due to the asso
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