Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 12 June 2018

Indication(s)

1 INDICATIONS AND USAGE 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) 1.1 Cushing’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.

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None (4)
Adverse reactions
6 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 [see Warnings and Precautions (5.5)] Pituitary Hormone Deficiency [see Warnings and Precautions (5.6)] 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 Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 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 (b.i.d.) 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 six-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. Adverse reactions are ranked by frequency, with the most frequent reactions listed first. Table 1 - Adverse reactions [n (%)] with an overall frequency of more than 5% in the combined dose group in the Phase III study in Cushing’s disease patients SIGNIFOR 0.6 mg bid N=82 SIGNIFOR 0.9 mg bid N=80 Overall N=162 Diarrhea 48 (59) 46 (58) 94 (58) Nausea 38 (46) 46 (58) 84 (52) Hyperglycemia 31 (38) 34 (43) 65 (40) Cholelithiasis 25 (30) 24 (30) 49 (30) Headache 23 (28) 23 (29) 46 (28) Abdominal pain 19 (23) 20 (25) 39 (24) Fatigue 12 (15) 19(24) 31 (19) Diabetes mellitus 13 (16) 16 (20) 29 (18) Injection site reactions 14 (17) 14 (18) 28 (17) Nasopharyngitis 10 (12) 11 (14) 21 (13) Alopecia 10 (12) 10 (13) 20 (12) Asthenia 13 (16) 5 (6) 18 (11) Glycosylated hemoglobin increased 10 (12) 8 (10) 18 (11) Alanine aminotransferase increased 11 (13) 6 (8) 17 (10) Gamma-glutamyl transferase increased 10 (12) 7 (9) 17 (10) Edema peripheral 9 (11) 8 (10) 17 (10) Abdominal pain upper 10 (12) 6 (8) 16 (10) Decreased appetite 7 (9) 9 (11) 16 (10) Hypercholesterolemia 7 (9) 9 (11) 16 (10) Hypertension 8 (10) 8 (10) 16 (10) Dizziness 8 (10) 7 (9) 15 (9) Hypoglycemia 12 (15) 3 (4) 15 (9) Type 2 diabetes mellitus 10 (12) 5 (6) 15 (9) Anxiety 5 (6) 9 (11) 14 (9) Influenza 9 (11) 5 (6) 14 (9) Insomnia 3 (4) 11 (14) 14 (9) Myalgia 10 (12) 4 (5) 14 (9) Arthralgia 5 (6) 8 (10) 13 (8) Pruritus 6 (7) 7 (9) 13 (8) Lipase increased 7 (9) 5 (6) 12 (7) Constipation 7 (9) 4 (5) 11 (7) Hypotension 5 (6) 6 (8) 11 (7) Vomiting 3 (4) 8 (10) 11 (7) Back pain 4 (5) 6 (8) 10 (6) Dry skin 5 (6) 5 (6) 10 (6) Electrocardiogram QT prolonged 5 (6) 5 (6) 10 (6) Hypokalemia 6 (7) 4 (5) 10 (6) Pain in extremity 6 (7) 4 (5) 10 (6) Sinus bradycardia 8 (10) 2 (3) 10 (6) Vertigo 4 (5) 6 (8) 10 (6) Abdominal distension 4 (5) 5 (6) 9 (6) Adrenal insufficiency 4 (5) 5 (6) 9 (6) Aspartate aminotransferase increased 6 (7) 3 (4) 9 (6) Blood glucose increased 6 (7) 3 (4) 9 (6) Other notable adverse reactions which occurred with a frequency less than 5% were: anemia (4%); blood amylase increased (2%) and prothrombin time prolonged (2%). 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%), and type 2 diabetes mellitus (9%). In general, increases in fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) were seen soon after initiation of SIGNIFOR and were sustained during the treatment period. In the SIGNIFOR 0.6 mg group, mean fasting plasma glucose (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 plasma glucose (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 Warning 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 three healthy volunteers [see Warnings and Precautions (5.4)]. In all four 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 four 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) and 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 association between cholelithiasis and acute pancreatitis. For hemoglobin levels, mean decreases that remained within normal range were observed. Also, post-baseline elevations in PT and PTT were noted in 33% and 47% of patients, respectively. The PT and PTT elevations were minimal. These laboratory findings are of unclear clinical significance.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Recommended initial dosage is either 0.6 mg or 0.9 mg by subcutaneous injection twice a day; recommended dosage range is 0.3 mg to 0.9 mg twice a day (2.1) Titrate dosage based on treatment response [clinically meaningful reduction in 24-hour urinary free cortisol (UFC) and/or improvements in signs and symptoms of disease] and tolerability (2.1) Testing Prior to Dosing: fasting plasma glucose, hemoglobin A1c, liver tests, electrocardiogram (ECG), gallbladder ultrasound, and serum potassium and magnesium levels (2.2) Patients with Hepatic Impairment: Child-Pugh B: Recommended initial dosage is 0.3 mg twice a day and maximum dosage is 0.6 mg twice a day (2.3, 8.6) Child-Pugh C: Avoid use in these patients (2.3, 8.6) 2.1 Recommended Dosage Range The recommended dosage range of SIGNIFOR is 0.3 to 0.9 mg by subcutaneous injection twice a day. The recommended initial dose is either 0.6 mg or 0.9 mg twice a day. Titrate dose based on response and tolerability. Patients should be evaluated for a treatment response [clinically meaningful reduction in 24-hour urinary free cortisol (UFC) levels and/or improvement in signs or symptoms of the disease] and should continue receiving therapy with SIGNIFOR as long as benefit is derived [see Clinical Studies (14)]. Maximum urinary free cortisol reduction is typically seen by two months of treatment [see Clinical Studies (14)]. For patients who are started on 0.6 mg twice a day, a dosage increase to 0.9 mg twice a day may be considered based on the response to the treatment, as long as the 0.6 mg dosage is well tolerated by the patient. Management of suspected adverse reactions may require temporary dose reduction of SIGNIFOR. Dose reduction by 0.3 mg decrements per injection is suggested. 2.2 Recommendations Prior to Initiation of SIGNIFOR Prior to the start of SIGNIFOR, patients should have baseline levels of the following: fasting plasma glucose [see Warnings and Precautions (5.2)] hemoglobin A1c [see Warnings and Precautions (5.2)] liver tests [see Warnings and Precautions (5.4)] serum potassium and magnesium levels [see Warnings and Precautions (5.3)] Patients should also have a baseline electrocardiogram and gallbladder ultrasound [see Warnings and Precautions (5.3, 5.5)] . Treatment of patients with poorly controlled diabetes mellitus should be intensively optimized with anti-diabetic therapy prior to starting SIGNIFOR [see Warnings and Precautions (5.2)] . 2.3 Dosage in Patients with Hepatic Impairment For patients with moderate hepatic impairment (Child-Pugh B), the recommended initial dosage is 0.3 mg twice a day and the maximum dosage is 0.6 mg twice a day. Avoid the use of SIGNIFOR in patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.6)]. 2.4 Important Administration Instructions Instruct patients to: Refer to the FDA-approved patient labeling (Instructions for Use) for detailed administration instructions. Prior to injection, visually inspect the product for particulate matter and discoloration. Do not use if particulates and/or discoloration are observed. Avoid injection in sites showing signs of inflammation or irritation. Prior to injection, gently pinch the skin at the injection site and hold the needle/syringe at an angle of approximately 45 degrees. Administer SIGNIFOR subcutaneously by self-injection into the top of the thigh or the abdomen. Avoid multiple subcutaneous injections at the same site within short periods of time. Use of the same injection site for two consecutive injections is not recommended. If a dose of SIGNIFOR is missed, the next injection should be administered at the scheduled time. Do not double doses to make up for a missed dose.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy (8.3) Safety and effectiveness of SIGNIFOR in children under 18 years have not been established (8.4) 8.1 Pregnancy 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 embryofetal 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 embryofetal 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 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 µg SIGNIFOR administered as a subcutaneous injection twice a day. In embryofetal 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. 8.2 Lactation Risk Summary There is no information available on the presence of SIGNIFOR in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Studies show that pasireotide administered subcutaneously passes into the milk of lactating rats; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SIGNIFOR and any potential adverse effects on the breastfed child from SIGNIFOR or from the underlying maternal condition. Data Available data in animals have shown excretion of pasireotide in milk. After a single 1 mg/kg [14C]-pasireotide subcutaneous dose to lactating rats, the transfer of radioactivity into milk was observed. The overall milk:plasma (M/P) exposure ratio of total radioactivity was 0.28, based on AUC0-∞ values. 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as the therapeutic benefits of a reduction or normalization of serum cortisol levels in female patients with Cushing’s disease treated with pasireotide may lead to improved fertility. 8.4 Pediatric Use Safety and effectiveness of SIGNIFOR have not been established in pediatric patients. 8.5 Geriatric Use Clinical studies of SIGNIFOR did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)]. 8.6 Hepatic Impairment Dose adjustment is not required in patients with mild impaired hepatic function (Child-Pugh A), but is required for patients with moderately impaired hepatic function (Child-Pugh B) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Avoid the use of SIGNIFOR in patients with severe hepatic impairment (Child-Pugh C). 8.7 Renal Impairment No dosage adjustment of SIGNIFOR in patients with impaired renal function is required [see Clinical Pharmacology (12.3)].

Interactions

7 DRUG 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) 7.1 Effects of Other Drugs on SIGNIFOR Drugs that Prolong QT Co-administration of drugs that prolong the QT interval with SIGNIFOR may have additive effects on the prolongation of the QT interval. Caution is required when co-administering SIGNIFOR with drugs that may prolong the QT interval [see Warnings and Precautions (5.3)]. 7.2 Effects 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 Co-administration of somatostatin analogues with bromocriptine may increase the blood levels of bromocriptine. Dose reduction of bromocriptine may be necessary.

More information

Category Value
Authorisation number NDA200677
Agency product number 98H1T17066
Orphan designation No
Product NDC 0078-0634,0078-0635,0078-0633
Date Last Revised 09-03-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1364109
Marketing authorisation holder Novartis Pharmaceuticals Corporation