Signifor

Warnings and Precautions, Steatorrhea and Malabsorption of Dietary Fats ( 5.7 ) 7/2024

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.

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 (FPG), hemoglobin A1c (HbA1c), 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 mg 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 UFC 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 (FPG) [see Warnings and Precautions (5.2)] hemoglobin A1c (HbA1c) [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 (ECG) 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 2 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.

3 DOSAGE FORMS AND STRENGTHS Injection: 0.3 mg/mL, 0.6 mg/mL, and 0.9 mg/mL in a single-dose, 1 mL colorless glass ampule. Injection: 0.3 mg/mL, 0.6 mg/mL, and 0.9 mg/mL in a single-dose ampule ( 3 )

4 CONTRAINDICATIONS None. None ( 4 )

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 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 . 6.1 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 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. 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 twice a day N = 82 SIGNIFOR 0.9 mg twice a day 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 …

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 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)] . 7.2 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 Coadministration of somatostatin analogues with bromocriptine may increase the blood levels of bromocriptine. Dose reduction of bromocriptine may be necessary.

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 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. 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 [ 14 C]-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 AUC 0-∞ values. 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as …

12.1 Mechanism of Action SIGNIFOR is an injectable cyclohexapeptide somatostatin analogue. Pasireotide exerts its pharmacological activity via binding to somatostatin receptors (SSTRs). Five human somatostatin receptor subtypes are known: SSTR 1, 2, 3, 4, and 5. These receptor subtypes are expressed in different tissues under normal physiological conditions. Corticotroph tumor cells from Cushing's disease patients frequently over-express SSTR5 whereas the other receptor subtypes are often not expressed or are expressed at lower levels. Pasireotide binds and activates the SSTRs resulting in inhibition of ACTH secretion, which leads to decreased cortisol secretion. The binding affinities of endogenous somatostatin and pasireotide are shown in Table 2. Table 2 - Binding Affinities of Somatostatin (SRIF-14) and Pasireotide to the Five Human Somatostatin Receptor Subtypes (SSTR1-5) Results are the mean ± SEM of IC50 values expressed as nmol/L. Compound SSTR1 SSTR2 SSTR3 SSTR4 SSTR5 Somatostatin (SRIF-14) 0.93 ± 0.12 0.15 ± 0.02 0.56 ± 0.17 1.5 ± 0.4 0.29 ± 0.04 Pasireotide 9.3 ± 0.1 1.0 ± 0.1 1.5 ± 0.3 > 100 0.16 ± 0.01

11 DESCRIPTION SIGNIFOR (pasireotide) injection is prepared as a sterile solution of pasireotide diaspartate in a tartaric acid buffer for administration by subcutaneous injection. SIGNIFOR is a somatostatin analog. Pasireotide diaspartate, chemically known as (2-Aminoethyl) carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminobutyl)-5-benzyl-8-(4-benzyloxybenzyl)-14-(1H-indol-3-ylmethyl)-4,7,10,13,16,19-hexaoxo-17-phenyloctadecahydro-3a,6,9,12,15,18-hexaazacyclopentacyclooctadecen-2-yl ester, di[(S)-2-aminosuccinic acid] salt, is a cyclohexapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin. The molecular formula of pasireotide diaspartate is C 58 H 66 N 10 O 9 • 2 C 4 H 7 NO 4 and the molecular weight is 1313.41 g/mol. The structural formula is: SIGNIFOR is supplied as a sterile solution in a single-dose, 1 mL colorless glass ampule containing pasireotide in 0.3 mg/mL, 0.6 mg/mL, or 0.9 mg/mL strengths for subcutaneous injection. Each glass ampule contains: * corresponds to 0.3/0.6/0.9 mg pasireotide base. Note: Each ampule contains an overfill of 0.1 mL to allow accurate administration of 1 mL from the ampule. 0.3 mg 0.6 mg 0.9 mg Pasireotide diaspartate 0.3762 * 0.7524 * 1.1286 * Mannitol 49.50 49.50 49.50 Tartaric acid 1.501 1.501 1.501 Sodium hydroxide ad pH 4.2 ad pH 4.2 ad pH 4.2 Water for injection ad 1 mL ad 1 mL ad 1 mL The structural formula of pasireotide diaspartate.

10 OVERDOSAGE No cases of overdosage have been reported in patients with Cushing's disease receiving SIGNIFOR subcutaneously. Doses up to 2.1 mg twice a day have been used in healthy volunteers with adverse reactions of diarrhea being observed at a high frequency. In the event of overdosage, it is recommended that appropriate supportive treatment be initiated, as dictated by the patient's clinical status, until resolution of the symptoms. Up-to-date information about the treatment of overdose can be obtained from a certified Regional Poison Center. Contact Poison Control (1-800-222-1222) for latest recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING SIGNIFOR is supplied as a single dose, colorless glass ampule packaged in a box of 60 ampules, arranged in 10 packs of 6 ampules each. The following packaging configurations are available. 0.3 mg/1 mL pasireotide (as diaspartate) Box of 60 ampules NDC# 55292-131-60 0.6 mg/1 mL pasireotide (as diaspartate) Box of 60 ampules NDC# 55292-132-60 0.9 mg/1 mL pasireotide (as diaspartate) Box of 60 ampules NDC# 55292-133-60 Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F), protect from light.