DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION Recommended initial dosage is either 0.6 mg or 0.9 mg by subcutaneous injection twice day; recommended dosage range is 0.3 mg to 0.9 mg twice 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 day and maximum dosage is 0.6 mg twice day (2.3, 8.6)Child-Pugh C: Avoid use in these patients (2.3, 8.6). Recommended initial dosage is either 0.6 mg or 0.9 mg by subcutaneous injection twice day; recommended dosage range is 0.3 mg to 0.9 mg twice 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 day and maximum dosage is 0.6 mg twice day (2.3, 8.6)Child-Pugh C: Avoid use in these patients (2.3, 8.6). Child-Pugh B: Recommended initial dosage is 0.3 mg twice day and maximum dosage is 0.6 mg twice 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 day. The recommended initial dose is either 0.6 mg or 0.9 mg twice day. Titrate dose based on response and tolerability. Patients should be evaluated for 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 day, dosage increase to 0.9 mg twice 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 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)] . 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)] 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 day and the maximum dosage is 0.6 mg twice 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 consecutive injections is not recommended. If dose of SIGNIFOR is missed, the next injection should be administered at the scheduled time. Do not double doses to make up for missed dose.. 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 consecutive injections is not recommended. If dose of SIGNIFOR is missed, the next injection should be administered at the scheduled time. Do not double doses to make up for missed dose.

ADVERSE REACTIONS SECTION.

6ADVERSE 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)] 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)] 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 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 Cushings disease patients were exposed to SIGNIFOR in the Phase III study [see Clinical Studies (14)]. At study entry, patients were randomized to receive twice 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 predominance of female patients (78%). The majority of the patients had persistent or recurrent Cushings 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 by randomized dose group and overall. Adverse reactions are ranked by frequency, with the most frequent reactions listed first.Table - Adverse Reactions [n (%)] With an Overall Frequency of More Than 5% in the Combined Dose Group in the Phase III Study in Cushings Disease PatientsSIGNIFOR0.6 mg twice dayN 82SIGNIFOR0.9 mg twice dayN 80Overall = 162Diarrhea48 (59)46 (58)94 (58)Nausea38 (46)46 (58)84 (52)Hyperglycemia31 (38)34 (43)65 (40)Cholelithiasis25 (30)24 (30)49 (30)Headache23 (28)23 (29)46 (28)Abdominal pain19 (23)20 (25)39 (24)Fatigue12 (15)19(24)31 (19)Diabetes mellitus13 (16)16 (20)29 (18)Injection-site reactions14 (17)14 (18)28 (17)Nasopharyngitis10 (12)11 (14)21 (13)Alopecia10 (12)10 (13)20 (12)Asthenia13 (16)5 (6)18 (11)Glycosylated hemoglobin increased10 (12)8 (10)18 (11)Alanine aminotransferase increased11 (13)6 (8)17 (10)Gamma-glutamyl transferase increased10 (12)7 (9)17 (10)Edema peripheral9 (11)8 (10)17 (10)Abdominal pain upper10 (12)6 (8)16 (10)Decreased appetite7 (9)9 (11)16 (10)Hypercholesterolemia7 (9)9 (11)16 (10)Hypertension8 (10)8 (10)16 (10)Dizziness8 (10)7 (9)15 (9)Hypoglycemia12 (15)3 (4)15 (9)Type diabetes mellitus10 (12)5 (6)15 (9)Anxiety5 (6)9 (11)14 (9)Influenza9 (11)5 (6)14 (9)Insomnia3 (4)11 (14)14 (9)Myalgia10 (12)4 (5)14 (9)Arthralgia5 (6)8 (10)13 (8)Pruritus6 (7)7 (9)13 (8)Lipase increased7 (9)5 (6)12 (7)Constipation7 (9)4 (5)11 (7)Hypotension5 (6)6 (8)11 (7)Vomiting3 (4)8 (10)11 (7)Back pain4 (5)6 (8)10 (6)Dry skin5 (6)5 (6)10 (6)Electrocardiogram QT prolonged5 (6)5 (6)10 (6)Hypokalemia6 (7)4 (5)10 (6)Pain in extremity6 (7)4 (5)10 (6)Sinus bradycardia8 (10)2 (3)10 (6)Vertigo4 (5)6 (8)10 (6)Abdominal distension4 (5)5 (6)9 (6)Adrenal insufficiency4 (5)5 (6)9 (6)Aspartate aminotransferase increased6 (7)3 (4)9 (6)Blood glucose increased6 (7)3 (4)9 (6)Other notable adverse reactions which occurred with frequency less than 5% were: anemia (4%), blood amylase increased (2%), and prothrombin time prolonged (2%).Gastrointestinal DisordersGastrointestinal 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 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 [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 TestsIn 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 of treatment. The elevations were not associated with clinical symptoms of hepatic disease.In the clinical development program of SIGNIFOR, there were patients with concurrent elevations in ALT greater than x ULN and bilirubin greater than x ULN: one patient with Cushings disease and healthy volunteers [see Warnings and Precautions (5.4)]. In all 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 Cushings disease developed jaundice. All cases had resolution of the laboratory abnormalities with discontinuation of SIGNIFOR.HypocortisolismCases of hypocortisolism were reported in the Phase III study in Cushings 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 ReactionsInjection-site reactions were reported in 17% of patients enrolled in the Phase III trial in Cushings disease. The events were most frequently reported as local pain, erythema, hematoma, hemorrhage, and pruritus. These events resolved spontaneously and required no intervention.Thyroid FunctionHypothyroidism, with the use of SIGNIFOR, was reported for seven patients participating in the Phase III study in Cushings disease. All seven patients presented with TSH close to or below the lower limit at study entry, which precludes establishing conclusive relationship between the adverse event and the use of SIGNIFOR.Other Abnormal Laboratory FindingsAsymptomatic and reversible elevations in lipase and amylase were observed in patients receiving SIGNIFOR in clinical studies. Pancreatitis is 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 prothrombin time (PT) and partial thromboplastin time (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.. 6.2 Postmarketing Experience. Additional adverse reactions have been identified during postapproval use of SIGNIFOR. Because these reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure.Cholelithiasis resulting in complications, including cholecystitis and cholangitis, which have sometimes required cholecystectomy. Cholelithiasis resulting in complications, including cholecystitis and cholangitis, which have sometimes required cholecystectomy.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 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 Cushings 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 - 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.CompoundSSTR1SSTR2SSTR3SSTR4SSTR5Somatostatin (SRIF-14)0.93 +- 0.120.15 +- 0.020.56 +- 0.171.5 +- 0.40.29 +- 0.04Pasireotide9.3 +- 0.11.0 +- 0.11.5 +- 0.3> 1000.16 +- 0.01. 12.2 Pharmacodynamics. Glucose MetabolismIn randomized, double-blind mechanism study conducted in healthy volunteers, the development of hyperglycemia with pasireotide at doses of 0.6 mg twice day and 0.9 mg twice day was related to significant decreases in insulin secretion as well as incretin hormones (i.e., glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) [see Warnings and Precautions (5.2), Adverse Reactions (6.1)].Cardiac ElectrophysiologyQTcI interval was evaluated in randomized, blinded, crossover study in healthy subjects investigating pasireotide doses of 0.6 mg twice day and 1.95 mg twice day. The maximum mean (95% upper confidence bound) placebo-subtracted QTcI change from baseline was 12.7 (14.7) ms and 16.6 (18.6) ms, respectively. Both pasireotide doses decreased heart rate, with maximum mean (95% lower confidence bound) placebo-subtracted change from baseline of -10.9 (-11.9) beats per minute (bpm) observed at 1.5 hours for pasireotide 0.6 mg twice day, and -15.2 (-16.5) bpm at 0.5 hours for pasireotide 1.95 mg twice day. The supra-therapeutic dose (1.95 mg twice day) produced mean steady-state Cmax values 3.3-fold the mean Cmax for the 0.6 mg twice day dose in the study.. 12.3 Pharmacokinetics. In healthy volunteers, pasireotide demonstrates approximately linear pharmacokinetics (PK) for dose range from 0.0025 to 1.5 mg. In Cushings disease patients, pasireotide demonstrates linear dose-exposure relationship in dose range from 0.3 mg to 1.2 mg.Absorption and DistributionIn healthy volunteers, pasireotide peak plasma concentration is reached within Tmax 0.25-0.5 hour. Cmax and AUC are dose-proportional following administration of single and multiple doses.No studies have been conducted to evaluate the absolute bioavailability of pasireotide in humans. Food effect is unlikely to occur since SIGNIFOR is administered via parenteral route.In healthy volunteers, pasireotide is widely distributed with large apparent volume of distribution (Vz/F 100 L). Distribution between blood and plasma is concentration independent and shows that pasireotide is primarily located in the plasma (91%). Plasma protein binding is moderate (88%) and independent of concentration.Pasireotide has low passive permeability and is likely to be substrate of P-glycoprotein (P-gp), but the impact of P-gp on ADME (absorption, distribution, metabolism, excretion) of pasireotide is expected to be low. In clinical testing in healthy volunteers, P-gp inhibition (e.g., verapamil) did not affect the rate or extent of pasireotide availability. Pasireotide is not substrate of efflux transporter BCRP (breast cancer resistance protein), influx transporter OCT1 (organic cation transporter 1), or influx transporters OATP (organic anion-transporting polypeptide) 1B1, 1B3, or 2B1.Metabolism and ExcretionPasireotide was shown to be metabolically stable in human liver and kidney microsomes systems. In healthy volunteers, pasireotide in its unchanged form is the predominant form found in plasma, urine, and feces. Somatropin may increase CYP450 enzymes and, therefore, suppression of growth hormone secretion by somatostatin analogs, including pasireotide may decrease the metabolic clearance of compounds metabolized by CYP450 enzymes.Pasireotide is eliminated mainly via hepatic clearance (biliary excretion) with small contribution of the renal route. In human ADME study 55.9 +- 6.63% of the radioactivity dose was recovered over the first 10 days post dosing, including 48.3 +- 8.16% of the radioactivity in feces and 7.63 +- 2.03% in urine. The clearance (CL/F) of pasireotide in healthy volunteers and Cushings disease patients is ~7.6 L/h and ~3.8 L/h, respectively.Steady-State PharmacokineticsFollowing multiple subcutaneous doses, pasireotide demonstrates linear pharmacokinetics in the dose range of 0.05 to 0.6 mg once day in healthy volunteers, and 0.3 mg to 1.2 mg twice day in Cushings disease patients. Based on the accumulation ratios of AUC, the calculated effective half-life (t1/2,eff) in healthy volunteers was approximately 12 hours (on average between 10 and 13 hours for 0.05, 0.2 and 0.6 mg once day doses).Specific PopulationsPopulation PK analyses of SIGNIFOR indicate that race, body weight, age, and gender do not have clinically relevant influence on PK parameters. No dose adjustment is required for demographics.Hepatic ImpairmentIn clinical study with single subcutaneous dose of 600 mcg pasireotide in subjects with impaired hepatic function (Child-Pugh A, B, and C), subjects with moderate and severe hepatic impairment (Child-Pugh and C) showed significantly higher exposures than subjects with normal hepatic function. Upon comparison with the control group, AUCinf was increased by 12%, 56%, and 42%; and Cmax increased by 3%, 46%, and 33%, respectively, in the mild, moderate, and severe hepatic impairment groups [see Use in Specific Populations (8.6), Dosage and Administration (2.3)].Pediatric PatientsNo studies have been performed in pediatric patients [see Use in Specific Populations (8.4)].Geriatric PatientsNo clinical pharmacology studies have been performed in geriatric patients.Renal ImpairmentRenal clearance has minor contribution to the elimination of pasireotide in humans. In clinical study with single subcutaneous dose of 900 mcg pasireotide, in subjects with impaired renal function, renal impairment of mild, moderate, or severe degree or end stage renal failure, did not have significant impact on the pharmacokinetics of pasireotide [see Use in Specific Populations (8.7)].Drug Interaction StudiesThere was no significant drug interaction between pasireotide and metformin, nateglinide or liraglutide.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES A Phase III, multicenter, randomized study was conducted to evaluate the safety and efficacy of two dose levels of SIGNIFOR over 6-month treatment period in Cushings disease patients with persistent or recurrent disease despite pituitary surgery or de novo patients for whom surgery was not indicated or who had refused surgery. Patients with baseline 24-hour urine free cortisol (UFC) >1.5 ULN were randomized to receive SIGNIFOR dosage of either 0.6 mg subcutaneous twice day or 0.9 mg subcutaneous twice day. After months of treatment, patients with mean 24-hour UFC <= 2.0 ULN and below or equal to their baseline values continued blinded treatment at the randomized dose until Month 6. Patients who did not meet these criteria were unblinded and the dose was increased by 0.3 mg twice day. After the initial months in the study, patients entered an additional 6-month open-label treatment period. The dosage could be reduced by 0.3 mg twice day at any time during the study for intolerability.A total of 162 patients were enrolled in this study. The majority of patients were female (78%) and had persistent or recurrent Cushings disease despite pituitary surgery (83%) with mean age of 40 years. few patients (4%) in either treatment group received previous pituitary irradiation. The median value of the baseline 24-hour UFC for all patients was 565 nmol/24 hours (normal range 30 to 145 nmol/24 hours). About two-thirds of all randomized patients completed months of treatment.The primary efficacy endpoint was the proportion of patients who achieved normalization of mean 24-hour UFC levels after months of treatment and did not dose increase during this period.24-Hour Urinary Free Cortisol ResultsAt Month 6, the percentages of responders for the primary endpoint were 15% and 26% in the 0.6 mg twice day and 0.9 mg twice day groups, respectively (Table 3). The percentages of patients with mUFC <= ULN or >= 50% reduction from baseline, less stringent endpoint than the primary endpoint, were 34% in the 0.6 mg twice day and 41% in the 0.9 mg twice day groups. Dose increases appeared to have minimal effect on 24-hour UFC response. Mean and median percentage changes in UFC from baseline are presented in Table 3.Table - 24-Hour Urinary Free Cortisol Study Results at Month in Patients With Cushings DiseaseSIGNIFOR0.6 mg twice dayN 82SIGNIFOR0.9 mg twice dayN 80UFC Responders n/N (95% CI)12/8215% (7%, 22%)21/8026% (17%, 36%)UFC Levels (nmol/24 hr) Baseline Mean (SD) MedianN 78 868 (764)704N 72 750 (930)470 Change from baseline Mean (95% CI) Median-22% (-44%, +1%)-47%-42% (-50%, -33%)-46%SIGNIFOR resulted in decrease in the mean 24-hour UFC after month of treatment (Figure 1). For patients (n 78) who stayed in the trial, similar UFC lowering was observed at Month 12.Note: Only patients who completed months of treatment are included in this analysis (n 110). The reference line is the ULN for UFC, which is 145 nmol/24hour; +/-Standard errors are displayed.Other EndpointsDecreases from baseline for blood pressure were observed at Month 6, including patients who did not receive any anti-hypertensive medication. However, due to the fact that the study allowed initiation of anti-hypertensive medication and dose increases in patients already receiving such medications, the individual contribution of SIGNIFOR or of anti-hypertensive medication adjustments cannot be clearly established.The mean decreases from baseline at Month for weight, body mass index, and waist circumference were 4.4 kg, 1.6 kg/m2 and 2.6 cm, respectively. Individual patients showed varying degrees of improvement in Cushings disease manifestations, but because of the variability in response and the absence of control group in this trial, it is uncertain whether these changes could be ascribed to the effects of SIGNIFOR.. Figure - Mean (+- SE) Urinary Free Cortisol (nmol/24h) at Time Points up to Month by Randomized Dose Group.

INSTRUCTIONS FOR USE SECTION.

Instructions for UseSIGNIFOR(R) [sig-na-for] (pasireotide)InjectionSupplies you will need to give your SIGNIFOR injection:1 SIGNIFOR ampule (See Figure A)1 sterile syringe (See Figure B)1 long sterile needle (See Figure B) This needle is used to draw up your SIGNIFOR from the ampule. You should only use this needle if your doctor or nurse tells you to. short sterile needle (See Figure B)Alcohol wipes1 cotton ball or gauzeA sharps disposal container or other closeable, puncture resistant disposal containerGetting started:Step 1: Wash your hands well with soap and water and dry them.Step 2: Take SIGNIFOR ampule out of the box.Step 3: Look at the SIGNIFOR ampule. Check that the ampule is not cracked or broken and that the liquid medicine in the ampule is clear and colorless.Do not use SIGNIFOR if the ampule is cracked or broken or if the liquid looks cloudy or contains particles. Take the whole box back to the pharmacy and get new one.Ampules should be opened just prior to administration and any unused portion discarded.Step 4: Check the dose and expiration date printed on the ampule (See Figure C).Preparing your SIGNIFOR dose:Step 5: Hold the SIGNIFOR ampule at the bottom with hand. With your other hand, tap the top of the SIGNIFOR ampule with your finger to make sure there is no liquid in the top of the ampule when you open it (See Figure D).Figure DStep 6: Hold the ampule with hand. With your other hand, hold the top of the ampule and pull it sideways until the top snaps off at the line marked on the ampule neck (See Figure E). Put the ampule upright on clean and flat surface.Figure EStep 7: Open the sterile needle package. Place the needle on the top of the syringe. Push down on the needle and twist it clockwise until it is tight (See Figure F). If you have been told to use long and short needle, you should use the long needle for this step. Figure FStep 8: Pull the needle cover straight off the sterile needle (See Figure G).Figure GStep 9: Put the needle into the ampule making sure you do not touch the outside of the ampule and pull up on the plunger to draw up all of the SIGNIFOR liquid into the syringe (See Figure H). If you have been told to use long and short needle, you should now take the long needle off of the syringe and put on the short one.Figure HStep 10: Hold the syringe upright in hand between fingers with your thumb at the bottom of the plunger. With your other hand, tap the syringe with your finger to get rid of air bubbles (See Figure I).Figure IStep 11: Push up on the plunger until you see drop of liquid on the tip of the needle (See Figure J). Do not let the needle touch anything. You are now ready to inject your dose of SIGNIFOR.Figure JInjecting your SIGNIFOR dose:Step 12: Choose your injection site and wipe the site with an alcohol wipe (See Figure K). Let the site dry.Figure KStep 13: With hand, gently pinch the skin at the injection site you have chosen and wiped with an alcohol wipe. With your other hand, pick up the syringe and hold it like pencil. Insert the needle into the pinched skin at 45 degree angle using quick dart like motion (See Figure L). Do not let go of the skin.Figure LStep 14: Gently press the plunger all the way down, until the syringe is empty (See Figure M).Figure MStep 15: When the syringe is empty, slowly let go of the skin and gently pull the needle out of the skin (See Figure N).Figure NStep 16: Place cotton ball or gauze over the injection site and press for about seconds. Do not massage the injection site. If there is bleeding, cover it with bandage. After injecting your SIGNIFOR dose: Put your used needles and syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash. If you do not have FDA-cleared sharps disposal container, you may use household container that is: made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: March 2020Distributed by:Recordati Rare Diseases Inc., Lebanon, NJ 08833 U.S.ARRD-LIAM-D2020-00. SIGNIFOR ampule (See Figure A). sterile syringe (See Figure B). long sterile needle (See Figure B) This needle is used to draw up your SIGNIFOR from the ampule. You should only use this needle if your doctor or nurse tells you to. This needle is used to draw up your SIGNIFOR from the ampule. You should only use this needle if your doctor or nurse tells you to.. short sterile needle (See Figure B). Alcohol wipes. cotton ball or gauze. sharps disposal container or other closeable, puncture resistant disposal container. Put the ampule upright on clean and flat surface.. If you have been told to use long and short needle, you should use the long needle for this step.. If you have been told to use long and short needle, you should now take the long needle off of the syringe and put on the short one.. Do not let the needle touch anything. You are now ready to inject your dose of SIGNIFOR.. Do not let go of the skin.. If there is bleeding, cover it with bandage.. Put your used needles and syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash. If you do not have FDA-cleared sharps disposal container, you may use household container that is: made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. If you do not have FDA-cleared sharps disposal container, you may use household container that is: made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container. made of heavy-duty plastic,. can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,. upright and stable during use,. leak-resistant, and. properly labeled to warn of hazardous waste inside the container.. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.. Figure and Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H. Figure I. Figure J. Figure K. Figure L. Figure M. Figure N. RRD logo.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. In healthy volunteers, pasireotide demonstrates approximately linear pharmacokinetics (PK) for dose range from 0.0025 to 1.5 mg. In Cushings disease patients, pasireotide demonstrates linear dose-exposure relationship in dose range from 0.3 mg to 1.2 mg.Absorption and DistributionIn healthy volunteers, pasireotide peak plasma concentration is reached within Tmax 0.25-0.5 hour. Cmax and AUC are dose-proportional following administration of single and multiple doses.No studies have been conducted to evaluate the absolute bioavailability of pasireotide in humans. Food effect is unlikely to occur since SIGNIFOR is administered via parenteral route.In healthy volunteers, pasireotide is widely distributed with large apparent volume of distribution (Vz/F 100 L). Distribution between blood and plasma is concentration independent and shows that pasireotide is primarily located in the plasma (91%). Plasma protein binding is moderate (88%) and independent of concentration.Pasireotide has low passive permeability and is likely to be substrate of P-glycoprotein (P-gp), but the impact of P-gp on ADME (absorption, distribution, metabolism, excretion) of pasireotide is expected to be low. In clinical testing in healthy volunteers, P-gp inhibition (e.g., verapamil) did not affect the rate or extent of pasireotide availability. Pasireotide is not substrate of efflux transporter BCRP (breast cancer resistance protein), influx transporter OCT1 (organic cation transporter 1), or influx transporters OATP (organic anion-transporting polypeptide) 1B1, 1B3, or 2B1.Metabolism and ExcretionPasireotide was shown to be metabolically stable in human liver and kidney microsomes systems. In healthy volunteers, pasireotide in its unchanged form is the predominant form found in plasma, urine, and feces. Somatropin may increase CYP450 enzymes and, therefore, suppression of growth hormone secretion by somatostatin analogs, including pasireotide may decrease the metabolic clearance of compounds metabolized by CYP450 enzymes.Pasireotide is eliminated mainly via hepatic clearance (biliary excretion) with small contribution of the renal route. In human ADME study 55.9 +- 6.63% of the radioactivity dose was recovered over the first 10 days post dosing, including 48.3 +- 8.16% of the radioactivity in feces and 7.63 +- 2.03% in urine. The clearance (CL/F) of pasireotide in healthy volunteers and Cushings disease patients is ~7.6 L/h and ~3.8 L/h, respectively.Steady-State PharmacokineticsFollowing multiple subcutaneous doses, pasireotide demonstrates linear pharmacokinetics in the dose range of 0.05 to 0.6 mg once day in healthy volunteers, and 0.3 mg to 1.2 mg twice day in Cushings disease patients. Based on the accumulation ratios of AUC, the calculated effective half-life (t1/2,eff) in healthy volunteers was approximately 12 hours (on average between 10 and 13 hours for 0.05, 0.2 and 0.6 mg once day doses).Specific PopulationsPopulation PK analyses of SIGNIFOR indicate that race, body weight, age, and gender do not have clinically relevant influence on PK parameters. No dose adjustment is required for demographics.Hepatic ImpairmentIn clinical study with single subcutaneous dose of 600 mcg pasireotide in subjects with impaired hepatic function (Child-Pugh A, B, and C), subjects with moderate and severe hepatic impairment (Child-Pugh and C) showed significantly higher exposures than subjects with normal hepatic function. Upon comparison with the control group, AUCinf was increased by 12%, 56%, and 42%; and Cmax increased by 3%, 46%, and 33%, respectively, in the mild, moderate, and severe hepatic impairment groups [see Use in Specific Populations (8.6), Dosage and Administration (2.3)].Pediatric PatientsNo studies have been performed in pediatric patients [see Use in Specific Populations (8.4)].Geriatric PatientsNo clinical pharmacology studies have been performed in geriatric patients.Renal ImpairmentRenal clearance has minor contribution to the elimination of pasireotide in humans. In clinical study with single subcutaneous dose of 900 mcg pasireotide, in subjects with impaired renal function, renal impairment of mild, moderate, or severe degree or end stage renal failure, did not have significant impact on the pharmacokinetics of pasireotide [see Use in Specific Populations (8.7)].Drug Interaction StudiesThere was no significant drug interaction between pasireotide and metformin, nateglinide or liraglutide.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: March 2020Medication GuideSIGNIFOR(R) [sig-na-for] (pasireotide)InjectionRead this Medication Guide before you start using SIGNIFOR and each time you get refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment. What is the most important information should know about SIGNIFORSIGNIFOR can cause serious side effects, including:Low cortisol levels in your blood (hypocortisolism). Tell your doctor right away if you have any signs and symptoms of hypocortisolism. Signs and symptoms of hypocortisolism may include: weakness fatigue loss of appetite nausea vomiting low blood pressure low level of sodium in your blood low blood sugarIf you get hypocortisolism while taking SIGNIFOR, your doctor may change your dose or ask you to stop taking it.High blood sugar (hyperglycemia). Your doctor should check your blood sugar level before you start taking SIGNIFOR and while you take it. Signs and symptoms of hyperglycemia may include: excessive thirst high urine output increased appetite with weight loss tirednessIf you get hyperglycemia while taking SIGNIFOR, your doctor may give you another medicine to take to lower your blood sugar. Your doctor may also change your dose of SIGNIFOR or ask you to stop taking it.What is SIGNIFORSIGNIFOR is prescription medicine used to treat Cushings disease in adults who cannot have surgery or have failed surgery.It is not known if SIGNIFOR is safe and effective in children.What should tell my doctor before using SIGNIFORBefore you take SIGNIFOR, tell your doctor if you:have or have had high blood sugar (hyperglycemia) have diabetes have or have had heart problems have history of low levels of potassium or magnesium in your blood have or have had liver problems have or have had gallstones have any other medical conditions are pregnant or plan to become pregnant. SIGNIFOR may harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if SIGNIFOR passes into your breast milk. You and your doctor should decide if you will take SIGNIFOR or breastfeed. You should not do both. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.Taking SIGNIFOR with certain other medicines can affect each other and cause side effects. Especially tell your doctor if you take:medicines to control your heart beat (anti-arrhythmics) medicines that can affect the electrical system of your heart (QT prolongation) medicines to control your blood pressure (such as beta-blockers or calcium channel blockers) medicines to control the electrolyte (such as potassium or magnesium) levels in your blood cyclosporine (Gengraf (R), Neoral (R), Restasis (R), Sandimmune (R)) bromocriptine (Cycloset (R), Parlodel (R))Ask your doctor for list of these medicines, if you are not sure.Know the medicines you take. Keep list of them to show to your doctor and pharmacist when you get new medicine.How should use SIGNIFOR Read the Instructions for Use at the end of this Medication Guide for information about the right way to use SIGNIFOR. Use SIGNIFOR exactly as your doctor tells you to. Your doctor may change your dose if needed. Before you use SIGNIFOR for the first time, your doctor should do blood test to check your blood sugar levels and your liver tests. Before you use SIGNIFOR for the first time, your doctor should do test to check your heart (electrocardiogram) and your gallbladder (ultrasound). SIGNIFOR should be clear and colorless. Before you inject your dose, check to make sure that SIGNIFOR is clear and colorless, and does not have any clumps or particles in it. SIGNIFOR is given as an injection into the fat just under your skin (subcutaneous injection). Do not inject SIGNIFOR into skin that is red or irritated. The recommended injection sites for SIGNIFOR are the top of your thigh or stomach area (abdomen). Change (rotate) your injection site with each dose. Do not inject SIGNIFOR into the exact same spot for each injection. Your doctor should show you how to prepare and give your dose of SIGNIFOR before you use it for the first time. You should not inject SIGNIFOR until your doctor has shown you how to use it the right way.If you take too much SIGNIFOR, tell your doctor right away.What are the possible side effects of SIGNIFOR SIGNIFOR may cause serious side effects, including:See What is the most important information should know about SIGNIFORslow heart rate (bradycardia). SIGNIFOR can cause your heart to beat slower, which may cause you to feel weak, dizzy or even faint. People who have, or have had, heart problems are at higher risk for bradycardia.problems with the electrical system of your heart (QT interval prolongation), which can put you at risk for abnormal heart beats, dizziness, and fainting spells that can be very serious. Call your doctor right away if you experience such spells.elevation of your liver tests. Your doctor should do blood tests to monitor your liver tests while you use SIGNIFOR. gallstones (cholelithiasis) and complications that can happen if you have gallstones. Gallstones are serious but common side effect of SIGNIFOR. Possible complications of gallstones include inflammation and infection of the gallbladder. Your doctor should do test (ultrasound) to check for gallstones before you start using SIGNIFOR and while you use it.Tell your healthcare provider if you get any of these symptoms. sudden pain in your upper right stomach area (abdomen)yellowing of your skin and whites of your eyesnauseasudden pain in your right shoulder or between your shoulder bladesfever with chills The most common side effects of SIGNIFOR include:diarrhea nausea high blood sugar headache abdominal pain fatigue diabetes mellitus injection-site reactions common cold hair loss weakness fluid retentionAbnormal blood test result for glycosylated hemoglobin (the level of glycosylated hemoglobin indicates the average blood sugar level over the previous months)Tell your doctor if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of SIGNIFOR. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store SIGNIFOR Store SIGNIFOR at 68F to 77F (20C to 25C). Keep SIGNIFOR out of the light.Keep SIGNIFOR and all medicines out of the reach of children.General information about the safe and effective use of SIGNIFOR.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use SIGNIFOR for condition for which it was not prescribed. Do not give SIGNIFOR to other people, even if they have the same symptoms that you have. It may harm them.This Medication Guide summarizes the most important information about SIGNIFOR. If you would like more information, talk to your doctor. You can ask your pharmacist or doctor for information about SIGNIFOR that is written for health professionals.For more information go to www.SIGNIFOR.com or call 1-888-575-8344.What are the ingredients in SIGNIFORActive ingredient: PasireotideInactive ingredients: Mannitol, sodium hydroxide, tartaric acid, and water for injection.RRD-LIAM-D2020-00. Low cortisol levels in your blood (hypocortisolism). Tell your doctor right away if you have any signs and symptoms of hypocortisolism. Signs and symptoms of hypocortisolism may include: weakness fatigue loss of appetite nausea vomiting low blood pressure low level of sodium in your blood low blood sugarIf you get hypocortisolism while taking SIGNIFOR, your doctor may change your dose or ask you to stop taking it.. weakness fatigue loss of appetite nausea vomiting low blood pressure low level of sodium in your blood low blood sugar. High blood sugar (hyperglycemia). Your doctor should check your blood sugar level before you start taking SIGNIFOR and while you take it. Signs and symptoms of hyperglycemia may include: excessive thirst high urine output increased appetite with weight loss tirednessIf you get hyperglycemia while taking SIGNIFOR, your doctor may give you another medicine to take to lower your blood sugar. Your doctor may also change your dose of SIGNIFOR or ask you to stop taking it.. excessive thirst high urine output increased appetite with weight loss tiredness. have or have had high blood sugar (hyperglycemia) have diabetes have or have had heart problems have history of low levels of potassium or magnesium in your blood have or have had liver problems have or have had gallstones have any other medical conditions are pregnant or plan to become pregnant. SIGNIFOR may harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if SIGNIFOR passes into your breast milk. You and your doctor should decide if you will take SIGNIFOR or breastfeed. You should not do both. medicines to control your heart beat (anti-arrhythmics) medicines that can affect the electrical system of your heart (QT prolongation) medicines to control your blood pressure (such as beta-blockers or calcium channel blockers) medicines to control the electrolyte (such as potassium or magnesium) levels in your blood cyclosporine (Gengraf (R), Neoral (R), Restasis (R), Sandimmune (R)) bromocriptine (Cycloset (R), Parlodel (R)). Read the Instructions for Use at the end of this Medication Guide for information about the right way to use SIGNIFOR. Use SIGNIFOR exactly as your doctor tells you to. Your doctor may change your dose if needed. Before you use SIGNIFOR for the first time, your doctor should do blood test to check your blood sugar levels and your liver tests. Before you use SIGNIFOR for the first time, your doctor should do test to check your heart (electrocardiogram) and your gallbladder (ultrasound). SIGNIFOR should be clear and colorless. Before you inject your dose, check to make sure that SIGNIFOR is clear and colorless, and does not have any clumps or particles in it. SIGNIFOR is given as an injection into the fat just under your skin (subcutaneous injection). Do not inject SIGNIFOR into skin that is red or irritated. The recommended injection sites for SIGNIFOR are the top of your thigh or stomach area (abdomen). Change (rotate) your injection site with each dose. Do not inject SIGNIFOR into the exact same spot for each injection. Your doctor should show you how to prepare and give your dose of SIGNIFOR before you use it for the first time. You should not inject SIGNIFOR until your doctor has shown you how to use it the right way.. See What is the most important information should know about SIGNIFORslow heart rate (bradycardia). SIGNIFOR can cause your heart to beat slower, which may cause you to feel weak, dizzy or even faint. People who have, or have had, heart problems are at higher risk for bradycardia.problems with the electrical system of your heart (QT interval prolongation), which can put you at risk for abnormal heart beats, dizziness, and fainting spells that can be very serious. Call your doctor right away if you experience such spells.elevation of your liver tests. Your doctor should do blood tests to monitor your liver tests while you use SIGNIFOR. gallstones (cholelithiasis) and complications that can happen if you have gallstones. Gallstones are serious but common side effect of SIGNIFOR. Possible complications of gallstones include inflammation and infection of the gallbladder. Your doctor should do test (ultrasound) to check for gallstones before you start using SIGNIFOR and while you use it.Tell your healthcare provider if you get any of these symptoms. sudden pain in your upper right stomach area (abdomen)yellowing of your skin and whites of your eyesnauseasudden pain in your right shoulder or between your shoulder bladesfever with chills slow heart rate (bradycardia). SIGNIFOR can cause your heart to beat slower, which may cause you to feel weak, dizzy or even faint. People who have, or have had, heart problems are at higher risk for bradycardia.. problems with the electrical system of your heart (QT interval prolongation), which can put you at risk for abnormal heart beats, dizziness, and fainting spells that can be very serious. Call your doctor right away if you experience such spells.. elevation of your liver tests. Your doctor should do blood tests to monitor your liver tests while you use SIGNIFOR. gallstones (cholelithiasis) and complications that can happen if you have gallstones. Gallstones are serious but common side effect of SIGNIFOR. Possible complications of gallstones include inflammation and infection of the gallbladder. Your doctor should do test (ultrasound) to check for gallstones before you start using SIGNIFOR and while you use it.Tell your healthcare provider if you get any of these symptoms. sudden pain in your upper right stomach area (abdomen)yellowing of your skin and whites of your eyesnauseasudden pain in your right shoulder or between your shoulder bladesfever with chills sudden pain in your upper right stomach area (abdomen). yellowing of your skin and whites of your eyes. nausea. sudden pain in your right shoulder or between your shoulder blades. fever with chills. diarrhea nausea high blood sugar headache abdominal pain fatigue diabetes mellitus injection-site reactions common cold hair loss weakness fluid retention. Abnormal blood test result for glycosylated hemoglobin (the level of glycosylated hemoglobin indicates the average blood sugar level over the previous months). Store SIGNIFOR at 68F to 77F (20C to 25C). Keep SIGNIFOR out of the light.

USE IN SPECIFIC POPULATIONS SECTION.

8USE 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)See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.. 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 SummaryThe limited data with SIGNIFOR in pregnant women are insufficient to inform 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. DataAnimal DataIn 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 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 nghr/mL, approximately 144 times the exposure in humans at the highest recommended dose of 900 mcg SIGNIFOR administered as subcutaneous injection twice day.In embryo-fetal development studies in rabbits given 0.05, 1, and mg/kg/day subcutaneously through organogenesis, maternal toxicity was observed at mg/kg/day, at maternal systemic exposure (AUC) of 1906 nghr/mL, approximately times higher than the maximum human therapeutic exposure. An increased incidence of unossified forepaw phalanx, indicative of 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 mg/kg/day during 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 SummaryThere 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 mothers clinical need for SIGNIFOR and any potential adverse effects on the breastfed child from SIGNIFOR or from the underlying maternal condition.DataAvailable data in animals have shown excretion of pasireotide in milk. After single 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 reduction or normalization of serum cortisol levels in female patients with Cushings 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), 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 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 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). Hypocortisolism: Decreases in circulating levels of cortisol may occur resulting in biochemical and/or clinical hypocortisolism. SIGNIFOR dose reduction or interruption and/or adding 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). 5.1 Hypocortisolism. Treatment with SIGNIFOR leads to suppression of adrenocorticotropic hormone (ACTH) secretion in Cushings disease. Suppression of ACTH may lead to 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.. 5.2 Hyperglycemia and Diabetes 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. Cushings disease patients with poor glycemic control (HbA1c 8%) may be at higher risk of developing severe hyperglycemia and associated complications, e.g., ketoacidosis.Assess the patients 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 result of SIGNIFOR require closer monitoring after discontinuation of SIGNIFOR, especially if the anti-diabetic therapy has risk of causing hypoglycemia.. 5.3 Bradycardia and QT Prolongation. BradycardiaBradycardia 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 ProlongationSIGNIFOR 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.. 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.. 5.4 Liver Test Elevations. In the Phase III trial, 5% of patients had an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level greater than times the upper limit of normal (ULN). In the entire clinical development program of SIGNIFOR, there were cases of concurrent elevations in ALT greater than x ULN and bilirubin greater than x ULN: one patient with Cushings disease and 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 weeks on treatment, then monthly for months, and every 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 week or within 48 hours if exceeding times ULN. If ALT is abnormal at baseline and elevations of ALT of to times the baseline values are observed on treatment, repeat the test within week or sooner if exceeding times ULN. Tests should be done in 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 times the baseline value in case of abnormal baselines, or 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.. 5.5 Cholelithiasis 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 T4, 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.