Pasireotide

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.

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 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%), type 2 diabetes mellitus (9%). In general, increases in FPG and HbA1c were seen soon after initiation of SIGNIFOR and were sustained during the treatment period. In the SIGNIFOR 0.6 mg group, mean FPG levels increased from 98.6 mg/dL at baseline to 125.1 mg/dL at Month 6. In the SIGNIFOR 0.9 mg group, mean fasting FPG levels increased from 97.0 mg/dL at baseline to 128.0 mg/dL at Month 6. In the SIGNIFOR 0.6 mg group, HbA1c increased from 5.8% at baseline to 7.2% at Month 6. In the SIGNIFOR 0.9 mg group, HbA1c increased from 5.8% at baseline to 7.3% at Month 6 [see Warnings and Precautions (5.2)] . At one-month follow-up visits, following discontinuation of SIGNIFOR, mean FPG and HbA1c levels decreased but remained above baseline values. Long-term follow-up data are not available. Elevated Liver Tests In the Phase III trial, there were transient mean elevations in aminotransferase values in patients treated with SIGNIFOR. Mean values returned to baseline levels by Month 4 of treatment. The elevations were not associated with clinical symptoms of hepatic disease. In the clinical development program of SIGNIFOR, there were 4 patients with concurrent elevations in ALT greater than 3 x ULN and bilirubin greater than 2 x ULN: one patient with Cushing's disease and 3 healthy volunteers [see Warnings and Precautions (5.4)] . In all 4 cases, the elevations were noted within the first 10 days of treatment. In all of these cases, total bilirubin elevations were seen either concomitantly or preceding the transaminase elevation. The patient with Cushing's disease developed jaundice. All 4 cases had resolution of the laboratory abnormalities with discontinuation of SIGNIFOR. Hypocortisolism Cases of hypocortisolism were reported in the Phase III study in Cushing's disease patients [see Adverse Reactions (6), Clinical Studies (14)] . The majority of cases were manageable by reducing the dose of SIGNIFOR and/or adding low-dose, short-term glucocorticoid therapy [see Warnings and Precautions (5.1)] . Injection-Site Reactions Injection-site reactions were reported in 17% of patients enrolled in the Phase III trial in Cushing's disease. The events were most frequently reported as local pain, erythema, hematoma, hemorrhage, and pruritus. These events resolved spontaneously and required no intervention. Thyroid Function Hypothyroidism, with the use of SIGNIFOR, was reported for seven patients participating in the Phase III study in Cushing's disease. All seven patients presented with a TSH close to or below the lower limit at study entry, which precludes establishing a conclusive relationship between the adverse event and the use of SIGNIFOR. Other Abnormal Laboratory Findings Asymptomatic and reversible elevations in lipase and amylase were observed in patients receiving SIGNIFOR in clinical studies. Pancreatitis is a potential adverse reaction associated with the use of somatostatin analogs due to the 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 a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cholelithiasis resulting in complications, including cholecystitis and cholangitis, which have sometimes required cholecystectomy

12.3 Pharmacokinetics In healthy volunteers, pasireotide demonstrates approximately linear pharmacokinetics (PK) for a dose range from 0.0025 to 1.5 mg. In Cushing's disease patients, pasireotide demonstrates linear dose-exposure relationship in a dose range from 0.3 mg to 1.2 mg. Absorption and Distribution In healthy volunteers, pasireotide peak plasma concentration is reached within T max 0.25-0.5 hour. C max 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 a parenteral route. In healthy volunteers, pasireotide is widely distributed with large apparent volume of distribution (V z /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 a 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 a 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 Excretion Pasireotide 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 a small contribution of the renal route. In a 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 Cushing's disease patients is ~7.6 L/h and ~3.8 L/h, respectively. Steady-State Pharmacokinetics Following multiple subcutaneous doses, pasireotide demonstrates linear pharmacokinetics in the dose range of 0.05 to 0.6 mg once a day in healthy volunteers, and 0.3 mg to 1.2 mg twice a day in Cushing's disease patients. Based on the accumulation ratios of AUC, the calculated effective half-life (t 1/2,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 a day doses). Specific Populations Population PK analyses of SIGNIFOR indicate that race, body weight, age, and gender do not have a clinically relevant influence on PK parameters. No dose adjustment is required for demographics. Hepatic Impairment In a clinical study with a 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 B and C) showed significantly higher exposures than subjects with normal hepatic function. Upon comparison with the control group, AUC inf was increased by 12%, 56%, and 42%; and C max 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 Patients No studies have been performed in pediatric patients [see Use in Specific Populations (8.4)] . Geriatric Patients No clinical pharmacology studies have been performed in geriatric patients. Renal Impairment Renal clearance has a minor contribution to the elimination of pasireotide in humans. In a clinical study with a 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 a significant impact on the pharmacokinetics of pasireotide [see Use in Specific Populations (8.7)] . Drug Interaction Studies There was no significant drug interaction between pasireotide and metformin, nateglinide or liraglutide.