See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: 3/2018

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1 HIGHLIGHTS F PRESCRIBING INFRMATIN These highlights d nt include all the infrmatin needed t use SIGNIFR safely and effectively. See full prescribing infrmatin fr SIGNIFR. SIGNIFR (pasiretide) injectin, fr subcutaneus use Initial U.S. Apprval: INDICATINS AND USAGE SIGNIFR is a smatstatin analg indicated fr the treatment f adult patients with Cushing s disease fr whm pituitary surgery is nt an ptin r has nt been curative (1) DSAGE AND ADMINISTRATIN Recmmended initial dsage is either 0.6 mg r 0.9 mg by subcutaneus injectin twice a day; recmmended dsage range is 0.3 mg t 0.9 mg twice a day (2.1) Titrate dsage based n treatment respnse [clinically meaningful reductin in 24-hur urinary free crtisl (UFC) and/r imprvements in signs and symptms f disease] and tlerability (2.1) Testing Prir t Dsing: fasting plasma glucse, hemglbin A1c, liver tests, electrcardigram (ECG), gallbladder ultrasund, and serum ptassium and magnesium levels (2.2) Patients with Hepatic Impairment: Child-Pugh B: Recmmended initial dsage is 0.3 mg twice a day and maximum dsage is 0.6 mg twice a day (2.3, 8.6) Child-Pugh C: Avid use in these patients (2.3, 8.6) DSAGE FRMS AND STRENGTHS Injectin: 0.3 mg/ml, 0.6 mg/ml, and 0.9 mg/ml in a single-dse ampule (3) CNTRAINDICATINS Nne (4) WARNINGS AND PRECAUTINS Hypcrtislism: Decreases in circulating levels f crtisl may ccur resulting in bichemical and/r clinical hypcrtislism. SIGNIFR dse reductin r interruptin and/r adding a lw-dse shrt-term gluccrticid may be necessary (5.1) Hyperglycemia and Diabetes (ccurs with initiatin): Intensive glucse mnitring is recmmended and may require initiatin r adjustment f anti-diabetic treatment per standard f care (5.2) Bradycardia and QT Prlngatin: Use with cautin in at-risk patients; ECG testing prir t dsing and n treatment (5.3, 7.1) Liver Test Elevatins: Evaluate liver tests prir t and during treatment (5.4) Chlelithiasis: Perfrm gallbladder ultrasunds befre starting treatment and at 6-mnth intervals (5.5) ADVERSE REACTINS Mst cmmn adverse reactins ccurring in 20% f patients are diarrhea, nausea, hyperglycemia, chlelithiasis, headache, abdminal pain, fatigue, and diabetes mellitus (6) T reprt SUSPECTED ADVERSE REACTINS, cntact Nvartis Pharmaceuticals Crpratin at r FDA at FDA r DRUG INTERACTINS Drugs that Prlng QT: Use with cautin in patients wh are at significant risk f develping QTc prlngatin (5.3, 7.1) Cyclsprine: Cnsider additinal mnitring (7.2) Brmcriptine: Cnsider brmcriptine dse reductin (7.2) USE IN SPECIFIC PPULATINS Females and Males f Reprductive Ptential: Advise premenpausal females f the ptential fr an unintended pregnancy (8.3) Safety and effectiveness f SIGNIFR in children under 18 years have nt been established (8.4) See 17 fr PATIENT CUNSELING INFRMATIN and Medicatin Guide Revised: 3/2018 FULL PRESCRIBING INFRMATIN: CNTENTS* 1 INDICATINS AND USAGE 1.1 Cushing s Disease 2 DSAGE AND ADMINISTRATIN 2.1 Recmmended Dsage Range 2.2 Recmmendatins Prir t Initiatin f SIGNIFR 2.3 Dsage in Patients with Hepatic Impairment 2.4 Imprtant Administratin Instructins 3 DSAGE FRMS AND STRENGTHS 4 CNTRAINDICATINS 5 WARNINGS AND PRECAUTINS 5.1 Hypcrtislism 5.2 Hyperglycemia and Diabetes 5.3 Bradycardia and QT Prlngatin 5.4 Liver Test Elevatins 5.5 Chlelithiasis 5.6 Mnitring fr Deficiency f Pituitary Hrmnes 6 ADVERSE REACTINS 6.1 Clinical Trials Experience 7 DRUG INTERACTINS 7.1 Effects f ther Drugs n SIGNIFR 7.2 Effects f SIGNIFR n ther Drugs 8 USE IN SPECIFIC PPULATINS 8.1 Pregnancy 8.2 Lactatin 8.3 Females and Males f Reprductive Ptential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 VERDSAGE 11 DESCRIPTIN 12 CLINICAL PHARMACLGY 12.1 Mechanism f Actin 12.2 Pharmacdynamics 12.3 Pharmackinetics 13 NNCLINICAL TXICLGY 13.1 Carcingenesis, Mutagenesis, Impairment f Fertility 14 CLINICAL STUDIES 16 HW SUPPLIED/STRAGE AND HANDLING 17 PATIENT CUNSELING INFRMATIN * Sectins r subsectins mitted frm the full prescribing infrmatin are nt listed

2 FULL PRESCRIBING INFRMATIN 1 INDICATINS AND USAGE 1.1 Cushing s Disease SIGNIFR is indicated fr the treatment f adult patients with Cushing s disease fr whm pituitary surgery is nt an ptin r has nt been curative. 2 DSAGE AND ADMINISTRATIN 2.1 Recmmended Dsage Range The recmmended dsage range f SIGNIFR is 0.3 t 0.9 mg by subcutaneus injectin twice a day. The recmmended initial dse is either 0.6 mg r 0.9 mg twice a day. Titrate dse based n respnse and tlerability. Patients shuld be evaluated fr a treatment respnse [clinically meaningful reductin in 24-hur urinary free crtisl (UFC) levels and/r imprvement in signs r symptms f the disease] and shuld cntinue receiving therapy with SIGNIFR as lng as benefit is derived [see Clinical Studies (14)]. Maximum urinary free crtisl reductin is typically seen by tw mnths f treatment [see Clinical Studies (14)]. Fr patients wh are started n 0.6 mg twice a day, a dsage increase t 0.9 mg twice a day may be cnsidered based n the respnse t the treatment, as lng as the 0.6 mg dsage is well tlerated by the patient. Management f suspected adverse reactins may require temprary dse reductin f SIGNIFR. Dse reductin by 0.3 mg decrements per injectin is suggested. 2.2 Recmmendatins Prir t Initiatin f SIGNIFR Prir t the start f SIGNIFR, patients shuld have baseline levels f the fllwing: fasting plasma glucse [see Warnings and Precautins (5.2)] hemglbin A1c [see Warnings and Precautins (5.2)] liver tests [see Warnings and Precautins (5.4)] serum ptassium and magnesium levels [see Warnings and Precautins (5.3)] Patients shuld als have a baseline electrcardigram and gallbladder ultrasund [see Warnings and Precautins (5.3, 5.5)]. Treatment f patients with prly cntrlled diabetes mellitus shuld be intensively ptimized with anti-diabetic therapy prir t starting SIGNIFR [see Warnings and Precautins (5.2)]. 2.3 Dsage in Patients with Hepatic Impairment Fr patients with mderate hepatic impairment (Child-Pugh B), the recmmended initial dsage is 0.3 mg twice a day and the maximum dsage is 0.6 mg twice a day. Avid the use f SIGNIFR in patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Ppulatins (8.6)]. 2.4 Imprtant Administratin Instructins Instruct patients t: Refer t the FDA-apprved patient labeling (Instructins fr Use) fr detailed administratin instructins. Prir t injectin, visually inspect the prduct fr particulate matter and disclratin. D nt use if particulates and/r disclratin are bserved. Avid injectin in sites shwing signs f inflammatin r irritatin. Prir t injectin, gently pinch the skin at the injectin site and hld the needle/syringe at an angle f apprximately 45 degrees. Administer SIGNIFR subcutaneusly by self-injectin int the tp f the thigh r the abdmen.

3 Avid multiple subcutaneus injectins at the same site within shrt perids f time. Use f the same injectin site fr tw cnsecutive injectins is nt recmmended. If a dse f SIGNIFR is missed, the next injectin shuld be administered at the scheduled time. D nt duble dses t make up fr a missed dse. 3 DSAGE FRMS AND STRENGTHS Injectin: 0.3 mg/ml, 0.6 mg/ml, and 0.9 mg/ml in a single-dse, 1 ml clrless glass ampule. 4 CNTRAINDICATINS Nne. 5 WARNINGS AND PRECAUTINS 5.1 Hypcrtislism Treatment with SIGNIFR leads t suppressin f adrencrtictrpic hrmne (ACTH) secretin in Cushing s disease. Suppressin f ACTH may lead t a decrease in circulating levels f crtisl and ptentially hypcrtislism. Mnitr and instruct patients n the signs and symptms assciated with hypcrtislism (e.g., weakness, fatigue, anrexia, nausea, vmiting, hyptensin, hypnatremia r hypglycemia). If hypcrtislism ccurs, cnsider temprary dse reductin r interruptin f treatment with SIGNIFR, as well as temprary, exgenus gluccrticid replacement therapy. 5.2 Hyperglycemia and Diabetes Elevatins in bld glucse levels have been seen in healthy vlunteers and patients treated with SIGNIFR. In the Phase III trial, the develpment f pre-diabetes and diabetes was bserved [see Clinical Studies (14)]. In this trial, nearly all patients including thse with nrmal glucse status at baseline, pre-diabetes, and diabetes develped wrsening glycemia in the first tw weeks f treatment. Cushing s disease patients with pr glycemic cntrl (as defined by HbA1c values >8% while receiving anti-diabetic therapy) may be at a higher risk f develping severe hyperglycemia and assciated cmplicatins, e.g., ketacidsis. Because f this predictable adverse reactin, the glycemic status [fasting plasma glucse (FPG) r hemglbin A1c (HbA1c)] shuld be assessed prir t starting treatment with SIGNIFR. In patients with uncntrlled diabetes mellitus intensive anti-diabetic therapy shuld be ptimized prir t treatment with SIGNIFR. Self-mnitring f bld glucse and/r FPG assessments shuld be dne every week fr the first tw t three mnths and peridically thereafter, as clinically apprpriate, as well as ver the first tw t fur weeks after any dse increase. After treatment discntinuatin, glycemic mnitring (e.g., FPG r HbA1c) shuld be dne accrding t clinical practice. Patients wh were initiated n anti-diabetic therapy as a result f SIGNIFR may require clser mnitring after discntinuatin f SIGNIFR, especially if the anti-diabetic therapy has a risk f causing hypglycemia. If hyperglycemia develps in a patient treated with SIGNIFR, the initiatin r adjustment f anti-diabetic treatment per standard f care is recmmended. The ptimal treatment fr the management f SIGNIFR-induced hyperglycemia is nt knwn. If uncntrlled hyperglycemia persists, despite apprpriate medical management, the dse f SIGNIFR shuld be reduced r discntinued. 5.3 Bradycardia and QT Prlngatin Bradycardia Bradycardia has been reprted with the use f SIGNIFR [see Adverse Reactins (6)]. Patients with cardiac disease and/r risk factrs fr bradycardia, such as histry f clinically significant bradycardia, high-grade heart blck, r cncmitant use f drugs assciated with bradycardia, shuld be carefully mnitred. Dse adjustments f beta-blckers, calcium channel blckers, r crrectin f electrlyte disturbances may be necessary. QT Prlngatin SIGNIFR is assciated with QT prlngatin. In tw thrugh QT studies with SIGNIFR, QT prlngatin ccurred at therapeutic and supra-therapeutic dses. SIGNIFR shuld be used with cautin in patients wh are at significant risk f develping prlngatin f QTc, such as thse: with cngenital lng QT prlngatin.

4 with uncntrlled r significant cardiac disease including recent mycardial infarctin, cngestive heart failure, unstable angina r clinically significant bradycardia. n anti-arrhythmic therapy r ther substances that are knwn t lead t QT prlngatin. with hypkalemia and/r hypmagnesemia. A baseline ECG is recmmended prir t initiating therapy with SIGNIFR and mnitring fr an effect n the QTc interval is advisable. Hypkalemia and hypmagnesemia must be crrected prir t SIGNIFR administratin and shuld be mnitred peridically during therapy. 5.4 Liver Test Elevatins In the Phase III trial, 5% f patients had an ALT r AST level greater than 3 times the upper limit f nrmal (ULN). In the entire clinical develpment prgram f SIGNIFR, there were 4 cases f cncurrent elevatins in ALT (alanine amintransferase) greater than 3 x ULN and bilirubin greater than 2 x ULN: ne patient with Cushing s disease and three healthy vlunteers [see Adverse Reactins (6)]. In these cases, ttal bilirubin elevatins were seen either cncmitantly r preceding the transaminase elevatin. Mnitring f liver tests shuld be dne after 1 t 2 weeks n treatment, then mnthly fr 3 mnths, and every 6 mnths thereafter. If ALT is nrmal at baseline and elevatins f ALT f 3-5 times the ULN are bserved n treatment, repeat the test within a week r within 48 hurs if exceeding 5 times ULN. If ALT is abnrmal at baseline and elevatins f ALT f 3-5 times the baseline values are bserved n treatment, repeat the test within a week r sner if exceeding 5 times ULN. Tests shuld be dne in a labratry that can prvide same-day results. If the values are cnfirmed r rising, interrupt SIGNIFR treatment and investigate fr prbable cause f the findings, which may r may nt be SIGNIFR-related. Serial measures f ALT, aspartate amintransferase, alkaline phsphatase, and ttal bilirubin, shuld be dne weekly, r mre frequently, if any value exceeds 5 times the baseline value in case f abnrmal baselines r 5 times the ULN in case f nrmal baselines. If reslutin f abnrmalities t nrmal r near nrmal ccurs, resuming treatment with SIGNIFR may be dne cautiusly, with clse bservatin, and nly if sme ther likely cause has been fund. 5.5 Chlelithiasis Chlelithiasis has been frequently reprted in clinical studies with SIGNIFR [see Adverse Reactins (6)]. Ultrasnic examinatin f the gallbladder befre, and at 6- t 12-mnth intervals during SIGNIFR therapy is recmmended. 5.6 Mnitring fr Deficiency f Pituitary Hrmnes As the pharmaclgical activity f SIGNIFR mimics that f smatstatin, inhibitin f pituitary hrmnes, ther than ACTH, may ccur. Mnitring f pituitary functin (e.g., TSH/free T 4, GH/IGF-1) shuld ccur prir t initiatin f therapy with SIGNIFR and peridically during treatment shuld be cnsidered as clinically apprpriate. Patients wh have undergne transsphenidal surgery and pituitary irradiatin are particularly at increased risk fr deficiency f pituitary hrmnes. 6 ADVERSE REACTINS Clinically significant adverse reactins that appear in ther sectins f the labeling include: Hypcrtislism [see Warnings and Precautins (5.1)] Hyperglycemia and Diabetes [see Warnings and Precautins (5.2)] Bradycardia and QT prlngatin [see Warnings and Precautins (5.3)] Liver Test Elevatins [see Warnings and Precautins (5.4)] Chlelithiasis [see Warnings and Precautins (5.5)] Pituitary Hrmne Deficiency [see Warnings and Precautins (5.6)] 6.1 Clinical Trials Experience Because clinical trials are cnducted under widely varying cnditins, adverse reactin rates bserved in clinical trials f a drug cannt be directly cmpared t rates in clinical trials f anther drug and may nt reflect the rates bserved in practice.

5 A ttal f 162 Cushing s disease patients were expsed t SIGNIFR in the Phase III study [see Clinical Studies (14)]. At study entry, patients were randmized t receive twice a day (b.i.d.) dses f either 0.6 mg r 0.9 mg f SIGNIFR given subcutaneusly. The mean age f patients was apprximately 40 years ld with a predminance f female patients (78%). The majrity f the patients had persistent r recurrent Cushing s disease (83%) and few patients ( 5%) in either treatment grup had received previus pituitary irradiatin. The median expsure t the treatment was 10.4 mnths ( ) with 68% f patients having at least six-mnths expsure. In the Phase III trial, adverse reactins were reprted in 98% f patients. The mst cmmn adverse reactins (frequency 20% in either grup) were diarrhea, nausea, hyperglycemia, chlelithiasis, headache, abdminal pain, fatigue, and diabetes mellitus. There were n deaths during the study. Serius adverse events were reprted in 25% f patients. Adverse events leading t study discntinuatin were reprted in 17% f patients. Adverse reactins with an verall frequency higher than 5% are presented in Table 1 by randmized dse grup and verall. Adverse reactins are ranked by frequency, with the mst frequent reactins listed first. Table 1 - Adverse reactins [n (%)] with an verall frequency f mre than 5% in the cmbined dse grup in the Phase III study in Cushing s disease patients SIGNIFR 0.6 mg bid N=82 SIGNIFR 0.9 mg bid N=80 verall N=162 Diarrhea 48 (59) 46 (58) 94 (58) Nausea 38 (46) 46 (58) 84 (52) Hyperglycemia 31 (38) 34 (43) 65 (40) Chlelithiasis 25 (30) 24 (30) 49 (30) Headache 23 (28) 23 (29) 46 (28) Abdminal pain 19 (23) 20 (25) 39 (24) Fatigue 12 (15) 19(24) 31 (19) Diabetes mellitus 13 (16) 16 (20) 29 (18) Injectin site reactins 14 (17) 14 (18) 28 (17) Naspharyngitis 10 (12) 11 (14) 21 (13) Alpecia 10 (12) 10 (13) 20 (12) Asthenia 13 (16) 5 (6) 18 (11) Glycsylated hemglbin increased 10 (12) 8 (10) 18 (11) Alanine amintransferase increased 11 (13) 6 (8) 17 (10) Gamma-glutamyl transferase 10 (12) 7 (9) 17 (10) increased Edema peripheral 9 (11) 8 (10) 17 (10) Abdminal pain upper 10 (12) 6 (8) 16 (10) Decreased appetite 7 (9) 9 (11) 16 (10) Hyperchlesterlemia 7 (9) 9 (11) 16 (10) Hypertensin 8 (10) 8 (10) 16 (10) Dizziness 8 (10) 7 (9) 15 (9) Hypglycemia 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) Insmnia 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) Cnstipatin 7 (9) 4 (5) 11 (7)

6 Hyptensin 5 (6) 6 (8) 11 (7) Vmiting 3 (4) 8 (10) 11 (7) Back pain 4 (5) 6 (8) 10 (6) Dry skin 5 (6) 5 (6) 10 (6) Electrcardigram QT prlnged 5 (6) 5 (6) 10 (6) Hypkalemia 6 (7) 4 (5) 10 (6) Pain in extremity 6 (7) 4 (5) 10 (6) Sinus bradycardia 8 (10) 2 (3) 10 (6) Vertig 4 (5) 6 (8) 10 (6) Abdminal distensin 4 (5) 5 (6) 9 (6) Adrenal insufficiency 4 (5) 5 (6) 9 (6) Aspartate amintransferase increased 6 (7) 3 (4) 9 (6) Bld glucse increased 6 (7) 3 (4) 9 (6) ther ntable adverse reactins which ccurred with a frequency less than 5% were: anemia (4%); bld amylase increased (2%) and prthrmbin time prlnged (2%). Gastrintestinal Disrders Gastrintestinal disrders, predminantly diarrhea, nausea, abdminal pain and vmiting were reprted frequently in the Phase III trial (see Table 1). These events began t develp primarily during the first mnth f treatment with SIGNIFR and required n interventin. Hyperglycemia and Diabetes Hyperglycemia-related terms were reprted frequently in the Phase III trial. Fr all patients, these terms included: hyperglycemia (40%), diabetes mellitus (18%), increased HbA1c (11%), and type 2 diabetes mellitus (9%). In general, increases in fasting plasma glucse (FPG) and hemglbin A1c (HbA1c) were seen sn after initiatin f SIGNIFR and were sustained during the treatment perid. In the SIGNIFR 0.6 mg grup, mean fasting plasma glucse (FPG) levels increased frm 98.6 mg/dl at baseline t mg/dl at Mnth 6. In the SIGNIFR 0.9 mg grup, mean fasting plasma glucse (FPG) levels increased frm 97.0 mg/dl at baseline t mg/dl at Mnth 6. In the SIGNIFR 0.6 mg grup, HbA1c increased frm 5.8% at baseline t 7.2% at Mnth 6. In the SIGNIFR 0.9 mg grup, HbA1c increased frm 5.8% at baseline t 7.3% at Mnth 6 [see Warning and Precautins (5.2)]. At ne-mnth fllw-up visits fllwing discntinuatin f SIGNIFR, mean FPG and HbA1c levels decreased but remained abve baseline values. Lng-term fllw-up data are nt available. Elevated Liver Tests In the Phase III trial, there were transient mean elevatins in amintransferase values in patients treated with SIGNIFR. Mean values returned t baseline levels by Mnth 4 f treatment. The elevatins were nt assciated with clinical symptms f hepatic disease. In the clinical develpment prgram f SIGNIFR, there were 4 patients with cncurrent elevatins in ALT greater than 3 x ULN and bilirubin greater than 2 x ULN: ne patient with Cushing s disease and three healthy vlunteers [see Warnings and Precautins (5.4)]. In all fur cases, the elevatins were nted within the first 10 days f treatment. In all f these cases, ttal bilirubin elevatins were seen either cncmitantly r preceding the transaminase elevatin. The patient with Cushing s disease develped jaundice. All fur cases had reslutin f the labratry abnrmalities with discntinuatin f SIGNIFR. Hypcrtislism Cases f hypcrtislism were reprted in the Phase III study in Cushing s disease patients [see Adverse Reactins (6) and Clinical Studies (14)]. The majrity f cases were manageable by reducing the dse f SIGNIFR and/r adding lw-dse, shrt-term gluccrticid therapy [see Warnings and Precautins (5.1)].

7 Injectin Site Reactins Injectin site reactins were reprted in 17% f patients enrlled in the Phase III trial in Cushing s disease. The events were mst frequently reprted as lcal pain, erythema, hematma, hemrrhage, and pruritus. These events reslved spntaneusly and required n interventin. Thyrid Functin Hypthyridism with the use f SIGNIFR was reprted fr seven patients participating in the Phase III study in Cushing s disease. All seven patients presented with a TSH clse t r belw the lwer limit at study entry which precludes establishing a cnclusive relatinship between the adverse event and the use f SIGNIFR. ther Abnrmal Labratry Findings Asymptmatic and reversible elevatins in lipase and amylase were bserved in patients receiving SIGNIFR in clinical studies. Pancreatitis is a ptential adverse reactin assciated with the use f smatstatin analgs due t the assciatin between chlelithiasis and acute pancreatitis. Fr hemglbin levels, mean decreases that remained within nrmal range were bserved. Als, pst-baseline elevatins in PT and PTT were nted in 33% and 47% f patients, respectively. The PT and PTT elevatins were minimal. These labratry findings are f unclear clinical significance. 7 DRUG INTERACTINS 7.1 Effects f ther Drugs n SIGNIFR Drugs that Prlng QT C-administratin f drugs that prlng the QT interval with SIGNIFR may have additive effects n the prlngatin f the QT interval. Cautin is required when c-administering SIGNIFR with drugs that may prlng the QT interval [see Warnings and Precautins (5.3)]. 7.2 Effects f SIGNIFR n ther Drugs Cyclsprine Cncmitant administratin f cyclsprine with pasiretide may decrease the relative biavailability f cyclsprine and, therefre, dse adjustment f cyclsprine t maintain therapeutic levels may be necessary. Brmcriptine C-administratin f smatstatin analgues with brmcriptine may increase the bld levels f brmcriptine. Dse reductin f brmcriptine may be necessary. 8 USE IN SPECIFIC PPULATINS 8.1 Pregnancy Risk Summary The limited data with SIGNIFR in pregnant wmen are insufficient t infrm a drug-assciated risk fr majr birth defects and miscarriage. In embryfetal develpment studies in rabbits, findings indicating develpmental delay were bserved with subcutaneus administratin f pasiretide during rgangenesis at dses less than the expsure in humans at the highest recmmended dse; maternal txicity was nt bserved at this dse [see Data]. The estimated backgrund risk f majr birth defects and miscarriage fr the indicated ppulatin is unknwn. In the U.S. general ppulatin, the estimated backgrund risk f majr birth defects and miscarriage in clinically recgnized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In embryfetal develpment studies in rats given 1, 5, and 10 mg/kg/day subcutaneusly thrughut rgangenesis, maternal txicity was bserved at all dses, including the lwest dse tested which had expsures 4 times higher than that at the maximum therapeutic dse based n AUC cmparisns acrss species. An increased incidence f early/ttal

8 resrptins and malrtated limbs was bserved in rats at 10 mg/kg/day. At 10 mg/kg/day in rats, the maternal systemic expsure (AUC) was ng*hr/ml, apprximately 144 times the expsure in humans at the highest recmmended dse f 900 µg SIGNIFR administered as a subcutaneus injectin twice a day. In embryfetal develpment studies in rabbits given 0.05, 1, and 5 mg/kg/day subcutaneusly thrugh rgangenesis, maternal txicity was bserved at 1 mg/kg/day, at a maternal systemic expsure (AUC) f 1906 ng*hr/ml, apprximately 7 times higher than the maximum human therapeutic expsure. An increased incidence f unssified frepaw phalanx, indicative f a develpmental retardatin, was bserved in rabbits at 0.05 mg/kg/day, with maternal systemic expsures less than the systemic expsure in humans at the highest recmmended dse. In pre- and pst-natal develpmental studies in rats given subcutaneus dses f 2, 5, and 10 mg/kg/day during gestatin thrugh lactatin and weaning, maternal txicity was bserved at all dses including the lwest dse (12 times higher than the maximum therapeutic dse based n surface area cmparisns acrss species). Retardatin f physilgical grwth, attributed t GH inhibitin was bserved at 2 mg/kg/day during a pre- and pst-natal study in rats. After weaning, bdy weight gains in the rat pups (F1 generatin) expsed t pasiretide were cmparable t cntrls, shwing reversibility f this develpmental delay. 8.2 Lactatin Risk Summary There is n infrmatin available n the presence f SIGNIFR in human milk, the effects f the drug n the breastfed infant, r the effects f the drug n milk prductin. Studies shw that pasiretide administered subcutaneusly passes int the milk f lactating rats; hwever, due t species-specific differences in lactatin physilgy, animal data may nt reliably predict drug levels in human milk [see Data]. The develpmental and health benefits f breastfeeding shuld be cnsidered alng with the mther s clinical need fr SIGNIFR and any ptential adverse effects n the breastfed child frm SIGNIFR r frm the underlying maternal cnditin. Data Available data in animals have shwn excretin f pasiretide in milk. After a single 1 mg/kg [ 14 C]-pasiretide subcutaneus dse t lactating rats, the transfer f radiactivity int milk was bserved. The verall milk:plasma (M/P) expsure rati f ttal radiactivity was 0.28, based n AUC 0- values. 8.3 Females and Males f Reprductive Ptential Discuss the ptential fr unintended pregnancy with premenpausal wmen as the therapeutic benefits f a reductin r nrmalizatin f serum crtisl levels in female patients with Cushing s disease treated with pasiretide may lead t imprved fertility. 8.4 Pediatric Use Safety and effectiveness f SIGNIFR have nt been established in pediatric patients. 8.5 Geriatric Use Clinical studies f SIGNIFR did nt include sufficient numbers f patients aged 65 and ver t determine whether they respnd differently frm yunger patients. ther reprted clinical experience has nt identified differences in respnses between the elderly and yunger patients. In general, dse selectin fr an elderly patient shuld be cautius, usually starting at the lw end f the dsing range, reflecting the greater frequency f decreased hepatic, renal, r cardiac functin, and cncmitant disease r ther drug therapy [see Clinical Pharmaclgy (12.3)]. 8.6 Hepatic Impairment Dse adjustment is nt required in patients with mild impaired hepatic functin (Child-Pugh A), but is required fr patients with mderately impaired hepatic functin (Child-Pugh B) [see Dsage and Administratin (2.3) and Clinical Pharmaclgy (12.3)]. Avid the use f SIGNIFR in patients with severe hepatic impairment (Child-Pugh C). 8.7 Renal Impairment N dsage adjustment f SIGNIFR in patients with impaired renal functin is required [see Clinical Pharmaclgy (12.3)].

9 10 VERDSAGE N cases f verdsage have been reprted in patients with Cushing s disease receiving SIGNIFR subcutaneusly. Dses up t 2.1 mg b.i.d. have been used in healthy vlunteers with adverse reactins f diarrhea being bserved at a high frequency. In the event f verdsage, it is recmmended that apprpriate supprtive treatment be initiated, as dictated by the patient s clinical status, until reslutin f the symptms. Up-t-date infrmatin abut the treatment f verdse can be btained frm a certified Reginal Pisn Center. 11 DESCRIPTIN SIGNIFR (pasiretide) injectin is prepared as a sterile slutin f pasiretide diaspartate in a tartaric acid buffer fr administratin by subcutaneus injectin. SIGNIFR is a smatstatin analg. Pasiretide diaspartate, chemically knwn as (2-Aminethyl) carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminbutyl)-5-benzyl-8-(4-benzylxybenzyl)-14- (1H-indl-3-ylmethyl)-4,7,10,13,16,19-hexax-17-phenylctadecahydr-3a,6,9,12,15,18- hexaazacyclpentacyclctadecen-2-yl ester, di[(s)-2-aminsuccinic acid] salt, is a cyclhexapeptide with pharmaclgic prperties mimicking thse f the natural hrmne smatstatin. The mlecular frmula f pasiretide diaspartate is C 58H 66N C 4H 7N 4 and the mlecular weight is The structural frmula is: N H 2 H N N N H N H H N H N HN N H NH 2 N H 2 H H H H 2 N H SIGNIFR is supplied as a sterile slutin in a single-dse, 1 ml clrless glass ampule cntaining pasiretide in 0.3 mg/ml, 0.6 mg/ml, r 0.9 mg/ml strengths fr subcutaneus injectin. Each glass ampule cntains: 0.3 mg 0.6 mg 0.9 mg Pasiretide diaspartate * * * Mannitl Tartaric acid Sdium hydrxide ad ph 4.2 ad ph 4.2 ad ph 4.2 Water fr injectin ad 1 ml ad 1 ml ad 1 ml * crrespnds t 0.3/0.6/0.9 mg pasiretide base Nte: Each ampule cntains an verfill f 0.1 ml t allw accurate administratin f 1 ml frm the ampule.

10 12 CLINICAL PHARMACLGY 12.1 Mechanism f Actin SIGNIFR is an injectable cyclhexapeptide smatstatin analgue. Pasiretide exerts its pharmaclgical activity via binding t smatstatin receptrs (SSTRs). Five human smatstatin receptr subtypes are knwn: SSTR 1, 2, 3, 4, and 5. These receptr subtypes are expressed in different tissues under nrmal physilgical cnditins. Crtictrph tumr cells frm Cushing s disease patients frequently ver-express SSTR5 whereas the ther receptr subtypes are ften nt expressed r are expressed at lwer levels. Pasiretide binds and activates the SSTRs resulting in inhibitin f ACTH secretin, which leads t decreased crtisl secretin. The binding affinities f endgenus smatstatin and pasiretide are shwn in Table 2. Table 2- Binding affinities f smatstatin (SRIF-14) and pasiretide t the five human smatstatin receptr subtypes (SSTR1-5) Cmpund SSTR1 SSTR2 SSTR3 SSTR4 SSTR5 Smatstatin (SRIF-14) 0.93± ± ± ± ±0.04 Pasiretide > Results are the mean±sem f IC 50 values expressed as nml/l 12.2 Pharmacdynamics Glucse Metablism In a randmized, duble-blind mechanism study cnducted in healthy vlunteers, the develpment f hyperglycemia with pasiretide at dses f 0.6 mg b.i.d. and 0.9 mg b.i.d. was related t significant decreases in insulin secretin as well as incretin hrmnes (i.e., glucagn-like peptide-1 [GLP-1] and glucse-dependent insulintrpic plypeptide [GIP]) [see Warnings and Precautins (5.2) and Adverse Reactins (6.1)]. Cardiac Electrphysilgy QTcI interval was evaluated in a randmized, blinded, crssver study in healthy subjects investigating pasiretide dses f 0.6 mg b.i.d. and 1.95 mg b.i.d. The maximum mean (95% upper cnfidence bund) placeb-subtracted QTcI change frm baseline was 12.7 (14.7) ms and 16.6 (18.6) ms, respectively. Bth pasiretide dses decreased heart rate, with a maximum mean (95% lwer cnfidence bund) placeb-subtracted change frm baseline f (-11.9) beats per minute (bpm) bserved at 1.5 hurs fr pasiretide 0.6 mg bid, and (-16.5) bpm at 0.5 hurs fr pasiretide 1.95 mg b.i.d. The supra-therapeutic dse (1.95 mg b.i.d) prduced mean steady-state C max values 3.3-fld the mean C max fr the 0.6 mg b.i.d dse in the study Pharmackinetics In healthy vlunteers, pasiretide demnstrates apprximately linear pharmackinetics (PK) fr a dse range frm t 1.5 mg. In Cushing s disease patients, pasiretide demnstrates linear dse-expsure relatinship in a dse range frm 0.3 t 1.2 mg. Absrptin and Distributin In healthy vlunteers, pasiretide peak plasma cncentratin is reached within T max hur. C max and AUC are dse-prprtinal fllwing administratin f single and multiple dses. N studies have been cnducted t evaluate the abslute biavailability f pasiretide in humans. Fd effect is unlikely t ccur since SIGNIFR is administered via a parenteral rute. In healthy vlunteers, pasiretide is widely distributed with large apparent vlume f distributin (V z/f > 100 L). Distributin between bld and plasma is cncentratin independent and shws that pasiretide is primarily lcated in the plasma (91%). Plasma prtein binding is mderate (88%) and independent f cncentratin. Pasiretide has lw passive permeability and is likely t be a substrate f P-gp (P-glycprtein), but the impact f P-gp n ADME (absrptin, distributin, metablism, excretin) f pasiretide is expected t be lw. In clinical testing in healthy vlunteers, P-gp inhibitin (e.g., verapamil) did nt affect the rate r extent f pasiretide availability. Pasiretide is nt a substrate f efflux transprter BCRP (breast cancer resistance prtein), influx transprter CT1 (rganic catin transprter 1), r influx transprters ATP (rganic anin-transprting plypeptide) 1B1, 1B3, r 2B1.

11 Metablism and Excretin Pasiretide was shwn t be metablically stable in human liver and kidney micrsmes systems. In healthy vlunteers, pasiretide in its unchanged frm is the predminant frm fund in plasma, urine, and feces. Smatrpin may increase CYP450 enzymes and, therefre, suppressin f grwth hrmne secretin by smatstatin analgs including pasiretide may decrease the metablic clearance f cmpunds metablized by CYP450 enzymes. Pasiretide is eliminated mainly via hepatic clearance (biliary excretin) with a small cntributin f the renal rute. In a human ADME study 55.9 ± 6.63% f the radiactivity dse was recvered ver the first 10 days pst dsing, including 48.3 ± 8.16% f the radiactivity in feces and 7.63 ± 2.03% in urine. The clearance (CL/F) f pasiretide in healthy vlunteers and Cushing s disease patients is ~7.6 L/h and ~3.8 L/h, respectively. Steady-state Pharmackinetics: Fllwing multiple subcutaneus dses, pasiretide demnstrates linear pharmackinetics in the dse range f 0.05 t 0.6 mg nce a day in healthy vlunteers, and 0.3 mg t 1.2 mg twice a day in Cushing s disease patients. Based n the accumulatin ratis f AUC, the calculated effective half-life (t 1/2,eff) in healthy vlunteers was apprximately 12 hurs (n average between 10 and 13 hurs fr 0.05, 0.2 and 0.6 mg nce a day dses). Specific Ppulatins: Ppulatin PK analyses f SIGNIFR indicate that race, bdy weight, age, and gender d nt have a clinically relevant influence n PK parameters. N dse adjustment is required fr demgraphics. Hepatic Impairment In a clinical study with a single subcutaneus dse f 600 µg pasiretide in subjects with impaired hepatic functin (Child-Pugh A, B and C), subjects with mderate and severe hepatic impairment (Child-Pugh B and C) shwed significantly higher expsures than subjects with nrmal hepatic functin. Upn cmparisn with the cntrl grup, AUC inf was increased by 12%, 56% and 42% and C max increased by 3%, 46% and 33%, respectively, in the mild, mderate and severe hepatic impairment grups [see Use in Specific Ppulatins (8.6) and Dsage and Administratin (2.3)]. Pediatric Patients N studies have been perfrmed in pediatric patients [see Use in Specific Ppulatins (8.4)]. Geriatric Patients N clinical pharmaclgy studies have been perfrmed in geriatric patients. Renal Impairment Renal clearance has a minr cntributin t the eliminatin f pasiretide in humans. In a clinical study with a single subcutaneus dse f 900 µg pasiretide in subjects with impaired renal functin, renal impairment f mild, mderate, r severe degree r end stage renal failure did nt have a significant impact n the pharmackinetics f pasiretide [see Use in Specific Ppulatins (8.7)]. Drug Interactin Studies There was n significant drug interactin between pasiretide and metfrmin, nateglinide r liraglutide. 13 NNCLINICAL TXICLGY 13.1 Carcingenesis, Mutagenesis, Impairment f Fertility Carcingenesis A life-time carcingenicity study was cnducted in rats and transgenic mice. Rats were given daily subcutaneus dses f pasiretide at 0.01, 0.05, 0.3 mg/kg/day fr 104 weeks. There were n drug-related tumrs in rats at expsures up t 7- fld higher than the maximum recmmended clinical expsure at the 1.8 mg/day dse. Mice were given subcutaneus dses f pasiretide at 0.5, 1.0, 2.5 mg/kg/day fr 26 weeks and did nt identify any carcingenic ptential.

12 Mutagenesis Pasiretide was nt gentxic in a battery f in vitr assays (Ames mutatin test in Salmnella and Escherichia cli and mutatin test in human peripheral lymphcytes). Pasiretide was nt gentxic in an in viv rat bne marrw nucleus test. Impairment f Fertility Subcutaneus dsing at 0.1 mg/kg/day befre mating and cntinuing int gestatin in rats at expsures less than the human clinical expsure based n bdy surface area cmparisns acrss species resulted in statistically significant increased implantatin lss and decreased viable fetuses, crpra lutea, and implantatin sites. Abnrmal cycles r acyclicity were bserved at 1 mg/kg/day (5-fld higher than the maximum therapeutic expsure based n surface area, cmparisns acrss species). 14 CLINICAL STUDIES A Phase III, multicenter, randmized study was cnducted t evaluate the safety and efficacy f tw dse levels f SIGNIFR ver a 6-mnth treatment perid in Cushing s disease patients with persistent r recurrent disease despite pituitary surgery r de nv patients fr whm surgery was nt indicated r wh had refused surgery. Patients with a baseline 24-hur urine free crtisl (UFC) >1.5 x upper limit f nrmal (ULN) were randmized t receive a SIGNIFR dsage f either 0.6 mg subcutaneus b.i.d. r 0.9 mg subcutaneus b.i.d. After three mnths f treatment, patients with a mean 24-hur UFC 2.0 x ULN and belw r equal t their baseline values cntinued blinded treatment at the randmized dse until Mnth 6. Patients wh did nt meet these criteria were unblinded and the dse was increased by 0.3 mg b.i.d. After the initial six mnths in the study, patients entered an additinal 6-mnth pen-label treatment perid. The dsage culd be reduced by 0.3 mg b.i.d. at any time during the study fr intlerability. A ttal f 162 patients were enrlled in this study. The majrity f patients were female (78%) and had persistent r recurrent Cushing s disease despite pituitary surgery (83%) with a mean age f 40 years. A few patients (4%) in either treatment grup received previus pituitary irradiatin. The median value f the baseline 24-hur UFC fr all patients was 565 nml/24 hurs (nrmal range 30 t 145 nml/24 hurs). Abut tw-thirds f all randmized patients cmpleted six mnths f treatment. The primary efficacy endpint was the prprtin f patients wh achieved nrmalizatin f mean 24-hur UFC levels after six mnths f treatment and did nt dse increase during this perid. 24-Hur Urinary Free Crtisl Results At Mnth 6, the percentages f respnders fr the primary endpint were 15% and 26% in the 0.6 mg b.i.d. and 0.9 mg b.i.d. grups, respectively (Table 3). The percentages f patients with mufc ULN r 50% reductin frm baseline, a less stringent endpint than the primary endpint, were 34% in the 0.6 mg bid and 41% in the 0.9 mg bid grups. Dse increases appeared t have minimal effect n 24-hur UFC respnse. Mean and median percentage changes in UFC frm baseline are presented in Table 3.

13 Table 3 24-Hur Urinary Free Crtisl (UFC) Study Results at Mnth 6 in Patients with Cushing s Disease UFC Respnders n/n % (95% CI) SIGNIFR 0.6 mg b.i.d. N=82 12/82 15% (7%, 22%) SIGNIFR 0.9 mg b.i.d. N=80 21/80 26% (17%, 36%) UFC Levels (nml/24hr) Baseline Mean (SD) Median % Change frm baseline Mean (95% CI) Median N= (764) % (-44%, +1%) -47% N= (930) % (-50%, -33%) -46% SIGNIFR resulted in a decrease in the mean 24-hur UFC after 1 mnth f treatment (Figure 1). Fr patients (n=78) wh stayed in the trial, similar UFC lwering was bserved at Mnth 12.

14 Figure 1 Mean (±SE) Urinary Free Crtisl (nml/24h) at time pints up t Mnth 6 by randmized dse grup nml/24h Nrmal Mnth SIGNIFR 0.9 mg SIGNIFR 0.6 mg Nte: nly patients wh cmpleted 6 mnths f treatment are included in this analysis (n=110). The reference line is the upper limit f nrmal fr UFC, which is 145 nml/24hur; +/-Standard errrs are displayed. ther endpints Decreases frm baseline fr bld pressure were bserved at Mnth 6, including patients wh did nt receive any antihypertensive medicatin. Hwever, due t the fact that the study allwed initiatin f antihypertensive medicatin and dse increases in patients already receiving such medicatins, the individual cntributin f SIGNIFR r f antihypertensive medicatin adjustments cannt be clearly established. The mean decreases frm baseline at Mnth 6 fr weight, bdy mass index and waist circumference were 4.4 kg, 1.6 kg/m 2 and 2.6 cm, respectively. Individual patients shwed varying degrees f imprvement in Cushing's disease manifestatins but because f the variability in respnse and the absence f a cntrl grup in this trial, it is uncertain whether these changes culd be ascribed t the effects f SIGNIFR. 16 HW SUPPLIED/STRAGE AND HANDLING SIGNIFR is supplied as a single dse, clrless glass ampule packaged in a bx f 60 ampules, arranged in 10 packs f 6 ampules each. The fllwing packaging cnfiguratins are available. 0.3 mg/1 ml pasiretide (as diaspartate) Bx f 60 ampules... NDC# mg/1 ml pasiretide (as diaspartate) Bx f 60 ampules... NDC# mg/1 ml pasiretide (as diaspartate) Bx f 60 ampules... NDC# Stre at 25 C (77 F); excursins permitted t C (59 86 F), prtect frm light. 17 PATIENT CUNSELING INFRMATIN See FDA apprved patient labeling (Medicatin Guide and Instructins fr Use). Cunsel patients n the fllwing pssible significant adverse reactins: Hypcrtislism [see Warnings and Precautins (5.1)]

15 Hyperglycemia and diabetes [see Warnings and Precautins (5.2)] Bradycardia and QT prlngatin [see Warnings and Precautins (5.3)] Liver test elevatins [see Warnings and Precautins (5.4)] Chlelithiasis [see Warnings and Precautins (5.5)] Pituitary hrmne deficiency [see Warnings and Precautins (5.6)] Pregnancy: Infrm female patients that treatment with SIGNIFR may result in unintended pregnancy [see Use in Specific Ppulatins (8.3)] Instruct the patients n the prper use f SIGNIFR, including instructins t: Carefully review the Medicatin Guide. D nt reuse unused prtins f SIGNIFR ampules and prperly dispse f the ampules after use. Avid multiple injectins at r near the same site within shrt perids f time. Fr instructins n the use f SIGNIFR glass ampules, refer t the Medicatin Guide that fllws. ** Trademark f Thmsn Healthcare, Inc. Distributed by: Nvartis Pharmaceuticals Crpratin East Hanver, NJ T

16 Medicatin Guide SIGNIFR [sig-na-fr] (pasiretide) Injectin Read this Medicatin Guide befre yu start using SIGNIFR and each time yu get a refill. There may be new infrmatin. This infrmatin des nt take the place f talking t yur dctr abut yur medical cnditin r yur treatment. What is the mst imprtant infrmatin I shuld knw abut SIGNIFR? SIGNIFR can cause serius side effects, including: Lw crtisl levels in yur bld (hypcrtislism). Tell yur dctr right away if yu have any signs and symptms f hypcrtislism. Signs and symptms f hypcrtislism may include: weakness fatigue lss f appetite nausea vmiting lw bld pressure lw level f sdium in yur bld lw bld sugar If yu get hypcrtislism while taking SIGNIFR, yur dctr may change yur dse r ask yu t stp taking it. High bld sugar (hyperglycemia). Yur dctr shuld check yur bld sugar level befre yu start taking SIGNIFR and while yu take it. Signs and symptms f hyperglycemia may include: excessive thirst high urine utput increased appetite with weight lss tiredness If yu get hyperglycemia while taking SIGNIFR, yur dctr may give yu anther medicine t take t lwer yur bld sugar. Yur dctr may als change yur dse f SIGNIFR r ask yu t stp taking it.

17 What is SIGNIFR? SIGNIFR is a prescriptin medicine used t treat Cushing s disease in adults wh cannt have surgery r have failed surgery. It is nt knwn if SIGNIFR is safe and effective in children. What shuld I tell my dctr befre using SIGNIFR? Befre yu take SIGNIFR, tell yur dctr if yu: have r have had high bld sugar (hyperglycemia) have diabetes have r have had heart prblems have a histry f lw levels f ptassium r magnesium in yur bld have r have had liver prblems have r have had gallstnes have any ther medical cnditins are pregnant r plan t becme pregnant. SIGNIFR may harm yur unbrn baby. are breastfeeding r plan t breastfeed. It is nt knwn if SIGNIFR passes int yur breast milk. Yu and yur dctr shuld decide if yu will take SIGNIFR r breastfeed. Yu shuld nt d bth. Tell yur dctr abut all the medicines yu take, including prescriptin and nnprescriptin medicines, vitamins, and herbal supplements. Taking SIGNIFR with certain ther medicines can affect each ther and cause side effects. Especially tell yur dctr if yu take: medicines t cntrl yur heart beat (anti-arrhythmics) medicines that can affect the electrical system f yur heart (QT prlngatin) medicines t cntrl yur bld pressure (such as beta-blckers r calcium channel blckers) medicines t cntrl the electrlyte (such as ptassium r magnesium) levels in yur bld cyclsprine (Gengraf, Neral, Restasis, Sandimmune ) brmcriptine (Cyclset, Parldel ) Ask yur dctr fr a list f these medicines, if yu are nt sure. Knw the medicines yu take. Keep a list f them t shw t yur dctr and pharmacist when yu get a new medicine.

18 Hw shuld I use SIGNIFR? Read the Instructins fr Use at the end f this Medicatin Guide fr infrmatin abut the right way t use SIGNIFR. Use SIGNIFR exactly as yur dctr tells yu t. Yur dctr may change yur dse if needed. Befre yu use SIGNIFR fr the first time, yur dctr shuld d a bld test t check yur bld sugar levels and yur liver tests. Befre yu use SIGNIFR fr the first time, yur dctr shuld d a test t check yur heart (electrcardigram) and yur gallbladder (ultrasund). SIGNIFR shuld be clear and clrless. Befre yu inject yur dse, check t make sure that SIGNIFR is clear and clrless, and des nt have any clumps r particles in it. SIGNIFR is given as an injectin int the fat just under yur skin (subcutaneus injectin). D nt inject SIGNIFR int skin that is red r irritated. The recmmended injectin sites fr SIGNIFR are the tp f yur thigh r stmach area (abdmen). Change (rtate) yur injectin site with each dse. D nt inject SIGNIFR int the exact same spt fr each injectin. Yur dctr shuld shw yu hw t prepare and give yur dse f SIGNIFR befre yu use it fr the first time. Yu shuld nt inject SIGNIFR until yur dctr has shwn yu hw t use it the right way. If yu take t much SIGNIFR, tell yur dctr right away. What are the pssible side effects f SIGNIFR? SIGNIFR may cause serius side effects, including: See What is the mst imprtant infrmatin I shuld knw abut SIGNIFR? slw heart rate (bradycardia). SIGNIFR can cause yur heart t beat slwer, which may cause yu t feel weak, dizzy r even faint. Peple wh have, r have had, heart prblems are at higher risk fr bradycardia. prblems with the electrical system f yur heart (QT interval prlngatin) which can put yu at risk fr abnrmal heart beats, dizziness and fainting spells that can be very serius. Call yur dctr right away if yu experience such spells. elevatin f yur liver tests. Yur dctr shuld d bld tests t mnitr yur liver tests while yu use SIGNIFR. gallstnes (chlelithiasis). Yur dctr shuld d an ultrasund t check fr gallstnes befre yu start using SIGNIFR and while yu use it. The mst cmmn side effects f SIGNIFR include: diarrhea nausea high bld sugar headache

19 abdminal pain fatigue diabetes mellitus injectin site reactins cmmn cld hair lss weakness fluid retentin Abnrmal bld test result fr glycsylated hemglbin (the level f glycsylated hemglbin indicates the average bld sugar level ver the previus mnths) Tell yur dctr if yu have any side effect that bthers yu r that des nt g away. These are nt all the pssible side effects f SIGNIFR. Fr mre infrmatin, ask yur dctr r pharmacist. Call yur dctr fr medical advice abut side effects. Yu may reprt side effects t FDA at FDA Hw shuld I stre SIGNIFR? Stre SIGNIFR at 68 F t 77 F (20 C t 25 C). Keep SIGNIFR ut f the light. Keep SIGNIFR and all medicines ut f the reach f children. General infrmatin abut the safe and effective use f SIGNIFR. Medicines are smetimes prescribed fr purpses ther than thse listed in a Medicatin Guide. D nt use SIGNIFR fr a cnditin fr which it was nt prescribed. D nt give SIGNIFR t ther peple, even if they have the same symptms that yu have. It may harm them. This Medicatin Guide summarizes the mst imprtant infrmatin abut SIGNIFR. If yu wuld like mre infrmatin, talk t yur dctr. Yu can ask yur pharmacist r dctr fr infrmatin abut SIGNIFR that is written fr health prfessinals. Fr mre infrmatin g t r call What are the ingredients in SIGNIFR? Active ingredient: Pasiretide Inactive ingredients: Mannitl, tartaric acid, sdium hydrxide and water fr injectin. T March 2018

20 Instructins fr Use SIGNIFR [sig-na-fr] (pasiretide) Injectin Supplies yu will need t give yur SIGNIFR injectin: 1 SIGNIFR ampule (See Figure A) 1 sterile syringe (See Figure B) 1 lng sterile needle (See Figure B) This needle is used t draw up yur SIGNIFR frm the ampule. Yu shuld nly use this needle if yur dctr r nurse tells yu t. 1 shrt sterile needle (See Figure B) Alchl wipes 1 cttn ball r gauze A sharps dispsal cntainer r ther clseable, puncture resistant dispsal cntainer Figure A Figure B Getting started: Step 1: Wash yur hands well with sap and water and dry them. Step 2: Take 1 SIGNIFR ampule ut f the bx. Step 3: Lk at the SIGNIFR ampule. Check that the ampule is nt cracked r brken and that the liquid medicine in the ampule is clear and clrless. D nt use SIGNIFR if the ampule is cracked r brken r if the liquid lks cludy r cntains particles. Take the whle bx back t the pharmacy and get a new ne. Ampules shuld be pened just prir t administratin and any unused prtin discarded.

21 Step 4: Check the dse and expiratin date printed n the ampule (See Figure C). Preparing yur SIGNIFR dse: Figure C Step 5: Hld the SIGNIFR ampule at the bttm with 1 hand. With yur ther hand, tap the tp f the SIGNIFR ampule with yur finger t make sure there is n liquid in the tp f the ampule when yu pen it (See Figure D). Figure D Step 6: Hld the ampule with 1 hand. With yur ther hand, hld the tp f the ampule and pull it sideways until the tp snaps ff at the line marked n the ampule neck (See Figure E). Put the ampule upright n a clean and flat surface. Figure E