Submitting a Statement of Medical Necessity (SMN) for Humatrope (somatropin for injection)

Transcription

1 Sumitting Sttement of Medicl Necessity (SMN) for Humtrope (somtropin for injection) INFORMATION NEEDED FOR FULL SMN FORM SUBMISSION PATIENT INFORMATION: Plese provide Ptient Nme nd Dte of Birth. PRIMARY CONTACT Humtrope DirectConnect will use this emil ddress to estlish initil contct with ptient/ cregiver nd collect the consents needed to support the cse. NOT ALL INFORMATION IS REQUIRED The Medicl Assessment informtion is NOT REQUIRED when only requesting Benefits Investigtion, Injection Trining, or Registrtion. INSURANCE INFORMATION: Plese ttch complete copy of the ptient s insurnce crd, oth front nd ck sides. DIAGNOSIS: Plese select the pproprite on-lel dignosis. PRESCRIPTION OPTIONS: Select Vil or Pen. Specify dose, dose frequency, nd numer of refills. PRESCRIBER CERTIFICATION: Plese provide prescrier s printed nme, signture, nd dte. ADDITIONAL GUIDANCE FOR SUBMISSION PRESCRIPTION OPTIONS INSURANCE CARD: Provide copy of oth the front nd ck of the insurnce crd (legile). PRESCRIBER CERTIFICATION: The prescrier s originl signture nd dte re needed to process the SMN. ADDITIONAL DOCUMENTATION: Recent visit notes, pertinent reports, nd/or supporting medicl documenttion tht you feel would ssist in otining uthoriztion for tretment. 6 mg crtridge / HumtroPen 6 mg mg dose rnge mg dose increments Crtridge NDC: Pen NDC: mg crtridge / HumtroPen 12 mg mg dose rnge 0.05 mg dose increments Crtridge NDC: Pen NDC: mg crtridge / HumtroPen 24 mg mg dose rnge 0.10 mg dose increments Crtridge NDC: Pen NDC: Plese see Importnt Sfety Informtion, nd ccompnying Full Prescriing Informtion nd Ptient Informtion on pges 4-15 of this file. 5 mg Vil Kit 5 mg vil, diluent NDC:

2 Supporting Mteril for Humtrope (somtropin for injection) PLEASE PROVIDE ALL AVAILABLE AND APPROPRIATE SUPPORTING MATERIALS. THE CHART BELOW INCLUDES INFORMATION GENERALLY CONSIDERED RELEVANT BASED ON THE DIAGNOSIS. ADULT PATIENTS Required Mterils Hypopituitrism Pnhypopituitrism GH deficiency History nd physicl exm Kryotype report Relevnt clinicl notes Stimultion test results * * Thyroid function test results IGF-1 results * * IGFBP-3 results * * Growth chrt Height velocity Bone ge X-ry report MRI scn report History of hed trum * * * Lipid profile results DEXA scn report * * * PEDIATRIC PATIENTS Required Mterils ISS: Short stture/ Growth filure/ Growth retrdtion Turner syndrome History nd physicl exm Kryotype report Relevnt clinicl notes Stimultion test results * Thyroid function test results SHOX deficiency Smll for gesttionl ge Pnhypopituitrism IGF-1 results IGFBP-3 results Growth chrt Height velocity Bone ge X-ry report MRI scn report * * * If ville 2 filed Include growth chrt from yers 0-2 including irth weight, length, nd gesttionl ge SHOX gene deletion or muttion confirmed y genetic testing GH deficiency List of hormonl deficiencies nd/or replcements Plese see Importnt Sfety Informtion, nd ccompnying Full Prescriing Informtion nd Ptient Informtion on pges 4-15 of this file.

3 Sttement of Medicl Necessity for Humtrope (somtropin for injection) Humtrope DirectConnect Fx: , Phone: 1-84HUMATROPE ( ) Plese check the oxes elow to register your ptient nd/or request one or more services. BENEFITS INVESTIGATION INJECTION TRAINING REGISTRATION ONLY (no insurnce support or injection trining needed) PATIENT INFORMATION Trnsltion Services Needed Lnguge: Interim Mediction Request (FstTrck) Ptient is: (choose one) New to Humtrope Therpy Currently Receiving Humtrope Therpy Currently Receiving Other Brnd of GH Therpy Ptient Nme (First, M.I., & Lst) Primry Contct Dte of Birth / / Reltionship to Ptient Gender Mle Femle Ptient Address City, Stte, ZIP Emil Primry Phone # Other Phone # INSURANCE INFORMATION Plese ttch complete copy of the ptient s insurnce crd, oth front nd ck sides. DIAGNOSIS (MORE THAN ONE DIAGNOSIS MAY BE SELECTED IF APPROPRIATE.) No Insurnce Prior Authoriztion Alredy Sumitted Growth Hormone Deficiency (E23.0) Short Stture/Growth Filure/ Smll for Gesttionl Age (P05.10), plus Turner Syndrome (Q96.9) Hypopituitrism (E23.1/E23.0) Growth Retrdtion (R62.52) Short Stture/Growth Filure (R62.52) Pnhypopituitrism (E23.0) SHOX Deficiency (E34.3) Russell-Silver Syndrome (Q87.1) MEDICAL ASSESSMENT (PLEASE ATTACH SUPPORTING DOCUMENTATION. COMPLETING THE SECTION BELOW IS OPTIONAL.) NEEDED FOR BOTH PEDIATRIC AND ADULT PATIENTS IGF-1 Results Dtes Thyroid Function Test Results Dtes GH Stimultion Test Results Dtes Agent Pek GH Dtes Agent Pek GH Dtes Strt Dte of GH Tretment (For Current Ptients Only) REQUIRED FOR PEDIATRIC PATIENTS ONLY Pre-tretment Height Velocity cm/yer Dte Bone Age yers months Dte Open Epiphyses Closed Epiphyses Predicted Adult Height cm Dte Growth Chrt Attched Dte PRESCRIPTION OPTIONS 6 mg crtridge / HumtroPen 6 mg Crtridge NDC: / Pen NDC: Dose rnge: mg / mg increments 12 mg crtridge / HumtroPen 12 mg Crtridge NDC: / Pen NDC: Dose rnge: mg / 0.05 mg increments 24 mg crtridge / HumtroPen 24 mg Crtridge NDC: / Pen NDC: Dose rnge: mg / 0.10 mg increments 5 mg Vil Kit NDC mg vil; diluent mount (1.5-5 ml) Needle guge/length Dose mg sc/dy Dose Frequency times/week Dys Supply Numer of Crtridges (optionl) Numer of Refills Needle guge/length: 4mm x 32G 5mm x 31G 8mm x 31G Other: Suggested Phrmcy (optionl): Phone # Plese order syringes nd needle guges for reconstitution nd dosing. PRESCRIBER CERTIFICATIONS By signing elow, I certify tht the therpy is mediclly necessry nd tht this informtion is ccurte to the est of my knowledge. I lso represent tht I m disclosing this informtion for purposes of tretment, pyment nd/or helthcre opertions nd otherwise hve consent to disclose this informtion, s well s other medicl informtion tht my e disclosed, including medicl records of the ptient, to Eli Lilly nd Compny nd Lilly USA, LLC nd its gents for the purpose of ssessing whether the ptient qulifies for ny reimursement enefits through the durtion of the ptient s therpy. I lso certify tht the ptient is wre nd hs consented to my disclosure of their informtion to Lilly so tht Lilly my contct the ptient to further enle these services. Prescrier Nme NPI # DEA License # Tx ID # Phone # Fx # Nme of Contct Person Contct Phone # Prescrier Signture Dte Dispense s written. No stmps llowed. Plese see Indictions for Use nd Importnt Sfety Informtion on the ck of this form nd ccompnying Full Prescriing Informtion nd Ptient Informtion. See Full Pen User Mnul tht ccompnies the HumtroPen 6 mg, 12 mg, 24 mg.

4 Importnt Sfety Informtion for Humtrope INDICATIONS FOR HUMATROPE Humtrope is indicted for the tretment of: Children who hve growth filure or short stture due to growth hormone (GH) deficiency, Turner syndrome, or SHOX deficiency; hve idiopthic short stture, defined y height SDS -2.25, ssocited with growth rtes unlikely to result in dult height in the norml rnge nd in whom other cuses of short stture hve een excluded; were orn smll for gesttionl ge nd fil to show ctch-up growth y 2 to 4 yers of ge. Adults who hve GH deficiency, either dult-onset (s result of pituitry disese, hypothlmic disese, surgery, rdition therpy, or trum) or childhood-onset. Ptients treted for growth hormone deficiency in childhood who hve closed epiphyses should e reevluted to determine if they should continue growth hormone. Contrindictions Acute Criticl Illness: Somtropin should not e used to tret ptients with cute criticl illness from complictions fter open hert surgery, dominl surgery or multiple ccidentl trum, or those with cute respirtory filure. Prder-Willi Syndrome in Children: Somtropin should not e used in peditric ptients with Prder-Willi syndrome who re severely oese, hve history of upper irwy ostruction or sleep pne, or hve severe respirtory impirment. Humtrope is not indicted for the tretment of peditric ptients who hve growth filure due to geneticlly confirmed Prder-Willi syndrome. Active Mlignncy: Somtropin is contrindicted in ptients with ny evidence of ctive mlignncy. Hypersensitivity: Humtrope is contrindicted in ptients with known hypersensitivity to somtropin or the supplied diluent. Dietic Retinopthy or Closed Epiphyses: Somtropin is contrindicted in ptients with ctive prolifertive or severe non-prolifertive dietic retinopthy. It should not e used for growth promotion in peditric ptients with closed epiphyses. Wrnings nd Precutions Acute Criticl Illness: Incresed mortlity in ptients with cute criticl illness from complictions fter open hert surgery, dominl surgery or multiple ccidentl trum, or those with cute respirtory filure hs een reported fter tretment with phrmcologic mounts of somtropin. Prder-Willi Syndrome in Children: There hve een reports of ftlities fter strting therpy with somtropin in peditric ptients with Prder-Willi syndrome who hd one or more of the following risk fctors: severe oesity, history of upper irwy ostruction or sleep pne, or unidentified respirtory infection. Ptients with Prder-Willi syndrome should e evluted for signs of upper irwy ostruction nd sleep pne efore initition of tretment with somtropin. Neoplsms: An incresed risk of second neoplsm hs een reported for childhood cncer survivors treted with somtropin for GH deficiency tht developed following rdition to the rin/hed. Intrcrnil tumors, in prticulr meningioms, were the most common of these second neoplsms. In dults, it is unknown whether there is ny reltionship etween somtropin replcement therpy nd CNS tumor recurrence. Monitor for progression or recurrence in ll ptients receiving somtropin therpy who hve history of GH deficiency secondry to n intrcrnil neoplsm. Glucose Intolernce nd Dietes Mellitus: Previously undignosed impired glucose tolernce nd overt dietes mellitus my e unmsked during somtropin tretment. New-onset type 2 dietes mellitus hs een reported. Blood glucose concentrtions should e monitored periodiclly in ll ptients tking somtropin, especilly in those with risk fctors for dietes mellitus nd those with pre-existing type 1 or type 2 dietes mellitus or impired glucose tolernce. The dose of ntihyperglycemic drugs my require djustment when somtropin tretment is instituted. Intrcrnil Hypertension: Intrcrnil hypertension with ppilledem, visul chnges, hedche, nuse, nd/or vomiting hve een reported in smll numer of ptients treted with somtropin. If ppilledem is oserved y funduscopy during tretment with somtropin, tretment should e stopped nd the ptient s condition should e ressessed efore tretment is resumed. Severe Hypersensitivity: Serious systemic hypersensitivity rections including nphylctic rections nd ngioedem hve een reported with use of somtropin products. Fluid Retention: Trnsient nd dose-dependent fluid retention during somtropin replcement in dults my occur frequently. Hypodrenlism: Ptients receiving somtropin therpy who hve or re t risk for pituitry hormone deficiencies my e t risk for reduced serum cortisol levels nd/or unmsking of centrl hypodrenlism. Ptients treted with glucocorticoid replcement for previously dignosed hypodrenlism my require n increse in their mintennce or stress doses following initition of somtropin tretment. Hypothyroidism: Ptients treted with somtropin should hve periodic thyroid function tests, nd thyroid hormone replcement therpy should e initited or djusted in cses of unmsked or worsening hypothyroidism. Slipped Cpitl Femorl Epiphysis in Peditric Ptients: Slipped cpitl femorl epiphysis my occur more frequently in ptients with endocrine disorders nd in ptients undergoing rpid growth. Any peditric ptient with the onset of limp or complints of hip or knee pin during somtropin therpy should e crefully evluted. Progression of Scoliosis in Peditric Ptients: Progression of scoliosis cn occur in ptients who experience rpid growth. Ptients with history of scoliosis who re treted with somtropin should e monitored for progression of scoliosis. Somtropin hs not een shown to increse the occurrence of scoliosis. Pncretitis: Cses of pncretitis hve een reported rrely in children nd dults receiving somtropin. Pncretitis should e considered in ny somtropin-treted ptient, especilly child, who develops dominl pin. Lipotrophy: Tissue trophy my result when somtropin is dministrted sucutneously t the sme site over long period of time. This cn e voided y rotting the injection site. Adverse Rections Common dverse rections reported in dult nd peditric ptients tking somtropin include injection site rections, hypersensitivity to the diluent, nd hypothyroidism. Additionl common dverse rections in dults include edem, rthrlgi, mylgi, crpl tunnel syndrome, presthesis, nd hyperglycemi. HG HCP ISI 13JAN2017 See ccompnying Full Prescriing Informtion nd Ptient Prescriing Informtion. Humtrope nd HumtroPen re registered trdemrks owned or licensed y Eli Lilly nd Compny, its susidiries or ffilites. Humtrope is ville y prescription only. Humtrope DirectConnect is service operted y Lsh Group under greement with Eli Lilly nd Compny. PP-HG-US /2017 Lilly USA, LLC All rights reserved.

5 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use HUMATROPE sfely nd effectively. See full prescriing informtion for HUMATROPE. Initil U.S. Approvl: 1987 RECENT MAJOR CHANGES Contrindictions, Hypersensitivity (4) 12/2016 Wrnings nd Precutions, Severe Hypersensitivity (5.6) 12/2016 Wrnings nd Precutions, Hypodrenlism (5.8) 12/2016 Wrnings nd Precutions, Lipotrophy (5.14) 12/2016 INDICATIONS AND USAGE Humtrope is recominnt humn growth hormone (somtropin) indicted for: Peditric Ptients: Tretment of children with short stture or growth filure ssocited with growth hormone (GH) deficiency, Turner syndrome, idiopthic short stture, SHOX deficiency, nd filure to ctch up in height fter smll for gesttionl ge irth. (1.1) Adult Ptients: Tretment of dults with either childhood-onset or dult-onset GH deficiency. (1.2) DOSAGE AND ADMINISTRATION Humtrope should e dministered sucutneously. (2.2) Injection sites should lwys e rotted regulrly to void lipotrophy. (2.2) For peditric ptients, the recommended weekly dosges in milligrms (mg) per kilogrm (kg) of ody weight (given in divided doses 6 to 7 times per week) re: Peditric GH deficiency: 0.18 to 0.30 mg/kg/week (2.3) Turner syndrome: Up to mg/kg/week (2.3) Idiopthic short stture: Up to 0.37 mg/kg/week (2.3) SHOX deficiency: 0.35 mg/kg/week (2.3) Smll for gesttionl ge: Up to 0.47 mg/kg/week (2.3) Adult GH deficiency: Either non-weight sed or weight-sed dosing regimen my e followed, with doses djusted sed on tretment response nd IGF-I concentrtions. (2.4) Non-weight sed dosing: A strting dose of pproximtely 0.2 mg/dy (rnge, mg/dy) my e used without considertion of ody weight, nd incresed grdully every 1-2 months y increments of pproximtely mg/dy. (2.4) Weight-sed dosing: The recommended initil dily dose is not more thn mg/kg (6 µg/kg); the dose my e incresed to mximum of mg/kg (12.5 µg/kg) dily. (2.4) DOSAGE FORMS AND STRENGTHS 5 mg vil nd 5-mL vil of Diluent for Humtrope (3) 6 mg (gold), 12 mg (tel) nd 24 mg (purple) crtridge, nd prefilled syringe of Diluent for Humtrope (3) Humtrope crtridges should e used only with the pproprite corresponding pen device CONTRAINDICATIONS Acute criticl illness. (4) Children with Prder-Willi syndrome who re severely oese or hve severe respirtory impirment reports of sudden deth. (4) Active mlignncy. (4) Hypersensitivity to somtropin or excipients. (4) Active prolifertive or severe non-prolifertive dietic retinopthy. (4) Children with closed epiphyses. (4) WARNINGS AND PRECAUTIONS Acute Criticl Illness: Evlute potentil enefit of tretment continution ginst potentil risk. (5.1) Prder-Willi Syndrome: Evlute for signs of upper irwy ostruction nd sleep pne efore initition of tretment for GH deficiency. Discontinue tretment if these signs occur. (5.2) Neoplsm: Monitor ptients with preexisting tumors for progression or recurrence. Incresed risk of second neoplsm in childhood cncer survivors treted with somtropin - in prticulr meningioms in ptients treted with rdition to the hed for their first neoplsm. (5.3) Impired Glucose Tolernce (IGT) nd Dietes Mellitus (DM): Periodiclly monitor glucose levels in ll ptients, s IGT or DM my e unmsked. Doses of concurrent ntihyperglycemic drugs in ptients with DM my require djustment. (5.4) Intrcrnil Hypertension (IH): Exclude preexisting ppilledem. IH my develop, ut is usully reversile fter discontinution or dose reduction. (5.5) Hypersensitivity: Serious hypersensitivity rections my occur. In the event of n llergic rection, seek prompt medicl ttention. (5.6) Fluid Retention (e.g., edem, rthrlgi, crpl tunnel syndrome especilly in dults): Reduce dose s necessry if such signs develop. (5.7) Hypodrenlism: Monitor ptients for reduced serum cortisol levels nd/or need for glucocorticoid dose increses in those with known hypodrenlism (5.8) Hypothyroidism: Monitor thyroid function periodiclly s hypothyroidism my first ecome evident or worsen fter initition of somtropin. (5.9) Slipped Cpitl Femorl Epiphysis (SCFE): Evlute ny child with onset of limp or hip/knee pin for possile SCFE. (5.10) Progression of Preexisting Scoliosis: Monitor ny child with scoliosis for progression of the curve. (5.11) Pncretitis: Consider pncretitis in ptients with dominl pin, especilly children. (5.13) ADVERSE REACTIONS Common dverse rections reported in dult nd peditric ptients receiving somtropin include injection site rections, hypersensitivity to the diluent, nd hypothyroidism (6). Additionl common dverse rections in dults include edem, rthrlgi, mylgi, crpl tunnel syndrome, presthesis, nd hyperglycemi (6, 6.1). To report SUSPECTED ADVERSE REACTIONS, contct Eli Lilly nd Compny t LillyRx ( ) or FDA t FDA-1088 or DRUG INTERACTIONS Inhiition of 11β-Hydroxysteroid Dehydrogense Type 1: My require the initition of glucocorticoid replcement therpy. Ptients treted with glucocorticoid replcement for previously dignosed hypodrenlism my require n increse in their mintennce doses. (7.1, 7.2) Glucocorticoid Replcement: Should e crefully djusted. (7.2) Cytochrome P450-Metolized Drugs: Monitor crefully if used with somtropin. (7.3) Orl Estrogen: Lrger doses of somtropin my e required in women. (7.4) Insulin nd/or Other Hypoglycemic Agents: My require djustment (7.5) See 17 for PATIENT COUNSELING INFORMATION nd FDA-pproved ptient leling Revised: 12/2016 FULL PRESCRIBING INFORMATION: CONTENTS * 1 INDICATIONS AND USAGE 1.1 Peditric Ptients 1.2 Adult Ptients 2 DOSAGE AND ADMINISTRATION 2.1 Reconstitution 2.2 Generl Administrtion Guidelines 2.3 Dosing for Peditric Ptients 2.4 Dosing for Ptients with Adult Growth Hormone Deficiency 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Acute Criticl Illness 5.2 Prder-Willi Syndrome in Children 5.3 Neoplsms 5.4 Glucose Intolernce nd Dietes Mellitus 5.5 Intrcrnil Hypertension 5.6 Severe Hypersensitivity 5.7 Fluid Retention 5.8 Hypodrenlism 5.9 Hypothyroidism 5.10 Slipped Cpitl Femorl Epiphysis in Peditric Ptients 5.11 Progression of Preexisting Scoliosis in Peditric Ptients 5.12 Otitis Medi nd Crdiovsculr Disorders in Ptients with Turner Syndrome 5.13 Pncretitis 5.14 Lipotrophy 5.15 Lortory Tests 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 6.2 Post-Mrketing Experience 7 DRUG INTERACTIONS β-Hydroxysteroid Dehydrogense Type Phrmcologic Glucocorticoid Therpy nd Suprphysiologic Glucocorticoid Tretment 7.3 Cytochrome P450-Metolized Drugs 7.4 Orl Estrogen 7.5 Insulin nd/or Other Hypoglycemic Agents 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.3 Nursing Mothers 8.5 Geritric Use 9 DRUG ABUSE AND DEPENDENCE 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 14 CLINICAL STUDIES 14.1 Adult Ptients with Growth Hormone Deficiency 14.2 Peditric Ptients with Turner Syndrome 14.3 Peditric Ptients with Idiopthic Short Stture 14.4 Peditric Ptients with SHOX Deficiency 14.5 Peditric Ptients Born Smll for Gesttionl Age (SGA) Who Fil to Demonstrte Ctch-up Growth y Age 2-4 Yers 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storge nd Hndling 17 PATIENT COUNSELING INFORMATION * Sections or susections omitted from the full prescriing informtion re not listed

6 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Peditric Ptients Growth Hormone Deficiency Humtrope is indicted for the tretment of peditric ptients who hve growth filure due to indequte secretion of endogenous growth hormone (GH). Short Stture Associted with Turner Syndrome Humtrope is indicted for the tretment of short stture ssocited with Turner syndrome [see Clinicl Studies (14.2)]. Idiopthic Short Stture Humtrope is indicted for the tretment of idiopthic short stture, lso clled non-gh-deficient short stture, defined y height SDS nd ssocited with growth rtes unlikely to permit ttinment of dult height in the norml rnge, in peditric ptients for whom dignostic evlution excludes other cuses of short stture tht should e oserved or treted y other mens [see Clinicl Studies (14.3)]; SDS = stndrd devition scores. SHOX Deficiency Humtrope is indicted for the tretment of short stture or growth filure in children with short stture homeoox-contining gene (SHOX) deficiency [see Clinicl Studies (14.4)]. Smll for Gesttionl Age Humtrope is indicted for the tretment of growth filure in children orn smll for gesttionl ge (SGA) who fil to demonstrte ctch-up growth y ge two to four yers [see Clinicl Studies (14.5)]. 1.2 Adult Ptients Humtrope is indicted for the replcement of endogenous GH in dults with GH deficiency who meet either of the following two criteri [see Clinicl Studies (14.1)]: Adult-Onset (AO): Ptients who hve GH deficiency, either lone or ssocited with multiple hormone deficiencies (hypopituitrism), s result of pituitry disese, hypothlmic disese, surgery, rdition therpy, or trum; or Childhood-Onset (CO): Ptients who were GH deficient during childhood s result of congenitl, genetic, cquired, or idiopthic cuses. Ptients who were treted with somtropin for GH deficiency in childhood nd whose epiphyses re closed should e reevluted efore continution of somtropin therpy t the reduced dose level recommended for GH deficient dults. According to current stndrds, confirmtion of the dignosis of dult GH deficiency in oth groups involves n pproprite GH provoctive test with two exceptions: (1) ptients with multiple other pituitry hormone deficiencies due to orgnic disese; nd (2) ptients with congenitl/genetic GH deficiency. 2 DOSAGE AND ADMINISTRATION For sucutneous injection. Therpy with Humtrope should e supervised y physicin who is experienced in the dignosis nd mngement of peditric ptients with short stture ssocited with GH deficiency, Turner syndrome, idiopthic short stture, SHOX deficiency, smll for gesttionl ge irth, or dult ptients with either childhood-onset or dult-onset GH deficiency. 2.1 Reconstitution Vil Ech 5-mg vil of Humtrope should e reconstituted with 1.5 to 5 ml of Diluent for Humtrope. The diluent should e injected into the vil of Humtrope y iming the strem of liquid gently ginst the vil wll. Following reconstitution, the vil should e swirled with GENTLE rotry motion until the contents re completely dissolved. DO NOT SHAKE. The resulting solution should e cler. If the solution is cloudy or contins prticulte mtter, the contents MUST NOT e injected. If sensitivity to the diluent should occur, the vils my e reconstituted with Bcteriosttic Wter for Injection (Benzyl Alcohol preserved), USP or Sterile Wter for Injection, USP. When Humtrope is reconstituted with Bcteriosttic Wter for Injection, USP, the solution should e kept refrigerted t 36 to 46 F (2 to 8 C) nd used within 14 dys. It is importnt to note tht enzyl lcohol used s preservtive in Bcteriosttic Wter hs een ssocited with toxicity in neworns. Therefore, Bcteriosttic Wter for Injection must not e used to reconstitute Humtrope for use in neworn infnt. When Humtrope is to e dministered to neworn infnt it should e reconstituted with the diluent provided or, if the infnt is sensitive to the diluent, Sterile Wter for Injection, USP. When reconstituted with Sterile Wter for Injection the solution should e kept refrigerted t 36 to 46 F (2 to 8 C) nd used within 24 hours. Crtridge The Humtrope crtridge hs een designed for use only with the Humtrope injection device. Ech crtridge of Humtrope should e reconstituted using only the diluent syringe tht ccompnies the crtridge nd should not e reconstituted with the Diluent for Humtrope provided with Humtrope vils. The reconstituted solution should e cler. If the solution is cloudy or contins prticulte mtter, the contents MUST NOT e injected. Humtrope crtridges should not e used if the ptient is llergic to metcresol or glycerin. The somtropin concentrtions for the reconstituted Humtrope crtridges re s follows: 6 mg crtridge (gold) 12 mg crtridge (tel) 24 mg crtridge (purple) 2.08 mg/ml 4.17 mg/ml 8.33 mg/ml [See How Supplied (16.2) nd Informtion for the Ptient for comprehensive directions on Humtrope crtridge reconstitution]. 2.2 Generl Administrtion Guidelines For ll indictions, the following generl principles for dministrtion should e followed: When using the Humtrope vil the septum of the vil should e wiped with n lcoholic ntiseptic solution efore nd fter ech injection to prevent contmintion of the contents y repeted needle insertions. Sterile disposle syringes nd needles should e used. The volume of the syringe should e smll enough so tht the prescried dose cn e withdrwn from the vil with resonle ccurcy. When using the Humtrope crtridge sterile disposle needle should e used for ech injection. Humtrope should e dministered y sucutneous injection with regulr rottion of injection sites to void lipotrophy. For peditric ptients the clculted weekly Humtrope dosge should e divided into equl doses given either 6 or 7 dys per week. For dult ptients the prescried dose should e dministered dily. 2.3 Dosing for Peditric Ptients The Humtrope dosge nd dministrtion schedule should e individulized for ech ptient sed on the growth response. Filure to increse height velocity, prticulrly during the first yer of tretment, should prompt close ssessment of complince nd evlution of other cuses of poor growth, such s hypothyroidism, under-nutrition, dvnced one ge nd ntiodies to recominnt humn growth hormone. Response to somtropin tretment tends to decrese with time. Somtropin tretment for stimultion of liner growth should e discontinued once epiphysel fusion hs occurred. The recommended weekly dosges in milligrms (mg) per kilogrm (kg) of ody weight for peditric ptients re: Growth hormone deficiency Turner syndrome Idiopthic short stture SHOX deficiency Smll for gesttionl ge to mg/kg/dy (0.18 to 0.30 mg/kg/week) up to mg/kg/dy (0.375 mg/kg/week) up to mg/kg/dy (0.37 mg/kg/week) mg/kg/dy (0.35 mg/kg/week) up to mg/kg/dy (0.47 mg/kg/week) Recent literture hs recommended initil tretment with lrger doses of somtropin (e.g., mg/kg/dy), especilly in very short children (i.e., height SDS < 3), nd/or older puertl children, nd tht reduction in dosge (e.g., grdully towrds mg/kg/dy) should e considered if sustntil ctch-up growth is oserved during the first few yers of therpy. On the other hnd, in younger SGA children (e.g., pproximtely <4 yers) (who respond the est in generl) with less severe short stture (i.e., seline height SDS vlues etween -2 nd -3), considertion should e given to inititing tretment t lower dose (e.g., mg/kg/dy), nd titrting the dose s needed over time. In ll children, clinicins should crefully monitor the growth response, nd djust the somtropin dose s necessry. 2.4 Dosing for Ptients with Adult Growth Hormone Deficiency Either of two pproches to Humtrope dosing my e followed: non-weight-sed regimen or weight-sed regimen. Non-weight sed sed on pulished consensus guidelines, strting dose of pproximtely 0.2 mg/dy (rnge, mg/dy) my e used without considertion of ody weight. This dose cn e incresed grdully every 1-2 months y increments of pproximtely mg/dy, ccording to individul ptient requirements sed on the clinicl response nd serum insulin-like growth fctor I (IGF-I) concentrtions. The dose should e decresed s necessry on the sis of dverse events nd/or serum IGF-I concentrtions ove the ge- nd gender-specific norml rnge. Mintennce dosges vry considerly from person to person, nd etween mle nd femle ptients. Weight-sed sed on the dosing regimen used in the originl dult GH deficiency registrtion trils, the recommended dosge t the strt of tretment is not more thn mg/kg (6 µg/kg) dily. The dose my e incresed ccording to individul ptient requirements to mximum of mg/kg (12.5 µg/kg) dily. Clinicl response, side effects, nd determintion of ge- nd gender-djusted serum IGF-I concentrtions should e used s guidnce in dose titrtion. A lower strting dose nd smller dose increments should e considered for older ptients, who re more prone to the dverse effects of somtropin thn younger individuls. In ddition, oese individuls re more likely to mnifest dverse effects when treted with weight-sed regimen. Estrogen-replete women my need higher doses thn men. Orl estrogen dministrtion my increse the dose requirements in women. 3 DOSAGE FORMS AND STRENGTHS Humtrope is sterile, white lyophilized powder ville in the following vil nd crtridge sizes: 5 mg vil nd 5-mL vil of Diluent for Humtrope 6 mg crtridge (gold) nd prefilled syringe of Diluent for Humtrope 12 mg crtridge (tel) nd prefilled syringe of Diluent for Humtrope 24 mg crtridge (purple) nd prefilled syringe of Diluent for Humtrope Humtrope crtridges should e used only with the pproprite corresponding pen device. 4 CONTRAINDICATIONS Acute Criticl Illness Tretment with phrmcologic mounts of somtropin is contrindicted in ptients with cute criticl illness due to complictions following open hert surgery, dominl surgery or multiple ccidentl trum, or those with cute respirtory filure [see Wrnings nd Precutions (5.1)]. Prder-Willi Syndrome in Children Somtropin is contrindicted in ptients with Prder-Willi syndrome who re severely oese, hve history of upper irwy ostruction or sleep pne, or hve severe respirtory impirment. There hve een reports of sudden deth when somtropin ws used in such ptients. Humtrope is not indicted for the tretment of peditric ptients who hve growth filure due to geneticlly confirmed Prder-Willi syndrome. [See Wrnings nd Precutions (5.2)]. Active Mlignncy In generl, somtropin is contrindicted in the presence of ctive mlignncy. Any preexisting mlignncy should e inctive nd its tretment complete prior to instituting therpy with somtropin. Somtropin should e discontinued if there is evidence of recurrent ctivity. Since GH deficiency my e n erly sign of the presence of pituitry tumor (or, rrely, other rin tumors), the presence of such tumors should e ruled out prior to initition of tretment. Somtropin should not e used in ptients with ny evidence of progression or recurrence of n underlying intrcrnil tumor [See Wrnings nd Precutions (5.3)]. Hypersensitivity Humtrope is contrindicted in ptients with known hypersensitivity to somtropin or ny of its excipients. Systemic hypersensitivity rections hve een reported with postmrketing use of somtropin products [see Wrnings nd Precutions (5.6)]. Dietic Retinopthy Somtropin is contrindicted in ptients with ctive prolifertive or severe non-prolifertive dietic retinopthy. Closed Epiphyses Somtropin should not e used for growth promotion in peditric ptients with closed epiphyses. 5 WARNINGS AND PRECAUTIONS 5.1 Acute Criticl Illness Incresed mortlity in ptients with cute criticl illness due to complictions following open hert surgery, dominl surgery or multiple ccidentl trum, or those with cute respirtory filure hs een reported fter tretment with phrmcologic doses of somtropin [see Contrindictions (4)]. Two plceocontrolled clinicl trils in non-gh deficient dult ptients (n=522) with these conditions in intensive cre

7 units reveled significnt increse in mortlity (42% vs. 19%) mong somtropin-treted ptients (doses mg/dy) compred to those receiving plceo. The sfety of continuing somtropin tretment in ptients receiving replcement doses for pproved indictions who concurrently develop these illnesses hs not een estlished. Therefore, the potentil enefit of tretment continution with somtropin in ptients experiencing cute criticl illnesses should e weighed ginst the potentil risk. 5.2 Prder-Willi Syndrome in Children There hve een reports of ftlities fter inititing therpy with somtropin in peditric ptients with Prder-Willi syndrome who hd one or more of the following risk fctors: severe oesity, history of upper irwy ostruction or sleep pne, or unidentified respirtory infection. Mle ptients with one or more of these fctors my e t greter risk thn femles. Ptients with Prder-Willi syndrome should e evluted for signs of upper irwy ostruction nd sleep pne efore initition of tretment with somtropin. If, during tretment with somtropin, ptients show signs of upper irwy ostruction (including onset of, or incresed, snoring) nd/or new onset sleep pne, tretment should e interrupted. All ptients with Prder-Willi syndrome treted with somtropin should lso hve effective weight control nd e monitored for signs of respirtory infection, which should e dignosed s erly s possile nd treted ggressively [see Contrindictions (4)]. Humtrope is not indicted for the tretment of peditric ptients who hve growth filure due to geneticlly confirmed Prder-Willi syndrome. 5.3 Neoplsms In childhood cncer survivors who were treted with rdition to the rin/hed for their first neoplsm nd who developed susequent GH deficiency nd were treted with somtropin, n incresed risk of second neoplsm hs een reported. Intrcrnil tumors, in prticulr meningioms, were the most common of these second neoplsms. In dults, it is unknown whether there is ny reltionship etween somtropin replcement therpy nd CNS tumor recurrence [see Contrindictions (4)]. Monitor ll ptients receiving somtropin therpy who hve history of GH deficiency secondry to n intrcrnil neoplsm for progression or recurrence of the tumor. Becuse children with certin rre genetic cuses of short stture hve n incresed risk of developing mlignncies, prctitioners should thoroughly consider the risks nd enefits of strting somtropin in these ptients. If tretment with somtropin is initited, these ptients should e crefully monitored for development of neoplsms. Monitor ptients receiving somtropin therpy crefully for incresed growth, or potentil mlignnt chnges, of preexisting nevi. 5.4 Glucose Intolernce nd Dietes Mellitus Tretment with somtropin my decrese insulin sensitivity, prticulrly t higher doses in susceptile ptients. As result, previously undignosed impired glucose tolernce nd overt dietes mellitus my e unmsked, nd new onset type 2 dietes mellitus hs een reported in ptients tking somtropin. Therefore, glucose levels should e monitored periodiclly in ll ptients treted with somtropin, especilly in those with risk fctors for dietes mellitus, such s oesity, Turner syndrome, or fmily history of dietes mellitus. Ptients with preexisting type 1 or type 2 dietes mellitus or impired glucose tolernce should e monitored closely during somtropin therpy. The doses of ntihyperglycemic drugs (e.g., insulin or orl gents) my require djustment when somtropin therpy is instituted in these ptients. 5.5 Intrcrnil Hypertension Intrcrnil hypertension (IH) with ppilledem, visul chnges, hedche, nuse, nd/or vomiting hs een reported in smll numer of ptients treted with somtropin products. Symptoms usully occurred within the first eight (8) weeks fter the initition of somtropin therpy. In ll reported cses, IH-ssocited signs nd symptoms rpidly resolved fter cesstion of therpy or reduction of the somtropin dose. Funduscopic exmintion should e performed routinely efore inititing tretment with somtropin to exclude preexisting ppilledem, nd periodiclly during the course of somtropin therpy. If ppilledem is oserved y funduscopy during somtropin tretment, tretment should e stopped. If somtropin-induced IH is dignosed, tretment with somtropin cn e restrted t lower dose fter IH-ssocited signs nd symptoms hve resolved. Ptients with Turner syndrome my e t incresed risk for the development of IH. 5.6 Severe Hypersensitivity Serious systemic hypersensitivity rections including nphylctic rections nd ngioedem hve een reported with postmrketing use of somtropin products. Ptients nd cregivers should e informed tht such rections re possile nd tht prompt medicl ttention should e sought if n llergic rection occurs [see Contrindictions (4)]. 5.7 Fluid Retention Fluid retention during somtropin replcement therpy in dults my frequently occur. Clinicl mnifesttions of fluid retention (e.g. edem, rthrlgi, mylgi, nerve compression syndromes including crpl tunnel syndrome/ presthesis) re usully trnsient nd dose dependent. 5.8 Hypodrenlism Ptients receiving somtropin therpy who hve or re t risk for pituitry hormone deficiency(s) my e t risk for reduced serum cortisol levels nd/or unmsking of centrl (secondry) hypodrenlism. In ddition, ptients treted with glucocorticoid replcement for previously dignosed hypodrenlism my require n increse in their mintennce or stress doses following initition of somtropin tretment [see Section 7.1, 11-β Hydroxysteroid Dehydrogense Type 1]. 5.9 Hypothyroidism Undignosed/untreted hypothyroidism my prevent n optiml response to somtropin, in prticulr, the growth response in children. Ptients with Turner syndrome hve n inherently incresed risk of developing utoimmune thyroid disese nd primry hypothyroidism. In ptients with GH deficiency, centrl (secondry) hypothyroidism my first ecome evident or worsen during somtropin tretment. Therefore, ptients treted with somtropin should hve periodic thyroid function tests performed, nd thyroid hormone replcement therpy should e initited or ppropritely djusted when indicted Slipped Cpitl Femorl Epiphysis in Peditric Ptients Slipped cpitl femorl epiphysis my occur more frequently in ptients with endocrine disorders (including peditric GH deficiency nd Turner syndrome) or in ptients undergoing rpid growth. Any peditric ptient with the onset of limp or complints of hip or knee pin during somtropin therpy should e crefully evluted Progression of Preexisting Scoliosis in Peditric Ptients Progression of scoliosis cn occur in ptients who experience rpid growth. Becuse somtropin increses growth rte, ptients with history of scoliosis who re treted with somtropin should e monitored for progression of scoliosis. However, somtropin hs not een shown to increse the occurrence of scoliosis. Skeletl normlities including scoliosis re commonly seen in untreted ptients with Turner syndrome. Scoliosis is lso commonly seen in untreted ptients with Prder-Willi syndrome. Physicins should e lert to these normlities, which my mnifest during somtropin therpy Otitis Medi nd Crdiovsculr Disorders in Ptients with Turner Syndrome Ptients with Turner syndrome should e evluted crefully for otitis medi nd other er disorders, s these ptients hve n incresed risk of er nd hering disorders. Somtropin tretment my increse the occurrence of otitis medi in ptients with Turner syndrome. In ddition, ptients with Turner syndrome should e monitored closely for crdiovsculr disorders (e.g., hypertension, ortic neurysm or dissection, stroke) s ptients with Turner syndrome re lso t incresed risk for these conditions Pncretitis Cses of pncretitis hve een reported rrely in children nd dults receiving somtropin tretment, with some evidence supporting greter risk in children compred with dults. Pulished literture indictes tht girls who hve Turner syndrome my e t greter risk thn other somtropintreted children. Pncretitis should e considered in ny somtropin-treted ptient, especilly child, who develops dominl pin Lipotrophy When somtropin is dministered sucutneously t the sme site over long period of time, tissue trophy my result. This cn e voided y rotting the injection site [see Dosge nd Administrtion (2.2)] Lortory Tests Serum levels of inorgnic phosphorus, lkline phosphtse, prthyroid hormone nd IGF-I my increse fter somtropin therpy. 6 ADVERSE REACTIONS The following importnt dverse rections re lso descried elsewhere in the leling: Incresed mortlity in ptients with cute criticl illness [see Wrnings nd Precutions (5.1)] Ftlities in children with Prder-Willi syndrome [see Wrnings nd Precutions (5.2)] Neoplsms [see Wrnings nd Precutions (5.3)] Glucose intolernce nd dietes mellitus [see Wrnings nd Precutions (5.4)] Intrcrnil hypertension [see Wrnings nd Precutions (5.5)] Severe hypersensitivity [see Wrnings nd Precutions (5.6)] Fluid retention [see Wrnings nd Precutions (5.7)] Hypodrenlism [see Wrnings nd Precutions (5.8)] Hypothyroidism [see Wrnings nd Precutions (5.9)] Slipped cpitl femorl epiphysis in peditric ptients [see Wrnings nd Precutions (5.10)] Progression of preexisting scoliosis in peditric ptients [see Wrnings nd Precutions (5.11)] Otitis medi nd crdiovsculr disorders in ptients with Turner syndrome [see Wrnings nd Precutions (5.12)] Pncretitis [see Wrnings nd Precutions (5.13)] Lipotrophy [see Wrnings nd Precutions (5.14)] 6.1 Clinicl Trils Experience Becuse clinicl trils re conducted under vrying conditions, dverse rection rtes oserved during the clinicl trils performed with one somtropin formultion cnnot lwys e directly compred to the rtes oserved during the clinicl trils performed with second somtropin formultion, nd my not reflect the dverse rection rtes oserved in prctice. Peditric Ptients GH Deficiency As with ll protein phrmceuticls, smll percentge of ptients my develop ntiodies to the protein. During the first 6 months of Humtrope therpy in 314 nive ptients, only 1.6% developed specific ntiodies to Humtrope (inding cpcity 0.02 mg/l). None hd ntiody concentrtions which exceeded 2 mg/l. Throughout 8 yers of this sme study, two ptients (0.6%) hd inding cpcity >2 mg/l. Neither ptient demonstrted decrese in growth velocity t or ner the time of incresed ntiody production. It hs een reported tht growth ttenution from pituitry-derived GH my occur when ntiody concentrtions re >1.5 mg/l. In ddition to n evlution of complince with the tretment progrm nd of thyroid sttus, testing for ntiodies to somtropin should e crried out in ny ptient who fils to respond to therpy. In studies with GH deficient peditric ptients, injection site pin ws reported infrequently. A mild nd trnsient edem, which ppered in 2.5% of ptients, ws oserved erly during the course of tretment. Turner Syndrome In rndomized, concurrent-controlled, open-lel tril, there ws sttisticlly significnt increse in the occurrence of otitis medi (43% vs. 26%), er disorders (18% vs. 5%) nd surgicl procedures (45% vs. 27%) in ptients receiving Humtrope compred with untreted control ptients (Tle 1). A similr increse in otitis medi ws oserved in n 18-month plceo-controlled tril. Tle 1: Tretment-Emergent Adverse Rections of Specil Interest y Tretment Group in Turner Syndrome Adverse Rection Tretment Group Untreted Humtrope Significnce Totl Numer of Ptients Surgicl procedure 17 (27.4%) 33 (44.6%) p 0.05 Otitis medi 16 (25.8%) 32 (43.2%) p 0.05 Er disorders 3 (4.8%) 13 (17.6%) p 0.05 Open-lel study. Dose=0.3 mg/kg/wk.

8 Idiopthic Short Stture In rndomized, plceo-controlled study of Humtrope tretment (0.22 mg/kg/week) to dult height in ptients with idiopthic short stture, the dverse events reported in Humtrope-treted ptients (Tle 2) were similr to those oserved in other peditric popultions treted with Humtrope. Men serum glucose concentrtion did not chnge during Humtrope tretment. Men fsting serum insulin concentrtion incresed 10% in the Humtrope tretment group t the end of tretment reltive to seline, ut remined within the norml reference rnge. For the sme durtion of tretment, the men fsting serum insulin concentrtion decresed y 2% in the plceo group. The occurrence rtes of ove-rnge vlues for glucose, insulin, nd HA 1c were similr in the Humtrope (somtropin)- nd plceo-treted groups. No ptient developed dietes mellitus. Consistent with the known mechnism of growth hormone ction, Humtrope-treted ptients hd greter men increses, reltive to seline, in serum insulin-like growth fctor-i (IGF-I) thn plceo-treted ptients t ech study oservtion. However, there ws no significnt difference etween the Humtrope nd plceo tretment groups in the proportion of ptients who hd t lest one serum IGF-I concentrtion more thn 2.0 SD ove the ge- nd gender-pproprite men (Humtrope: 9 of 35 ptients [26%]; plceo: 7 of 28 ptients [25%]). Tle 2: Non-serious Cliniclly Significnt Tretment-Emergent Adverse Rections y Tretment Group in Idiopthic Short Stture Adverse Rection Tretment Group Plceo Humtrope Totl Numer of Ptients Scoliosis 4 (12.9%) 7 (18.9%) Otitis medi 2 (6.5%) 6 (16.2%) Hyperlipidemi 1 (3.2%) 3 (8.1%) Gynecomsti 1 (3.2%) 2 (5.4%) Hip pin 0 1 (2.7%) Arthrlgi 1 (3.2%) 4 (10.8%) Arthrosis 2 (6.5%) 4 (10.8%) Mylgi 4 (12.9%) 9 (24.3%) Hypertension 0 1 (2.7%) The dverse events oserved in the dose-response study (239 ptients treted for 2 yers) did not indicte pttern suggestive of somtropin dose effect. Among Humtrope dose groups, men fsting lood glucose, men glycosylted hemogloin, nd the incidence of elevted fsting lood glucose concentrtions were similr. One ptient developed normlities of crohydrte metolism (glucose intolernce nd high serum HA 1c ) on tretment. SHOX Deficiency Cliniclly significnt dverse events (dverse events previously oserved in ssocition with growth hormone tretment in generl) were ssessed prospectively during the 2-yer rndomized, open-lel study; those oserved re presented in Tle 3. In oth tretment groups, the men fsting plsm glucose concentrtion t the end of the first yer ws similr to the seline vlue nd remined in the norml rnge. No ptient developed dietes mellitus or hd n ove norml vlue for fsting plsm glucose t the end of one-yer of tretment. During the 2 yer study period, the proportion of ptients who hd t lest one IGF-I concentrtion greter thn 2.0 SD ove the ge- nd gender-pproprite men ws 10 of 27 [37.0%] for the Humtrope-treted group vs. 0 of 24 ptients [0.0%] for the untreted group. The proportion of ptients who hd t lest one IGFBP-3 concentrtion greter thn 2.0 SD ove the ge nd gender pproprite men ws 16 of 27 [59.3%] for the Humtrope treted group vs. 7 of 24 [29.2%] for the untreted group. Tle 3: Cliniclly Significnt Tretment-Emergent Adverse Rections, y Tretment Group in Ptients with SHOX Deficiency Adverse Rection Tretment Group Untreted Humtrope Totl Numer of Ptients Ptients with t lest one event 2 5 Arthrlgi 2 (8.0%) 3 (11.1%) Gynecomsti c 0 (0.0%) 1 (8.3%) Excessive numer of cutneous nevi 0 (0.0%) 2 (7.4%) Scoliosis 0 (0.0%) 1 (3.7%) All events were non-serious. Events re included only if reported for greter numer of Humtrope-treted thn Untreted ptients. c Percentge clculted for mles only (1/12). Smll for Gesttionl Age Study 1 In 2-yer, multicenter, rndomized study, 193 non-gh deficient children with short stture orn SGA who filed to demonstrte ctch-up growth were treted with 2 different Humtrope tretment regimens: fixed dose of mg/kg/dy (FHD group) or n individully djusted dose regimen (IAD group; strting dose mg/kg/dy which could e incresed s erly s Month 3 to mg/kg/dy sed on vlidted growth prediction model). The most frequently reported dverse events were common childhood infectious diseses. Adverse events possily/proly relted to Humtrope were otitis medi nd hedches (where there ws suggestion of modest dose response), nd slipped cpitl femorl epiphysis (1 child) [see Wrnings nd Precutions (5.10) nd Adverse Rections (6)]. There were no cler cut cses of new-onset dietes mellitus, no children treted for hyperglycemi, nd no children whose fsting lood glucose exceeded 126 mg/dl t ny time during the study. However, 6 children (4 in the FHD group nd 2 in the IAD group whose dose ws incresed from mg/kg/dy to mg/kg/dy [one t Month 3 nd one t Yer 1]) mnifested impired fsting glucose t Yer 2. Two of these six children displyed impired fsting glucose during the study s well, nd one of them ws required to discontinue Humtrope t Month 15 s consequence [see Wrnings nd Precutions (5.4) nd Adverse Rections (6)]. A modestly dose-dependent increse in men serum IGF-I SDS concentrtions within the reference rnge ws oserved; of note, t study completion, 20-25% of these children hd serum IGF-I SDS vlues > +2. Study 2 A 2-yer, open-lel, single-rm study of Humtrope t dosge of mg/kg/dy in 35 non-gh deficient children with short stture orn SGA who filed to demonstrte ctch-up growth did not revel further sfety dt of note. Study 3 Additionl sfety informtion ws otined from 340 short children orn SGA followed in n oservtionl study who received n verge Humtrope dosge of mg/kg/dy (mximum dose: mg/kg/dy) for n verge of 3.0 yers. Type 2 dietes mellitus pprently precipitted y Humtrope therpy ws reported in single ptient, ut ppered to resolve fter discontinution of Humtrope tretment, s the child hd norml orl glucose tolernce test nd ws receiving no ntihyperglycemic medictions 9 months fter the drug ws discontinued. One ptient mnifested crpl tunnel syndrome [see Adverse Rections (6)] nd nother developed n excertion of preexisting scoliosis [see Wrnings nd Precutions (5.11) nd Adverse Rections (6)] which my hve een relted to Humtrope tretment. In oth Study 1 nd Study 2, fter tretment with Humtrope, one mturtion did not ccelerte excessively, nd the timing of puerty ws ge-pproprite in oys nd girls. Therefore, it cn e concluded tht no novel dverse events potentilly relted to tretment with Humtrope were reported in either short-term study or were pprent fter review of the post-mrketing, oservtionl, sfety dtse. Adult Ptients In clinicl studies in which high doses of Humtrope were dministered to helthy dult volunteers, the following events occurred infrequently: hedche, loclized muscle pin, wekness, mild hyperglycemi, nd glucosuri. Adult-Onset GH Deficiency In the first 6 months of controlled linded trils during which ptients received either Humtrope or plceo, dult-onset GH deficient dults who received Humtrope experienced sttisticlly significnt increse in edem (Humtrope 17.3% vs. plceo 4.4%, p=0.043) nd peripherl edem (11.5% vs. 0%, respectively, p=0.017). In ptients with dult-onset GH deficiency, edem, muscle pin, joint pin, nd joint disorder were reported erly in therpy nd tended to e trnsient or responsive to dosge titrtion. Two of 113 dult-onset ptients developed crpl tunnel syndrome fter eginning mintennce therpy without low dose ( mg/kg/dy) led-in phse. Symptoms ted in these ptients fter dosge reduction. All tretment-emergent dverse events with 5% overll occurrence rte during 12 or 18 months of replcement therpy with Humtrope re shown in Tle 4 (dult-onset ptients) nd in Tle 5 (childhood-onset ptients). Adult ptients treted with Humtrope who hd een dignosed with GH deficiency in childhood reported side effects less frequently thn those with dult-onset GH deficiency. Tle 4: Tretment-Emergent Adverse Rections with 5% Overll Occurrence in Adult-Onset Growth Hormone-Deficient Ptients Treted with Humtrope for 18 Months s Compred with 6-Month Plceo nd 12-Month Humtrope Exposure Adverse Rection 18 Months Exposure [Plceo (6 Months)/GH (12 Months)] (N=46) 18 Months GH Exposure (N=52) n % n % Edem Arthrlgi Presthesi Mylgi Pin Rhinitis Peripherl edem c Bck pin Hedche Hypertension Acne Joint disorder Surgicl procedure Flu syndrome Arevitions: GH=Humtrope; N=numer of ptients receiving tretment in the period stted; n=numer of ptients reporting ech tretment-emergent dverse event. p=0.04 s compred to plceo (6 months). c p=0.02 s compred to plceo (6 months). Childhood-Onset GH Deficiency Two doule-lind, plceo-controlled trils were conducted in 67 dult ptients with childhood-onset GH deficiency who hd received previous somtropin tretment during childhood. Ptients were rndomized to receive either plceo injections or Humtrope ( mg/kg/dy [6.25 µg/kg/dy] for the first 4 weeks, then mg/kg/dy [12.5 µg/kg/dy] therefter) for the first 6 months, followed y open-lel Humtrope for the next 12 months for ll ptients. The ptients in these studies reported side effects less frequently thn those with dult-onset GH deficiency. During the plceo-controlled phse (first 6 months) of the study, elevtions of serum glutmic oxlocetic

9 trnsferse were reported significntly more often for Humtrope-treted (12.5%) thn plceo-treted ptients (0.0%, p=0.031). No other events were reported significntly more often for Humtropetreted ptients during the plceo-controlled phse. The following events were reported for t lest 5% of ptients in either of the 2 tretment groups over the 18-month durtion of the study, listed in descending order of mximum frequency for either group: sprtte minotrnsferse incresed 13%, hedche 11%, edem 9%, pin 9%, lnine minotrnsferse incresed 6%, stheni 6%, mylgi 6%, respirtory disorder 6%. Tle 5: Tretment-Emergent Adverse Rections with 5% Overll Occurrence in Childhood-Onset Growth Hormone-Deficient Ptients Treted with Humtrope for 18 Months s Compred with 6-Month Plceo nd 12-Month Humtrope Exposure 18 Months Exposure 18 Months GH Exposure Adverse Rection [Plceo (6 Months)/GH (12 Months)] (N=35) (N=32) n % n % Flu syndrome AST incresed Hedche Astheni Cough incresed Edem Hypesthesi Mylgi Pin Rhinitis ALT incresed Respirtory disorder Gstritis Phryngitis Arevitions: GH=Humtrope; N=numer of ptients receiving tretment in the period stted; n=numer of ptients reporting ech tretment-emergent dverse event; ALT=lnine minotrnsferse, formerly SGPT; AST=sprtte minotrnsferse, formerly SGOT. p=0.03 s compred to plceo (6 months). 6.2 Post-Mrketing Experience Becuse these dverse events re reported voluntrily from popultion of uncertin size, it is not lwys possile to relily estimte their frequency or estlish cusl reltionship to drug exposure. The dverse events reported during post-mrketing surveillnce do not differ from those listed/discussed ove in Sections 6 nd 6.1 in children nd dults. Other dverse events tht hve een reported in somtropin-treted ptients include the following: Severe Hypersensitivity Rections Serious systemic hypersensitivity rections including nphylctic rections nd ngioedem hve een reported with postmrketing use of somtropin products [see Wrnings nd Precutions (5.6)]. Neurologic Hedches (common in children nd occsionl in dults). Skin Increse in size or numer of cutneous nevi, especilly in ptients with Turner syndrome nd those with SHOX deficiency [see Wrnings nd Precutions (5.3)]. Endocrine Gynecomsti. Gstrointestinl Pncretitis. Cses of pncretitis hve een reported rrely in children nd dults receiving somtropin tretment, with some evidence supporting greter risk in children compred with dults. Pulished literture indictes tht girls who hve Turner syndrome my e t greter risk thn other somtropin-treted children. Pncretitis should e considered in ny somtropintreted ptient, especilly child, who develops dominl pin [see Wrnings nd Precutions (5.13)]. Metolic New-onset type 2 dietes mellitus in ptients. Neoplsi Leukemi hs een reported in smll numer of GH deficient children treted with somtropin, somtrem (methionylted rhgh), nd GH of pituitry origin. It is uncertin whether these cses of leukemi re relted to GH therpy, the pthology of GH deficiency itself, or other ssocited tretments such s rdition therpy. On the sis of current evidence, experts hve not een le to conclude tht GH therpy per se ws responsile for these cses of leukemi. The risk for children with GH deficiency, if ny, remins to e estlished [see Contrindictions (4) nd Wrnings nd Precutions (5.3)]. In n ongoing post-mrketing oservtionl study of somtropin tretment in 3,102 GH-deficient dults, hypertension, dyspne, nd sleep pne were reported y 1% to less thn 10% of ptients fter vrious durtions of tretment. 7 DRUG INTERACTIONS β-Hydroxysteroid Dehydrogense Type 1 The microsoml enzyme 11β-hydroxysteroid dehydrogense type 1 (11βHSD-1) is required for conversion of cortisone to its ctive metolite, cortisol, in heptic nd dipose tissue. GH nd somtropin inhiit 11βHSD-1. Consequently, individuls with untreted GH deficiency hve reltive increses in 11βHSD-1 nd serum cortisol. Introduction of somtropin tretment my result in inhiition of 11βHSD-1 nd reduced serum cortisol concentrtions. As consequence, previously undignosed centrl (secondry) hypodrenlism my e unmsked nd glucocorticoid replcement my e required in ptients treted with somtropin. In ddition, ptients treted with glucocorticoid replcement for previously dignosed hypodrenlism my require n increse in their mintennce or stress doses following initition of somtropin tretment; this my e especilly true for ptients treted with cortisone cette nd prednisone since conversion of these drugs to their iologiclly ctive metolites is dependent on the ctivity of 11βHSD-1 [see Wrnings nd Precutions (5.8)]. 7.2 Phrmcologic Glucocorticoid Therpy nd Suprphysiologic Glucocorticoid Tretment Phrmcologic glucocorticoid therpy nd suprphysiologic glucocorticoid tretment my ttenute the growth promoting effects of somtropin in children. Therefore, glucocorticoid replcement dosing should e crefully djusted in children receiving concomitnt somtropin nd glucocorticoid tretments to void oth hypodrenlism nd n inhiitory effect on growth. 7.3 Cytochrome P450-Metolized Drugs Limited pulished dt indicte tht somtropin tretment increses cytochrome P450 (CP450)-medited ntipyrine clernce in mn. These dt suggest tht somtropin dministrtion my lter the clernce of compounds metolized y CP450 liver enzymes (e.g., corticosteroids, sex steroids, nticonvulsnts, cyclosporine). Therefore, creful monitoring is dvised when somtropin is dministered in comintion with drugs metolized y CP450 liver enzymes. However, forml drug interction studies hve not een conducted. 7.4 Orl Estrogen Becuse orl estrogens my reduce the serum IGF-I response to somtropin tretment, girls nd women receiving orl estrogen replcement my require greter somtropin dosges [see Dosge nd Administrtion (2.4)]. 7.5 Insulin nd/or Other Hypoglycemic Agents Ptients with dietes mellitus who receive concomitnt tretment with somtropin my require djustment of their doses of insulin nd/or other hypoglycemic gents [see Wrnings nd Precutions (5.4)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy Pregnncy Ctegory C Animl reproduction studies hve not een conducted with Humtrope. It is not known whether Humtrope cn cuse fetl hrm when dministered to pregnnt womn or cn ffect reproductive cpcity. Humtrope should e given to pregnnt womn only if clerly needed. 8.3 Nursing Mothers There hve een no studies conducted with Humtrope in nursing mothers. It is not known whether this drug is excreted in humn milk. Becuse mny drugs re excreted in humn milk, cution should e exercised when Humtrope is dministered to nursing womn. 8.5 Geritric Use The sfety nd effectiveness of Humtrope in ptients ged 65 yers nd over hs not een evluted in clinicl studies. Elderly ptients my e more sensitive to the ction of somtropin, nd therefore my e more prone to development of dverse rections. A lower strting dose nd smller dose increments should e considered for older ptients [see Dosge nd Administrtion (2.4)]. 9 DRUG ABUSE AND DEPENDENCE Inpproprite use of somtropin y individuls who do not hve indictions for which somtropin is pproved, my result in significnt negtive helth consequences. Somtropin is not drug of dependence. 10 OVERDOSAGE Short-term Acute overdosge could led initilly to hypoglycemi nd susequently to hyperglycemi. Long-term Long-term overdosge could result in signs nd symptoms of gigntism or cromegly consistent with the known effects of excess endogenous humn GH. 11 DESCRIPTION Humtrope (somtropin, rdna origin, for injection) is polypeptide hormone of recominnt DNA origin. Humtrope is synthesized in strin of Escherichi coli tht hs een modified y the ddition of the gene for humn GH. The peptide is comprised of 191 mino cid residues nd hs moleculr weight of out 22,125 dltons. The mino cid sequence of the peptide is identicl to tht of humn GH of pituitry origin. Humtrope is sterile, white, lyophilized powder intended for sucutneous or intrmusculr dministrtion fter reconstitution to its liquid form. Humtrope is highly purified preprtion. Phosphoric cid nd/or sodium hydroxide my hve een dded to djust the ph. Reconstituted solutions hve ph of pproximtely 7.5. This product is oxygen sensitive. Vil Ech vil of Humtrope contins 5 mg somtropin (15 IU or 225 nnomoles); 25 mg mnnitol; 5 mg glycine; nd 1.13 mg disic sodium phosphte. Ech vil is supplied in comintion pckge with n ccompnying 5-mL vil of diluting solution (diluent). The diluent contins Wter for Injection with 0.3% metcresol s preservtive nd 1.7% glycerin. Crtridge Crtridges of Humtrope contin either 6 mg (18 IU), 12 mg (36 IU), or 24 mg (72 IU) of somtropin. Ech Humtrope crtridge contins the following: Crtridge 6 mg (gold) 12 mg (tel) 24 mg (purple) Component Somtropin 6 mg 12 mg 24 mg Mnnitol 18 mg 36 mg 72 mg Glycine 6 mg 12 mg 24 mg Disic sodium phosphte 1.36 mg 2.72 mg 5.43 mg Ech crtridge is supplied in comintion pckge with n ccompnying syringe contining pproximtely 3 ml of diluting solution (diluent). The diluent contins Wter for Injection; 0.3% metcresol s preservtive; nd 1.7%, 0.29%, nd 0.29% glycerin in the 6, 12, nd 24 mg crtridges, respectively. 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action GH inds to dimeric GH receptors locted within the cell memrnes of trget tissue cells. This interction results in intrcellulr signl trnsduction nd susequent induction of trnscription nd trnsltion of GH-dependent proteins including IGF-I, IGF BP-3 nd cid-lile suunit. GH hs direct

10 tissue nd metolic effects, including stimultion of chondrocyte differentition, stimultion of lipolysis nd stimultion of heptic glucose output. In ddition, some effects of somtropin re medited indirectly y IGF-I, including stimultion of protein synthesis nd chondrocyte prolifertion Phrmcodynmics In vitro, preclinicl, nd clinicl testing hve demonstrted tht Humtrope is therpeuticlly equivlent to humn GH of pituitry origin nd chieves equivlent phrmcokinetic profiles in helthy dults. The following effects hve een reported for humn GH of pituitry origin, nd/or somtropin. Cell Growth Totl numers of muscle cells re reduced in GH deficient children. Somtropin increses the numer nd size of muscle cells in such children. Skeletl Growth Somtropin stimultes skeletl growth in children with GH deficiency s result of effects on the growth pltes (epiphyses) of long ones. Concentrtions of IGF-I, which ply role in skeletl growth, re low in the serum of GH deficient children ut increse during somtropin tretment in most ptients. The stimultion of skeletl growth increses liner growth rte (height velocity) in most somtropin-treted children. Protein Metolism Liner growth is fcilitted in prt y incresed cellulr protein synthesis s reflected y nitrogen retention, which cn e demonstrted y decresed urinry nitrogen excretion nd serum ure nitrogen. Connective Tissue Metolism Somtropin stimultes the synthesis of chondroitin sulfte nd collgen, nd increses the urinry excretion of hydroxyproline. Crohydrte Metolism GH hs physiologicl role in the mintennce of normoglycemi during times of sustrte restriction (e.g., fsting), vi mechnisms such s stimultion of heptic gluconeogenesis nd suppression of insulin-stimulted glucose uptke y peripherl tissues. Becuse of these ctions GH is considered n insulin ntgonist with respect to crohydrte metolism. Consequently, the fsting hypoglycemi tht my occur in some children with hypopituitrism my e improved y somtropin tretment. As n extension of its physiologicl ctions, suprphysiologicl GH concentrtions my increse glucose production sufficiently to stimulte insulin secretion to mintin normoglycemi. Lrge doses of somtropin my impir glucose tolernce if compenstory insulin secretion is indequte. Administrtion of somtropin to helthy dults nd ptients with Turner syndrome resulted in increses in men serum fsting nd postprndil insulin concentrtions, lthough men vlues remined in the norml rnge. In ddition, men HA 1c concentrtions nd men fsting nd postprndil glucose concentrtions remined in the norml rnge. Lipid Metolism Somtropin stimultes intrcellulr lipolysis, nd dministrtion of somtropin leds to n increse in plsm free ftty cids nd triglycerides. Untreted GH deficiency is ssocited with incresed ody ft stores, including incresed dominl viscerl nd sucutneous dipose tissue. Tretment of GH deficient ptients with somtropin results in generl reduction of ft stores, nd decresed serum concentrtions of low density lipoprotein (LDL) cholesterol. Minerl Metolism Administrtion of somtropin results in n increse in totl ody potssium nd phosphorus nd to lesser extent sodium, proly s the result of cell growth. Serum concentrtions of inorgnic phosphte increse in somtropin-treted GH deficient children ecuse of the metolic ctivities ssocited with one growth. Although urinry clcium excretion is incresed, there is simultneous increse in clcium sorption from the intestine. Consequently, serum clcium concentrtions generlly re not ltered, lthough negtive clcium lnce my occur occsionlly during somtropin tretment. Associted with the chnges in minerl metolism, prthyroid hormone my increse during somtropin tretment Phrmcokinetics Asorption Humtrope hs een studied following intrmusculr, sucutneous, nd intrvenous dministrtion in dult volunteers (see Figure 1). The solute iovilility of somtropin is 75% nd 63% fter sucutneous nd intrmusculr dministrtion, respectively. Distriution The volume of distriution of somtropin fter intrvenous injection is out 0.07 L/kg (Tle 6). Metolism Extensive metolism studies hve not een conducted. The metolic fte of somtropin involves clssicl protein ctolism in oth the liver nd kidneys. In renl cells, t lest portion of the rekdown products of somtropin is returned to the systemic circultion. In helthy volunteers, men somtropin clernce is 0.14 L/hr/kg. The men hlf-life of intrvenous somtropin is 0.36 hours, wheres sucutneously nd intrmusculrly dministered somtropin hve men hlf-lives of 3.8 nd 4.9 hours, respectively. The longer hlf-life oserved fter sucutneous or intrmusculr dministrtion is due to slow sorption from the injection site. Excretion Urinry excretion of intct Humtrope hs not een mesured. Smll mounts of somtropin hve een detected in the urine of peditric ptients following replcement therpy. Geritric ptients The phrmcokinetics of Humtrope hve not een studied in ptients greter thn 65 yers of ge. Peditric ptients The phrmcokinetics of Humtrope in peditric ptients re similr to those of dults. Gender No gender-specific phrmcokinetic studies hve een performed with Humtrope. The ville literture indictes tht the phrmcokinetics of somtropin re similr in men nd women. Rce No dt re ville. Renl, heptic insufficiency No studies hve een performed with Humtrope. Tle 6: Summry of Somtropin Prmeters in Helthy Adult Volunteers 0.02 mg (0.05 IU )/kg, iv Men (SD) 0.1 mg (0.27 IU )/kg, im Men (SD) 0.1 mg (0.27 IU )/kg, sc Men (SD) C mx (ng/ml) t 1/2 (hr) AUC 0- (ng hr/ml) Cls (L/kg hr) 415 (75) (0.053) 156 (33) (0.029) 53.2 (25.9) 4.93 (2.66) 495 (106) (0.047) 63.3 (18.2) 3.81 (1.40) 585 (90) (0.028) Vβ (L/kg) (0.0173) 1.55 (0.91) (0.301) Arevitions: C mx =mximum concentrtion; t 1/2 =hlf-life; AUC 0- =re under the curve; Cls=systemic clernce; Vβ=volume distriution; iv=intrvenous; SD=stndrd devition; im=intrmusculr; sc=sucutneous. Bsed on previous Interntionl Stndrd of 2.7 IU=1 mg. Figure 1 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility There hs een no evidence to dte of Humtrope-induced mutgenicity. No long-term niml studies for crcinogenicity or impirment of fertility with somtropin hve een performed. 14 CLINICAL STUDIES 14.1 Adult Ptients with Growth Hormone Deficiency Two multicenter trils in ptients with dult-onset GH deficiency (n=98) nd two studies in ptients with childhood-onset GH deficiency (n=67) were designed to ssess the effects of replcement therpy with Humtrope. These four studies ech included 6-month rndomized, linded, plceocontrolled phse, during which pproximtely hlf of the ptients received plceo injections, while the other hlf received Humtrope injections. The Humtrope dosges for ll studies were identicl: 1 month of tretment t mg/kg/dy (6.25 µg/kg/dy) followed y mg/kg/dy (12.5 µg/kg/dy) for the next 5 months. The 6-month, doule-lind phse ws followed y 12 months of open-lel Humtrope tretment for ll ptients. The primry efficcy mesures were ody composition (len ody mss nd ft mss), lipid prmeters, nd qulity of life, s mesured y the Nottinghm Helth Profile ( generl helth-relted qulity of life questionnire). Len ody mss ws determined y ioelectricl impednce nlysis (BIA), vlidted with potssium 40. Body ft ws ssessed y BIA nd sum of skinfold thickness. Lipid sufrctions were nlyzed y stndrd ssy methods in centrl lortory. Adult-onset ptients nd childhood-onset ptients differed y dignosis (orgnic vs. idiopthic pituitry disese), ody size (verge vs. smll [men height nd weight]), nd ge (men 44 vs. 29 yers). In ptients with dult-onset GH deficiency, Humtrope tretment (vs. plceo) resulted in n increse in men len ody mss (2.59 vs kg, p<0.001) nd decrese in ody ft (-3.27 vs kg, p<0.001). Similr chnges were seen in childhood-onset GH deficient ptients. These significnt chnges in len ody mss persisted throughout the 18-month period for oth the dult-onset nd childhood-onset groups; the chnges in ft mss persisted in the childhood-onset group. Serum concentrtions of high-density lipoprotein (HDL) cholesterol which were low t seline (men, 30.1 mg/ml nd 33.9 mg/ml in dult-onset nd childhood-onset ptients, respectively) hd normlized y the end of 18 months of Humtrope tretment (men chnge of 13.7 nd 11.1 mg/dl for the dult-onset nd childhood-onset groups, respectively p<0.001). After 6 months, the physicl moility nd socil isoltion domins on the Nottinghm Helth Profile were significntly improved in Humtrope-treted vs. plceo-treted ptients with dult-onset GH deficiency (p<0.01) (Tle 7). There were no significnt etween-group differences (Humtrope vs. plceo) for the other Nottinghm Helth Profile domins (energy level, emotionl rections, sleep, pin) in ptients with dult-onset GH deficiency, nd no significnt etween-group differences in ny of the domins were demonstrted for ptients with childhood-onset GH deficiency. Two dditionl studies on the effect of Humtrope on exercise cpcity were conducted. Improved physicl function ws documented y incresed exercise cpcity (VO 2 mx, p<0.005) nd work performnce (Wtts, p<0.01). Outcome Mesure Tle 7: Chnges in Nottinghm Helth Profile Scores in Adult-Onset Growth Hormone-Deficient Ptients Plceo (6 Months) Humtrope Therpy (6 Months) Significnce Energy level NS c Physicl moility p<0.01 Socil isoltion p<0.01 Emotionl rections NS c Sleep NS c Pin NS c An improvement in score is indicted y more negtive chnge in the score. To ccount for multiple nlyses, pproprite sttisticl methods were pplied nd the required level of significnce is c NS=not significnt.

11 Two studies evluting the effect of Humtrope on one minerliztion were conducted susequently. In 2-yer, rndomized, doule-lind, plceo-controlled tril, 67 ptients with previously untreted dult-onset GH deficiency received plceo or Humtrope injections titrted to mintin serum IGF-I within the ge-djusted norml rnge. In men, ut not women, lumr spine one minerl density (BMD) incresed with Humtrope tretment compred to plceo, with tretment difference of pproximtely 4% (p=0.001). There ws no significnt chnge in hip BMD with Humtrope tretment in men or women, when compred to plceo. In 2-yer, open-lel, rndomized tril, 149 ptients with childhood-onset GH deficiency who hd completed peditric somtropin therpy, hd ttined finl height (height velocity <1 cm/yr) nd were confirmed to e GH-deficient s young dults (commonly referred to s trnsition ptients), were rndomized to receive Humtrope mg/kg/dy (12.5 µg/kg/dy), Humtrope mg/kg/dy (25 µg/kg/dy), or no injections (control). Ptients who were rndomized to tretment with Humtrope t 12.5 µg/kg/dy chieved 2.9% greter increse from seline thn control ptients in totl ody one minerl content (BMC) (8.1 ± 9.0% vs. 5.2 ± 8.2%, p=0.02), wheres ptients treted with Humtrope t 25 µg/kg/dy hd no significnt chnge in BMC. These results include dt from ptients who received less thn 2 yers of tretment. A greter tretment effect ws oserved for ptients who completed 2 yers of tretment. Increses in lumr spine BMD nd BMC were lso sttisticlly significnt compred to control with the 12.5 µg/kg/dy dose ut not the 25 µg/kg/dy dose. Hip BMD nd BMC did not chnge significntly compred to control with either dose. The effect of GH tretment on BMC nd BMD in trnsition ptients t doses lower thn12.5 µg/kg/dy ws not studied. The effect of Humtrope on the occurrence of osteoporotic frctures hs not een studied Peditric Ptients with Turner Syndrome One long-term, rndomized, open-lel, Cndin multicenter, concurrently controlled study, two long-term, open-lel multicenter, historiclly controlled US studies nd one long-term, rndomized, US dose-response study were conducted to evlute the efficcy of somtropin tretment of short stture due to Turner syndrome. The Cndin rndomized study compred ner-dult height outcomes for Humtrope-treted ptients to those of concurrent control group who received no injections. The Humtrope-treted ptients received dosge of 0.3 mg/kg/week given in divided doses 6 times per week from men ge of 11.7 yers for men durtion of 4.7 yers. Puerty ws induced with stndrdized estrogen regimen initited t 13 yers of ge for oth tretment groups. The Humtrope-treted group (n=27) ttined men (± SD) ner-finl height of ± 6.2 cm; the untreted control group (n=19) ttined ner-finl height of ± 4.8 cm. By nlysis of covrince (with djustments for seline height nd mid-prentl height), the effect of somtropin tretment ws men height increse of 5.4 cm (p=0.001). In two of the US studies, the effect of long-term somtropin tretment (0.375 mg/kg/week given in divided doses either 3 times per week or dily) on dult height ws determined y compring dult heights in the treted ptients with those of ge-mtched historicl controls with Turner syndrome who received no growth-promoting therpy. Puerty ws induced with stndrdized estrogen regimen initited fter 14 yers of ge in one study; in the second study ptients treted with erly somtropin (efore 11 yers of ge) were rndomized to egin puertl induction t either ge 12 (n=26) or 15 (n=29) yers (conjugted estrogens, 0.3 mg esclting to mg dily); those whose somtropin ws initited fter 11 yers of ge egn estrogen replcement fter 1 yer of somtropin. Men height gins from seline to dult (or ner-dult) height rnged from 5.0 to 8.3 cm, depending on ge t initition of somtropin tretment nd estrogen replcement (Tle 8). In the third US study, rndomized, linded dose-response study, ptients were treted from men ge of 11.1 yers for men durtion of 5.3 yers with weekly Humtrope dosge of either 0.27 mg/kg or 0.36 mg/kg dministered in divided doses 3 or 6 times weekly. The men ner-finl height of Humtrope-treted ptients ws ± 6.5 cm (n=31). When compred to historicl control dt, the men gin in dult height ws pproximtely 5 cm. In summry, ptients with Turner syndrome (totl n=181 from the 4 studies ove) treted to dult height chieved sttisticlly significnt verge height gins rnging from 5.0 to 8.3 cm. Study Group Study Design Tle 8: Summry Tle of Efficcy Results Numer t Adult Height GH Age (yr) Estrogen Age (yr) GH Durtion (yr) Adult Height Gin (cm) c Cndin RCT US 1 MHT US 2 A e MHT B f C g US 3 RDT ~5 d Dt shown re men vlues. RCT: rndomized controlled tril; MHT: mtched historicl controlled tril; RDT: rndomized doseresponse tril. c Anlysis of covrince vs. controls. d Compred with historicl dt. e GH ge <11 yr, estrogen ge 15 yr. f GH ge <11 yr, estrogen ge 12 yr. g GH ge >11 yr, estrogen t month Peditric Ptients with Idiopthic Short Stture Two rndomized, multicenter trils, 1 plceo-controlled nd 1 dose-response, were conducted in peditric ptients with idiopthic short stture, lso clled non-gh-deficient short stture. The dignosis of idiopthic short stture ws mde fter excluding other known cuses of short stture, s well s GH deficiency. Limited sfety nd efficcy dt re ville elow the ge of 7 yers. No specific studies hve een conducted in peditric ptients with fmilil short stture. The plceo-controlled study enrolled 71 peditric ptients (55 mles, 16 femles) 9 to 15 yers old (men ge 12.4 ± 1.5 yers), with short stture, 68 of whom received Humtrope. Ptients were predomintely prepuertl (Tnner I, 45%) or in erly puerty (Tnner II, 47%) t seline. In this doule-lind tril, ptients received sucutneous injections of either Humtrope mg/kg/week (equivlent to 32 µg/kg/dy), or plceo given in divided doses 3 times per week until height velocity decresed to 1.5 cm/yer ( finl height ). Finl height mesurements were ville for 33 sujects (22 Humtrope, 11 plceo) fter men tretment durtion of 4.4 yers (rnge yers). The Humtrope-treted group chieved men finl height SDS of -1.8 (Tle 9), wheres plceo-treted ptients hd men finl height SDS of -2.3 (men tretment difference, 0.51 SDS, p=0.017). Height gin cross the durtion of the study nd finl height SDS minus seline predicted height SDS were lso significntly greter in Humtrope-treted ptients thn in plceo-treted ptients (Tles 9 nd 10). In ddition, the numer of ptients whose finl height ws ove the 5th percentile of the generl popultion height stndrd for ge nd sex ws significntly greter in the Humtrope group thn the plceo group (41% vs. 0%, p<0.05), s ws the numer of ptients who gined t lest 1 SDS unit in height cross the durtion of the study (50% vs. 0%, p<0.05). Tle 9: Bseline Height Chrcteristics nd Effect of Humtrope on Finl Height in Plceo-Controlled Study, Plceo (n=11) Men (SD) Humtrope (n=22) Men (SD) Tretment Effect Men (95%CI) p-vlue Bseline height SDS (0.6) -2.7 (0.6) NA 0.77 BPH SDS -2.3 (0.8) -2.1 (0.7) NA 0.53 Finl height SDS c -2.3 (0.6) -1.8 (0.8) 0.51 (0.10, 0.92) FH SDS - seline height SDS 0.4 (0.2) 0.9 (0.7) 0.51 (0.04, 0.97) FH SDS - BPH SDS -0.1 (0.6) 0.3 (0.6) 0.46 (0.02, 0.89) Arevitions: BPH=seline predicted height; CI=confidence intervl; FH=finl height; NA=not pplicle; SDS=stndrd devition score. For finl height popultion. c Between-group comprison ws performed using nlysis of covrince with seline predicted height SDS s the covrite. Tretment effect is expressed s lest squres men (95% CI). The dose-response study included 239 peditric ptients (158 mles, 81 femles), 5 to 15 yers old, (men ge 9.8 ± 2.3 yers). Men ± SD seline chrcteristics included: height SDS ± 0.70, predicted dult height SDS ± 1.08, nd height velocity SDS ± All ut 3 ptients were prepuertl. Ptients were rndomized to one of three Humtrope tretment groups: 0.24 mg/kg/week (equivlent to 34 µg/kg/dy); 0.24 mg/kg/week for 1 yer, followed y 0.37 mg/kg/week (equivlent to 53 µg/kg/dy); nd 0.37 mg/kg/week. The primry hypothesis of this study ws tht tretment with Humtrope would increse height velocity during the first 2 yers of therpy in dose-dependent mnner. Additionlly, fter completing the initil 2-yer dose-response phse of the study, 50 ptients were followed to finl height. Ptients who received the Humtrope dosge of 0.37 mg/kg/week hd significntly greter increse in men height velocity fter 2 yers of tretment thn ptients who received 0.24 mg/kg/week (4.04 vs cm/yer, p=0.003). The men difference etween finl height nd seline predicted height ws 7.2 cm for ptients who received Humtrope 0.37 mg/kg/week nd 5.4 cm for ptients who received 0.24 mg/kg/week (Tle 10). While no ptient hd height ove the 5th percentile in ny dosge group t seline, 82% of the ptients who received 0.37 mg/kg/week nd 47% of the ptients who received 0.24 mg/kg/week chieved finl heights ove the 5th percentile of the generl popultion height stndrds (p=ns). Tle 10: Idiopthic Short Stture Trils: Finl Height Minus Bseline Predicted Height FH - Bseline PH Men (95% CI), cm Plceo-controlled Tril 3x per week dosing Plceo Humtrope 0.22 mg/kg (n=10) (n=22) -0.7 (-3.6, 2.3) +2.2 (0.4, 3.9) Humtrope 0.24 mg/kg (n=13) +5.4 (2.8, 7.9) Dose Response Tril 6x per week dosing Humtrope 0.24/0.37 mg/kg (n=13) +6.7 (4.1, 9.2) Humtrope 0.37 mg/kg (n=13) +7.2 (4.6, 9.8) Arevitions: FH=finl height; PH=predicted height; CI=confidence intervl; cm=centimeters Peditric Ptients with SHOX Deficiency SHOX deficiency my result either from deletion of one copy of the short stture homeooxcontining (SHOX) gene or from muttion within or outside one copy of the SHOX gene tht impirs the production or function of SHOX protein. A rndomized, controlled, two-yer, three-rm, open-lel study ws conducted to evlute the efficcy of Humtrope tretment of short stture in peditric ptients with SHOX deficiency who were not GH deficient. 52 ptients (24 mle, 28 femle) with SHOX deficiency, 3.0 to 12.3 yers of ge, were rndomized to either Humtrope-treted rm (27 ptients; men ge 7.3 ± 2.1 yers) or n untreted control rm (25 ptients; men ge 7.5 ± 2.7 yers). To determine the comprility of tretment effect etween ptients with SHOX deficiency nd ptients with Turner syndrome, the third study rm enrolled 26 ptients with Turner syndrome, 4.5 to 11.8 yers of ge (men ge 7.5 ± 1.9 yers), to Humtrope tretment. All ptients were prepuertl t study entry. Ptients in the Humtrope-treted group(s) received dily sucutneous injections of 0.05 mg/kg (50 µg/kg) of Humtrope, equivlent to 0.35 mg/kg/week. Ptients in the untreted group received no injections. Ptients with SHOX deficiency who received Humtrope hd significntly greter first-yer height velocity thn untreted ptients (8.7 cm/yer vs. 5.2 cm/yer, p<0.001, primry efficcy nlysis) nd similr first-yer height velocity to Humtrope-treted ptients with Turner syndrome (8.7 cm/yer vs. 8.9 cm/yer). In ddition, ptients who received Humtrope hd significntly greter second yer height velocity, nd first- nd second-yer height gin (cm nd SDS) thn untreted ptients (Tle 11).

12 Tle 11: Summry of Efficcy Results in Ptients with SHOX deficiency nd Turner Syndrome Height Velocity (cm/yr) 1 st Yer 2 nd Yer Height Gin (cm) Bseline to 1 st Yer Bseline to 2 nd Yer Height SDS Gin Bseline to 1 st Yer Bseline to 2 nd Yer Untreted (n=24) Men (SD) 5.2 (1.1) 5.4 (1.2) +5.4 (1.2) (1.9) +0.1 (0.5) +0.2 (0.5) SHOX Deficiency Humtrope (n=27) Men (SD) Turner Syndrome Tretment Difference Men (95% CI) 8.7 (1.6) +3.5 (2.8, 4.2) 7.3 (1.1) +2.0 (1.3, 2.6) +9.1 (1.5) +3.7 (2.9, 4.5) (2.0) +5.8 (4.6, 7.1) +0.7 (0.5) +0.5 (0.3, 0.8) +1.2 (0.7) +1.0 (0.7, 1.3) Humtrope (n=26) Men (SD) 8.9 (2.0) 7.0 (1.1) +8.9 (1.9) (2.7) +0.8 (0.5) +1.2 (0.7) Ptients with height SDS > -2.0 t 2 yers 1 (4%) 11 (41%) c -- 8 (31%) Positive vlues fvor Humtrope Sttisticlly significntly different from untreted, p< c Sttisticlly significntly different from untreted, p< Peditric Ptients Born Smll for Gesttionl Age (SGA) Who Fil to Demonstrte Ctch-up Growth y Age 2-4 Yers Dt from 2 clinicl trils demonstrte the effectiveness of Humtrope in promoting liner growth in short children orn SGA who fil to demonstrte ctch-up growth. The primry ojective of Study 1 ws to demonstrte tht the increse from seline in height SDS fter 1 yer of tretment would e similr when Humtrope is dministered ccording to n individully djusted dose (IAD) regimen or fixed high dose (FHD) regimen. The height increses would e considered similr if the lower ound of the 95% confidence intervl (CI) for the men difference etween the groups (IAD FHD) ws greter thn -0.5 height SDS. This 2-yer, open-lel, multicenter, Europen study enrolled 193 prepuertl, non-gh deficient children with men chronologicl ge 6.8 ± 2.4 yers (rnge: 3.0 to 12.3). Additionl study entry criteri included irth weight <10th percentile nd/or irth length SDS <-2 for gesttionl ge, nd height SDS for chronologicl ge -3. Exclusion criteri included syndroml conditions (e.g., Turner syndrome), chronic disese (e.g., dietes mellitus), nd tumor ctivity. Children were rndomized to either FHD (0.067 mg/kg/dy [0.47 mg/kg/week]; n=99) or n IAD tretment group (n=94). The initil Humtrope dosge in the IAD tretment group ws mg/kg/dy (0.25 mg/kg/week). The dosge ws incresed to mg/kg/dy in those ptients in the IAD group whose 1-yer height gin predicted t Month 3 ws <0.75 height SDS (n=40) or whose ctul height gin mesured t Yer 1 ws <0.75 height SDS (n=11). Approximtely 85% of the rndomized ptients completed 2 yers of therpy. At seline, the FHD nd IAD tretment groups hd comprle height SDS (men -3.9; Tle 12). Although the men 1-yer height increse in the IAD group ws sttisticlly significntly lower thn tht oserved in the FHD group, the study chieved its primry ojective y demonstrting tht the increse from seline in height SDS in the IAD group ws cliniclly similr (non-inferior) to tht in the FHD group (men etween-group difference = -0.3 SDS [95% CI: -0.4, -0.2 SDS]). The men chnges from seline in height SDS t the end of the 2-yer study were 1.4 nd 1.6 SDS in the IAD nd FHD groups, respectively. The results were similr when children who entered puerty during the study were removed from the nlysis. Bseline Tle 12: Study 1 Results for Height SDS nd Chnge from Bseline in Height SDS t Yer 1 nd Yer 2 After Humtrope Tretment of Short Children Born SGA Who Fil to Demonstrte Ctch-up Growth Yer 1 Height SDS Chnge from seline Yer 2 Height SDS Chnge from seline IAD Group to mg/kg/dy Men (SD) (n=86) -3.9 (0.6) (n=86) c -3.0 (0.7) 0.9 (0.4) (n=82) c -2.5 (0.8) 1.4 (0.5) FHD Group mg/kg/dy Men (SD) (n=93) -3.9 (0.7) (n=93) c -2.7 (0.7) 1.1 (0.4) (n=88) c -2.2 (0.7) 1.6 (0.5) Between-Group Difference IAD FHD -0.0 ± 0.1 (-0.2, 0.2) p-vlue = ± 0.1 (-0.4, -0.2) p-vlue < ± 0.1 (-0.4, -0.1) p-vlue = Arevitions: IAD=individully djusted dose; FHD=fixed high dose; SD=stndrd devition; SDS=stndrd devition score Lest squres men difference ± stndrd error nd 95% confidence intervl sed on ANCOVA model with tretment nd gender s fixed effects, nd seline height SDS, seline chronologicl ge, seline one ge, nd mid-prentl trget height SDS s covrites. c Only children with ctul height mesurements were included in the Yer 1 nd Yer 2 nlyses. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Vils Vil Kit (VL7335) 5 mg vil (No. 7335) nd 5-mL vil of Diluent for Humtrope (No. 7336) 1 Kit: NDC Crtridges 6 mg Crtridge Kit (MS8147): NDC (gold) 6 mg crtridge (gold) (VL7554) nd prefilled syringe of Diluent for Humtrope (VL7616) 12 mg Crtridge Kit (MS8148): NDC (tel) 12 mg crtridge (tel) (VL7555) nd prefilled syringe of Diluent for Humtrope (VL7617) 24 mg Crtridge Kit (MS8149): NDC (purple) 24 mg crtridge (purple) (VL7556) nd prefilled syringe of Diluent for Humtrope (VL7617) 16.2 Storge nd Hndling Vils Before Reconstitution Vils of Humtrope nd Diluent for Humtrope re stle when refrigerted t 2 to 8 C (36 to 46 F). Avoid freezing Diluent for Humtrope. Expirtion dtes re stted on the lels. After Reconstitution Vils of Humtrope re stle for up to 14 dys when reconstituted with Diluent for Humtrope or Bcteriosttic Wter for Injection, USP nd refrigerted t 2 to 8 C (36 to 46 F). Avoid freezing the reconstituted vil of Humtrope. After Reconstitution with Sterile Wter, USP Use only one dose per Humtrope vil nd discrd the unused portion. If the solution is not used immeditely, it must e refrigerted t 2 to 8 C (36 to 46 F) nd used within 24 hours. Crtridges Before Reconstitution Crtridges of Humtrope nd Diluent for Humtrope re stle when refrigerted t 2 to 8 C (36 to 46 F). Avoid freezing Diluent for Humtrope. Expirtion dtes re stted on the lels. After Reconstitution Crtridges of Humtrope re stle for up to 28 dys when reconstituted with Diluent for Humtrope nd refrigerted t 2 to 8 C (36 to 46 F). Store the Humtrope injection device without the needle ttched. Avoid freezing the reconstituted crtridge of Humtrope. Crtridges should e reconstituted only with the supplied diluent. Crtridges should not e reconstituted with the Diluent for Humtrope provided with Humtrope vils, or with ny other solution. 17 PATIENT COUNSELING INFORMATION See FDA-pproved ptient leling. Ptients eing treted with Humtrope (nd/or their prents) should e informed out the potentil enefits nd risks ssocited with Humtrope tretment, nd the contents of the Ptient Informtion Insert should e reviewed. This informtion is intended to educte ptients (nd cregivers); it is not disclosure of ll possile intended or dverse effects. Ptients nd cregivers who will dminister Humtrope should receive pproprite trining nd instruction on the proper use of Humtrope from the physicin or other suitly qulified helth cre professionl. A puncture-resistnt continer for the disposl of used needles nd syringes should e strongly recommended. Ptients nd/or prents should e thoroughly instructed in the importnce of proper disposl, nd cutioned ginst ny reuse of needles nd syringes. This informtion is intended to id in the sfe nd effective dministrtion of the mediction. Literture revised Decemer 13, 2016 Study 2 ws n open-lel, multicenter, single rm study conducted in Frnce, during which 35 prepuertl, non-gh deficient children were treted for 2 yers with Humtrope mg/kg/dy (0.47 mg/kg/week). Men chronologicl ge t seline ws 9.3 ± 0.9 yers (rnge: 6.7 to 10.8). Additionl study entry criteri included irth length SDS <-2 or <3rd percentile for gesttionl ge, nd height SDS for chronologicl ge <-2. Exclusion criteri included syndroml conditions (e.g., Turner syndrome), chronic disese (e.g., dietes mellitus), nd ny ctive disese. All 35 ptients completed the study. Men height SDS incresed from seline vlue of -2.7 (SD 0.5) to -1.5 (SD 0.6) fter 2 yers of Humtrope tretment. Mrketed y: Lilly USA, LLC, Indinpolis, IN 46285, USA Copyright 1987, 2016, Eli Lilly nd Compny. All rights reserved.

13 INFORMATION AND PATIENT INSTRUCTIONS HUMATROPE Somtropin (rdna origin) for Injection CARTRIDGES HUMATROPE CARTRIDGES ARE ONLY TO BE USED WITH HUMATROPEN OR HUMATROPEN 3 INJECTION DEVICES. Importnt Things to Know It is importnt to lern the nmes of the prts of the Humtrope Crtridge Kit nd how these prts work efore injecting yourself or your child. Mke sure you hve een properly trined y your nurse, phrmcist or doctor efore you mix the drug (dd the diluent liquid to the dry Humtrope powder) or inject it. Wsh your hnds nd e creful to follow the instructions given to you y your nurse, phrmcist or doctor. After mixing, throw wy the diluent syringe in puncture resistnt continer such s the type your nurse, phrmcist or doctor hs told you to use. Storge Humtrope must e kept refrigerted (36 to 46 F [2 to 8 C]) efore nd fter it is mixed. Do not freeze. Once Humtrope hs een mixed nd is in liquid form, it must e used within 28 dys. Throw wy ny mixed Humtrope left over fter 28 dys. Before giving n injection, check the dte on the crtridge. Do not use the crtridge if it hs expired. WARNING HUMATROPE CARTRIDGES SHOULD NOT BE USED IF THE PATIENT IS ALLERGIC TO METACRESOL OR GLYCERIN. Contents one crtridge with 6, 12, or 24 mg of dried Humtrope one prefilled syringe with diluent (the liquid used to mix the dried Humtrope) NOTE: There re three kinds of Humtrope crtridges tht hve different mounts of Humtrope (6, 12, or 24 mg). Mke sure tht you hve the crtridge tht your doctor prescried. Mixing the Humtrope in the Crtridge Use only the prefilled diluent syringe to mix the Humtrope in the crtridge. DO NOT use the diluent tht comes in the Humtrope vil ox, or ny other liquid. Plunger Diluent Syringe Diluent* Needle Cover Prts Blck Tringles Humtrope Crtridge White Tip End Cp Use only this kit to prepre the Humtrope crtridge. *Note: The liquid is colorless. It is shown here s lue for illustrtion purposes only. Prepring Your New Crtridge 1 1 Plunger 1c 2 Plunger Needle Cover Needle Cover Blck Tringles Remove ALL contents from the try. Note: This product is designed for left or right hnded use so you my use whichever hnd is most comfortle for you. Grsp the gry Needle Cover, t the ottom of the Diluent Syringe. Remove the Needle Cover nd discrd. DO NOT depress the Plunger yet. It is oky if drop of fluid is lost. It is not necessry to relese ir from the Diluent Syringe. Hold the crtridge, with the Blck Tringles towrd the Diluent Syringe. Align the crtridge nd Diluent Syringe in stright line. DO NOT insert the crtridge t n ngle.

14 PUSH the crtridge STRAIGHT in until it stops AND the Blck Tringles ARE COVERED. You my her or feel click. DO NOT twist the crtridge. Hold the Diluent Syringe nd the crtridge together with TWO HANDS. Push nd relese the Plunger 2 or 3 times until the Diluent is in the crtridge. Remove your thum from the Plunger nd check tht the Diluent Syringe is empty [it is norml for smll drops of Diluent to remin in the Diluent Syringe]. With your thum OFF the Plunger, pull the crtridge wy from the Diluent Syringe. 6 Plce the End Cp on hrd, flt surfce. Push the Diluent Syringe onto the End Cp nd immeditely discrd the Diluent Syringe s instructed y your helthcre professionl. 7 Mix the crtridge y gently inverting 10 times nd let it sit for 3 minutes, DO NOT SHAKE. x 10 7 Inspect the solution. The Humtrope solution should e cler. If the solution is cler, your crtridge is now prepred nd redy to e ttched to your pen injection device (see the User Mnul for your pen injection device). If the solution is cloudy or contins prticles, gently invert the crtridge 10 dditionl times. Let the crtridge sit for 5 more minutes. If the solution remins cloudy or contins prticles, DO NOT USE THE CARTRIDGE. Contct your helthcre professionl or Lilly. If you hve questions out prepring your Humtrope crtridge, you should contct your Humtrope provider or your helthcre professionl. Injections cn e given in the following res: Adomen (ove, elow, or either side of the nvel) Front of the upper thighs Upper, outer uttocks Bck of the rms ove the elow nd elow the shoulder Discuss use of the pen injection device, the right plces to inject, nd site rottion with your nurse or doctor. Literture revised August 1, 2011 Mrketed y: Lilly USA, LLC, Indinpolis, IN 46285, USA RA 119 FSAM 00

15 HUMATROPE Somtropin (rdna origin) for Injection INFORMATION FOR THE PATIENT Do not mix (reconstitute) the drug or inject it until you hve een thoroughly trined in the proper techniques y your doctor. Use sterile techniques s instructed y your doctor. Destroy nd discrd syringes nd/or needles fter ech use. Humtrope should e kept refrigerted (36 to 46 F [2 to 8 C]) efore nd fter reconstitution. Do not freeze. Reconstituted Humtrope should e used within 14 dys. Reconstituting the Vil of Humtrope Reconstitute Humtrope only with Diluent for Humtrope. Do not use other solutions for reconstitution unless instructed to do so y your doctor. Your doctor will lso tell you wht size syringe nd needle to use nd how much diluent to dd to the vil of Humtrope. Alwys strt y wshing your hnds. 1. Remove nd discrd plstic cps from tops of vils of diluent nd Humtrope. Wipe tops of oth vils with n lcohol sw (Figure 1). Remove needle cover nd sve. Pull ck on syringe plunger to drw up n mount of ir equl to the mount of diluent your doctor hs prescried. Insert needle in stopper of diluent vil, nd inject ir into vil. 2. Hold vil upside down nd, mking sure needle tip remins in solution, withdrw the mount of diluent your doctor hs prescried (Figure 2). After mking sure tht no ir ules re in the syringe, turn vil upright nd, holding rrel, remove syringe. 3. Insert sme needle into vil of Humtrope nd gently im needle tip towrd wll of vil. Slowly inject the diluent y iming the strem of liquid ginst the wll of vil (Figure 3). Do not im it t the white powder t the ottom of the vil. To equlize the pressure, withdrw volume of ir equl to the mount of diluent dded efore removing the syringe from the vil. If the needle cn e removed from the rrel of the syringe, remove, destroy, nd discrd the needle. If the needle nd syringe re mde s 1 unit, destroy nd discrd the entire unit. Prepring the Injection 1. Do not use reconstituted Humtrope if it is cloudy or contins prticles. 2. If the needle cn e removed from the type of syringe you re using, new needle should e plced on the syringe efore the injection. If the syringe nd needle re mde s 1 unit, nother unit should e used for the injection. 3. Before nd fter injection, the ruer stopper of the vil should e wiped with ruing lcohol or n lcoholic ntiseptic solution to prevent contmintion of the contents y repeted needle insertions. 4. Remove the needle cover nd drw n mount of ir into the syringe equl to your dose of Humtrope. 5. Insert needle into vil of reconstituted Humtrope nd inject the ir into the vil. Turn the vil upside down, nd, mking sure needle tip is in solution, withdrw your correct dose (see Figure 2). Mke sure tht no ir ules re in the syringe. 6. Remove syringe nd replce needle cover. Write dte of reconstitution on vil lel, nd discrd unused diluent. 7. Return unused portion of reconstituted Humtrope to refrigertor nd use within 14 dys. 8. Destroy needle or the needle nd syringe fter use. Injecting Humtrope 1. Gently tp injection site severl times with fingers. 2. Wipe the re thoroughly with n lcohol sw. Use circulr motion nd work outwrd from the inside of the circle. 3. Sucutneous Injection: With the thum nd forefinger, stilize the skin y spreding or pinching up lrge re of skin. Holding the syringe t 90 degree ngle to injection site, quickly insert the needle ll the wy into the skin. Slowly inject the solution. Remove the needle quickly, nd pply pressure over the injection site with dry guze pd or cotton ll. Ru for severl seconds. Destroy needle or needle nd syringe fter use. 4. Intrmusculr Injection: With the thum nd first 2 fingers, press the skin down firmly ginst lrge muscle mss, such s the thigh. Holding the syringe t 90 degree ngle to injection site, quickly insert the needle ll the wy into the skin. When the needle is in plce, slowly pull ck on the plunger. If lood enters the syringe, remove needle, discrd syringe nd drug, nd prepre nother injection. If no lood enters the syringe, slowly inject the solution. Remove the needle quickly, nd pply pressure over the injection site with dry guze pd or cotton ll. Ru for severl seconds. Destroy needle or needle nd syringe fter use. If you hve ny questions, consult your doctor. 4. Swirl the vil with gentle rotry motion until contents re completely dissolved (Figure 4). Do not shke. Literture revised August 1, 2011 Mrketed y: LILLY USA, LLC, INDIANAPOLIS, IN 46285, USA PA 1686 AMP HUMATROPE Somtropin (rdna origin) for Injection PA 1686 AMP HUMATROPE Somtropin (rdna origin) for Injection PA 1686 AMP