Home

Humatrope Statement of Medical Necessity form

1. 18 Months Exposure Placebo 6 Months GH 12 Months 18 Months GH Exposure Adverse Reaction N 46 N 52 n n Edema 7 15 2 11 21 2 Arthralgia 7 15 2 9 17 3 Paresthesia 6 13 0 9 17 3 Myalgia 6 13 0 7 13 5 Pain 6 13 0 7 13 5 Rhinitis 5 10 9 7 13 5 Peripheral edema 8 17 4 6 11 5 Back pain 5 10 9 5 9 6 Headache 5 10 9 4 7 7 Hypertension 2 4 3 4 7 7 Acne 0 0 3 5 8 Joint disorder 1 2 2 3 5 8 Surgical procedure 1 2 2 3 5 8 Flu syndrome 3 6 5 2 3 9 i Abbreviations GH Humatrope N number of patients receiving treatment in the period stated n number of patients reporting each treatment emergent adverse event p 0 04 as compared to placebo 6 months p 0 02 as compared to placebo 6 months oO fo Childhood Onset GH Deficiency Two double blind placebo controlled trials were conducted in 67 adult patients with childhood onset GH deficiency who had received previous somatropin treatment during childhood Patients were randomized to receive either placebo injections or Humatrope 0 00625 mg kg day 6 25 g kg day for the first 4 weeks then 0 0125 mg kg day 12 5 ug kg day thereafter for the first 6 months followed by open label Humatrope for the next 12 months for all patients The patients in these studies reported side effects less frequently than those with adult onset GH deficiency During the placebo controlled phase first 6 months of the study elevations of serum glutamic oxaloacet
2. Slipped capital femoral epiphysis in pediatric patients see Warnings and Precautions 5 9 Progression of preexisting scoliosis in pediatric patients see Warnings and Precautions 5 10 Fluid retention manifested by edema arthralgia myalgia nerve compression syndromes including carpal tunnel syndrome paraesthesias see Warnings and Precautions 5 6 Unmasking of latent central hypothyroidism see Warnings and Precautions 5 8 Injection site reactions rashes and lipoatrophy as well as rare generalized hypersensitivity reactions see Warnings and Precautions 5 13 6 2 Clinical Trials Experience Because Clinical trials are conducted under varying conditions adverse reaction rates observed during the clinical trials performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical trials performed with a second somatropin formulation and may not reflect the adverse reaction rates observed in practice Pediatric Patients GH Deficiency 7 As with all protein pharmaceuticals a small percentage of patients may develop antibodies to the protein During the first 6 months of Humatrope therapy in 314 naive patients only 1 6 developed specific antibodies to Humatrope binding capacity 20 02 mg L None had antibody concentrations which exceeded 2 mg L Throughout 8 years of this same study two patients 0 6 had binding capacity gt 2 mg L Neither patient demonstrated a
3. ADDITIONAL DOCUMENTATION Recent visit notes pertinent reports and or supporting medical documentation that you feel would assist in obtaining authorization for treatment Please see Important Safety Information and accompanying Full Prescribing Information and Patient Information on pages 4 30 of this file ieee 5 6 mg cartridge HumatroPen 6 mg 0 025 1 50 mg dose range 0 025 mg dose increments Cartridge NDC 0002 8147 01 Pen NDC 0002 9560 01 12 mg cartridge HumatroPen 12 mg 0 05 3 00 mg dose range 0 05 mg dose increments Cartridge NDC 0002 8148 01 Pen NDC 0002 9561 01 24 mg cartridge HumatroPen 24 mg 0 10 6 00 mg dose range 0 10 mg dose increments Cartridge NDC 0002 8149 01 Pen NDC 0002 9562 01 5 mg Vial Kit 5 mg vial diluent NDC 0002 7335 11 Supporting Material for Humatrope somatropin rDNA origin 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 Materials Panhypopituitarism Hypopituitarism GH deficiency History and physical exam Karyotype report Relevant clinical notes Stimulation test results Thyroid function test results IGF 1 results IGFBP 3 results Growth chart Height velocity Bone age X ray report MRI scan report
4. unit destroy and discard the entire unit Swirl the vial with a gentle rotary motion until contents are completely dissolved Figure 4 Do not shake 4 A vay WL 3 Preparing the Injection 1 2 Do not use reconstituted Humatrope if it is cloudy or contains particles If the needle can be removed from the type of syringe you are using a new needle should be placed on the syringe before the injection If the syringe and needle are made as 1 unit another unit should be used for the injection Before and after injection the rubber stopper of the vial should be wiped with rubbing alcohol or an alcoholic antiseptic solution to prevent contamination of the contents by repeated needle insertions Remove the needle cover and draw an amount of air into the syringe equal to your dose of Humatrope Insert needle into vial of reconstituted Humatrope and inject the air into the vial Turn the vial upside down and making sure needle tip is in solution withdraw your correct dose see Figure 2 Make sure that no air bubbles are in the syringe Remove syringe and replace needle cover Write date of reconstitution on vial label and discard unused diluent 7 Return unused portion of reconstituted Humatrope to refrigerator and use within 14 days 8 Destroy needle or the needle and syringe after use Injecting Humatrope 1 2 Gently tap injection site several times with fingers Wipe the area thorough
5. SD 0 029 0 0173 0 1 mg 0 27 IU kg im 53 2 25 9 4 93 2 66 495 106 0 215 1 55 0 91 Mean SD 0 047 0 1 mg 0 27 IU kg sc 63 3 18 2 3 81 1 40 585 90 0 179 0 957 0 301 Mean SD 0 028 Abbreviations Cma maximum concentration t12 half life AUCo area under the curve Cls systemic clearance VB volume distribution iv intravenous SD standard deviation im intramuscular sc subcutaneous gt Based on previous International Standard of 2 7 IU 1 mg Single Dose Average Plasma Concentrations vs Time in Normal Adult Volunteers 1000 Mean SE n 8 0 02 mg kg intravenous injection lt 0 10 mg kg intramuscular injection 0 1 mg kg subcutaneous injection Plasma Concentration ng mL 0 6 12 18 Time hours Figure 1 13 NONCLINICAL TOXICOLOGY 13 1 Carcinogenesis Mutagenesis Impairment of Fertility 14 There has been no evidence to date of Humatrope induced mutagenicity No long term animal studies for carcinogenicity or impairment of fertility with somatropin have been performed 14 CLINICAL STUDIES 14 1 Adult Patients with Growth Hormone Deficiency Two multicenter trials in patients with adult onset GH deficiency n 98 and two studies in patients with childhood onset GH deficiency n 67 were designed to assess the effects of replacement therapy with Humatrope These four studies each included a 6 month randomized blinded placebo controlled phase during wh
6. childhood onset groups the changes in fat mass persisted in the childhood onset group Serum concentrations of high density lipoprotein HDL cholesterol which were low at baseline mean 30 1 mg mL and 33 9 mg mL in adult onset and childhood onset patients respectively had normalized by the end of 18 months of Humatrope treatment mean change of 13 7 and 11 1 mg dL for the adult onset and childhood onset groups respectively p lt 0 001 After 6 months the physical mobility and social isolation domains on the Nottingham Health Profile were significantly improved in Humatrope treated vs placebo treated patients with adult onset GH deficiency p lt 0 01 Table 7 There were no significant between group differences Humatrope vs placebo for the other Nottingham Health Profile domains energy level emotional reactions sleep pain in patients with adult onset GH deficiency and no significant between group differences in any of the domains were demonstrated for patients with childhood onset GH deficiency Two additional studies on the effect of Humatrope on exercise capacity were conducted Improved physical function was documented by increased exercise capacity VO2 max p lt 0 005 and work performance Watts p lt 0 01 Table 7 Changes in Nottingham Health Profile Scores in Adult Onset Growth Hormone Deficient Patients Outcome Measure Placebo Humatrope Therapy Significance 6 Months 6 Months Energy l
7. decrease in growth velocity at or near the time of increased antibody production It has been reported that growth attenuation from pituitary derived GH may occur when antibody concentrations are gt 1 5 mg L In addition to an evaluation of compliance with the treatment program and of thyroid status testing for antibodies to somatropin should be carried out in any patient who fails to respond to therapy In studies with GH deficient pediatric patients injection site pain was reported infrequently A mild and transient edema which appeared in 2 5 of patients was observed early during the course of treatment Turner Syndrome In a randomized concurrent controlled open label trial there was a statistically significant increase in the occurrence of otitis media 43 vs 26 ear disorders 18 vs 5 and surgical procedures 45 vs 27 in patients receiving Humatrope compared with untreated control patients Table 1 A similar increase in otitis media was observed in an 18 month placebo controlled trial Table 1 Treatment Emergent Adverse Reactions of Special Interest by Treatment Group in Turner Syndrome Adverse Reaction Treatment Group 5 Untreated Humatrope Significance Total Number of Patients 62 74 Surgical procedure 17 27 4 33 44 6 p lt 0 05 Otitis media 16 25 8 32 43 2 p lt 0 05 Ear disorders 3 4 8 13 17 6 p lt 0 05 Open label study P Dose 0 3 mg kg wk Idiopathic Sho
8. e eA 12 1 Mechanism of Action 5 9 Slipped Capital Femoral Epiphysis in Pediatric Patients 12 2 Pharmacodynamics 5 10 Progression of Preexisting Scoliosis in Pediatric Patients 12 3 Pharmacokinetics 5 11 Otitis Media and Cardiovascular Disorders in Patients with Tumer Syridrome 13 NONCLINICAL TOXICOLOGY 5142 Pancreatitis 13 1 Carcinogenesis Mutagenesis Impairment of Fertility 5 13 Local and Systemic Reactions 14 CLINICAL STUDIES 5 14 Laboratory Tests 14 1 Adult Patients with Growth Hormone Deficiency 6 ADVERSE REACTIONS 14 2 Pediatric Patients with Turner Syndrome 14 3 Pediatric Patients with Idiopathic Short Stature 14 4 Pediatric Patients with SHOX Deficiency 14 5 Pediatric Patients Born Small for Gestational Age SGA Who Fail to Demonstrate Catch up Growth by Age 2 4 Years 16 HOW SUPPLIED STORAGE AND HANDLING 6 1 Most Serious and or Most Frequently Observed Adverse Reactions 6 2 Clinical Trials Experience 6 3 Post Marketing Experience 7 DRUG INTERACTIONS 7 1 11B Hydroxysteroid Dehydrogenase Type 1 7 2 Pharmacologic Glucocorticoid Therapy and 16 1 How Supplied Supraphysiologic Glucocorticoid Treatment 16 2 Storage and Handling 7 3 Cytochrome P450 Metabolized Drugs 17 PATIENT COUNSELING INFORMATION 7 4 Oral Estrogen 7 5 Insulin and or Other Hypoglycemic Agents Sections or subsections omitted from the full prescribing information 8 USE IN SPECIFIC POPULATIONS are not listed FULL PRESCRIBING INFORMATION 1 INDICA
9. hepatic glucose output In addition some effects of somatropin are mediated indirectly by IGF I including stimulation of protein synthesis and chondrocyte proliferation 12 2 Pharmacodynamics In vitro preclinical and clinical testing have demonstrated that Humatrope is therapeutically equivalent to human GH of pituitary origin and achieves equivalent pharmacokinetic profiles in healthy adults The following effects have been reported for human GH of pituitary origin and or somatropin Cell Growth Total numbers of muscle cells are reduced in GH deficient children Somatropin increases the number and size of muscle cells in such children Skeletal Growth Somatropin stimulates skeletal growth in children with GH deficiency as a result of effects on the growth plates epiphyses of long bones Concentrations of IGF I which play a role in skeletal growth are low in the serum of GH deficient children but increase during somatropin treatment in most patients The stimulation of skeletal growth increases linear growth rate height velocity in most somatropin treated children Protein Metabolism Linear growth is facilitated in part by increased cellular protein synthesis as reflected by nitrogen retention which can be demonstrated by decreased urinary nitrogen excretion and serum urea nitrogen Connective Tissue Metabolism Somatropin stimulates the synthesis of chondroitin sulfate and collagen and increases the urinary excretion of hydr
10. patients with Prader Willi syndrome who had one or more of the following risk factors severe obesity history of upper airway obstruction or sleep apnea or unidentified respiratory infection Male patients with one or more of these factors may be at greater risk than females Patients with Prader Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin e Neoplasms An increased risk of a second neoplasm has been reported for childhood cancer survivors treated with somatropin for GH deficiency that developed ollowing radiation to the brain head Intracranial tumors in particular meningiomas were the most common of these The relationship between somatropin therapy and CNS tumor recurrence in adults is unknown Monitor for progression or recurrence in patients receiving somatropin therapy who have a history of GH deficiency secondary o an intracranial neoplasm Thoroughly consider the risks and benefits of starting somatropin in children at increased risk for developing malignancies due to certain rare genetic causes These patients should be carefully monitored for development of neoplasms Any pre existing nevi should be monitored carefully for increased growth or malignant transformation e Glucose Intolerance and Diabetes Mellitus Previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked during somatropin treatment New onset
11. pe feel History of head trauma Lipid profile results pete le DEXA scan report List of hormonal deficiencies Pete and or replacements Please see Important Safety Information and accompanying Full Prescribing Information and Patient Information on pages 4 30 of this file PEDIATRIC PATIENTS Required Materials History and physical exam Karyotype report Relevant clinical notes Stimulation test results Thyroid function test results IGF 1 results IGFBP 3 results Growth chart Height velocity Bone age X ray report MRI scan report If available 12 failed v D Oo wO S E DER i e 5 i 5 6 E 2 T E 05 o 1 gt gt oo Z oO n 5 O B28 2 T Ez S roo S D a gt 5 Occ n 13 O Q iS HSe 5 x lt T s l G E lt Sp res et 5 T E x NOOO n n As oO e ts e EF Fe pe Include growth chart from years 0 2 including birth weight length and gestational age 5SHOX gene deletion or mutation confirmed by genetic testing Statement of Medical Necessity for Humatrope somatropin rDNA origin for injection Humatrope DirectConnect Fax 1 800 642 5442 Phone 1 84HUMATROPE 1 844 862 8767 Humatrope somatropin rDNA origin for injection Please check the boxes below to register your patient and or request one or more services 6 mg 12 mg 24 mg cartridges 5 mg vial D i rectConnect BENEFITS INVESTIGATION INJE
12. percentile for gestational age and height SDS for chronological age lt 2 Exclusion criteria included syndromal conditions e g Turner syndrome chronic disease e g diabetes mellitus and any active disease All 35 patients completed the study Mean height SDS increased from a baseline value of 2 7 SD 0 5 to 1 5 SD 0 6 after 2 years of Humatrope treatment 16 HOW SUPPLIED STORAGE AND HANDLING 16 1 How Supplied Vials Vial Kit VL7335 5 mg vial No 7335 and 5 mL vial of Diluent for Humatrope No 7336 1 Kit NDC 0002 7335 11 Cartridges 6 mg Cartridge Kit MS8147 NDC 0002 8147 01 gold 6 mg cartridge gold VL7554 and prefilled syringe of Diluent for Humatrope VL7616 12 mg Cartridge Kit MS8148 NDC 0002 8148 01 teal 12 mg cartridge teal VL7555 and prefilled syringe of Diluent for Humatrope VL7617 24 mg Cartridge Kit MS8149 NDC 0002 8149 01 purple 24 mg cartridge purple VL7556 and prefilled syringe of Diluent for Humatrope VL7617 16 2 Storage and Handling Vials Before Reconstitution Vials of Humatrope and Diluent for Humatrope are stable when refrigerated at 2 to 8 C 36 to 46 F Avoid freezing Diluent for Humatrope Expiration dates are stated on the labels After Reconstitution Vials of Humatrope are stable for up to 14 days when reconstituted with Diluent for Humatrope or Bacteriostatic Water for Injection USP and refrigerated at 2 to 8 C 36 to 46 F Avoid freezing th
13. purple cartridge and prefilled syringe of Diluent for Humatrope 3 Humatrope cartridges should be used only with the appropriate corresponding pen device 1 222220 0 CONTRAINDICATIONS Acute critical illness 4 1 5 1 Children with Prader Willi syndrome who are severely obese or have severe respiratory impairment reports of sudden death 4 2 5 2 Active malignancy 4 3 Active proliferative or severe non proliferative diabetic retinopathy 4 4 Children with closed epiphyses 4 5 Hypersensitivity to somatropin or diluent 4 6 1 222220 WARNINGS AND PRECAUTIONS Acute Critical Illness Evaluate potential benefit of treatment continuation against potential risk 5 1 Prader Willi Syndrome Evaluate for signs of upper airway obstruction and sleep apnea before initiation of treatment for GH deficiency Discontinue treatment if these signs occur 5 2 Neoplasm Monitor patients with preexisting tumors for progression or recurrence Increased risk of a second neoplasm in childhood cancer survivors treated with somatropin in particular meningiomas in patients treated with radiation to the head for their first neoplasm 5 3 Impaired Glucose Tolerance IGT and Diabetes Mellitus DM Periodically monitor glucose levels in all patients as IGT or DM may be unmasked Doses of concurrent antihyperglycemic drugs in patients with DM may r
14. type 2 diabetes mellitus has been reported As a result blood glucose concentrations should be monitored periodically in all patients taking somatropin especially in those with risk factors for diabetes mellitus Patients with pre existing type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during somatropin treatment Humatrope and HumatroPen are registered trademarks owned or licensed by Eli Lilly and Company its subsidiaries or affiliates Humatrope is available by prescription only Humatrope DirectConnect is a service operated by Lash Group under agreement with Eli Lilly and Company PP HG US 0029 07 2015 PRINTEDINUSA Lilly USA LLC 2015 All rights reserved Humatrope somatropin rDNA origin for injection e Intracranial Hypertension Intracranial hypertension with papilledema visual changes headache nausea and or vomiting have been reported in a small number of patients treated with somatropin Funduscopic examination is recommended at the initiation of and periodically during therapy If papilledema is observed by funduscopy during treatment with somatropin treatment should be stopped and the patient s condition should be reassessed before treatment is resumed e Fluid Retention Transient and dose dependent fluid retention during somatropin replacement in adults may frequently occur e Hypopituitarism In patients with hypopituitarism standard hormone replacement therapy s
15. your nurse pharmacist or doctor has told you to use Storage Humatrope must be kept refrigerated 36 to 46 F 2 to 8 C before and after it is mixed Do not freeze Once Humatrope has been mixed and is in liquid form it must be used within 28 days Throw away any mixed Humatrope left over after 28 days Before giving an injection check the date on the cartridge Do not use the cartridge if it has expired WARNING HUMATROPE CARTRIDGES SHOULD NOT BE USED IF THE PATIENT IS ALLERGIC TO METACRESOL OR GLYCERIN Contents e one cartridge with 6 12 or 24 mg of dried Humatrope e one prefilled syringe with diluent the liquid used to mix the dried Humatrope NOTE There are three kinds of Humatrope cartridges that have different amounts of Humatrope 6 12 or 24 mg Make sure that you have the cartridge that your doctor prescribed Mixing the Humatrope in the Cartridge Use only the prefilled diluent syringe to mix the Humatrope in the cartridge DO NOT use the diluent that comes in the Humatrope vial box or any other liquid Reconstitution Instructions Plunger Black Triangles Humatrope Cartridge Diluent Syringe Diluent Cap Use only this kit to prepare the Humatrope cartridge Needle Cover Note The liquid is colorless It is shown here as blue for illustration purposes only Preparing Your New Cartridge Remove ALL contents from the Grasp the gray Needle Cover at Remove the Needle Cov
16. 1 and Year 2 After Humatrope Treatment of Short Children Born SGA Who Fail to Demonstrate Catch up Growth IAD Group FHD Group Between Group 0 035 to 0 067 mg kg day 0 067 mg kg day Difference Mean SD Mean SD IAD FHD Baseline n 86 n 93 0 0 0 1 3 9 0 6 3 9 0 7 0 2 0 2 p value 0 95 Year 1 n 86 n 93 0 3 0 1 Height SDS 3 0 0 7 2 7 0 7 0 4 0 2 Change from baseline 0 9 0 4 1 1 0 4 p value lt 0 001 Year 2 n 82 n 88 0 3 0 1 Height SDS 2 5 0 8 2 2 0 7 0 4 0 1 Change from baseline 1 4 0 5 1 6 0 5 p value 0 003 Abbreviations AD individually adjusted dose FHD fixed high dose SD standard deviation SDS standard deviation score gt Least squares mean difference standard error and 95 confidence interval based on ANCOVA model with treatment and gender as fixed effects and baseline height SDS baseline chronological age baseline bone age and mid parental target height SDS as covariates Only children with actual height measurements were included in the Year 1 and Year 2 analyses Study 2 was an open label multicenter single arm study conducted in France during which 35 prepubertal non GH deficient children were treated for 2 years with Humatrope 0 067 mg kg day 0 47 mg kg week Mean chronological age at baseline was 9 3 0 9 years range 6 7 to 10 8 Additional study entry criteria included birth length SDS lt 2 or lt 3rd
17. CTION TRAINING REGISTRATION ONIY ee mndi Check here to submit your own Institutional SMN instead of completing the entire ATTACHED INSTITUTIONAL SMN form below If doing so please fill out only Patient Name and Date of Birth in Patient Information and the entire Prescriber Certification section below PATIENT INFORMATION Translation Services Needed Temporary Medication Patient is New to Humatrope Currently Receiving Currently Receiving Other Language Request choose one Therapy Humatrope Therapy Brand of GH Therapy Patient Name First M I amp Last Primary Contact Date of Birth Relationship to Patient Gender Male Female Home Phone L Preferred Patient Address Work Phone LI Preferred City State ZIP Other Phone LI Preferred INSURANCE INFORMATION g Prior Authorization Please attach a complete copy of the patient s insurance card both front and back sides Already Submitted L No Insurance DIAGNOSIS MORE THAN ONE DIAGNOSIS MAY BE SELECTED IF APPROPRIATE LI Growth Hormone Deficiency E23 0 LI Short Stature Growth Failure L Small for Gestational Age P05 10 plus L Turner Syndrome Q96 9 Hypopituitarism E23 1 E23 rowth Retardation R62 5 ort Stature Growth Failure R62 5 L Hy E23 1 E23 0 G h d R62 52 LI Short S G h Failure R62 52 L Panhypopituitarism E23 0 C SHOX Defi
18. Submitting a Statement of Medical Necessity SMN for Humatrope somatropin rDNA origin for injection INFORMATION NEEDED FOR FULL SMN FORM SUBMISSION PATIENT INFORMATION Please provide Patient Name and Date of Birth INSURANCE INFORMATION Please attach a complete copy of the patient s insurance card both front and back sides PRESCRIPTION OPTIONS Select Vial or Pen Specify dose dose frequency and number of refills PRESCRIBER CERTIFICATION Please provide prescriber s printed name signature and date DIAGNOSIS Please select the appropriate on label diagnosis NOT ALL INFORMATION IS REQUIRED The Medical Assessment information is NOT REQUIRED when only requesting Benefits Investigation Injection Training or Registration OPTIONAL INSTITUTIONAL SMN FORM Instead of completing the entire Humatrope SMN you can submit a completed institutional SMN as an attachment To do so please check the box for Attached Institutional SMN fill out the Prescriber Certification section and provide Patient Name and Date of Birth in the Patient Information section of the Humatrope SMN ADDITIONAL GUIDANCE FOR SUBMISSION PRESCRIPTION OPTIONS INSURANCE CARD Provide a copy of both the front and back of the insurance card legible PRESCRIBER CERTIFICATION The prescriber s original signature and date are needed to process the SMN
19. TIONS AND USAGE 1 1 Pediatric Patients Growth Hormone Deficiency Humatrope is indicated for the treatment of pediatric patients who have growth failure due to inadequate secretion of endogenous growth hormone GH Short Stature Associated with Turner Syndrome Humatrope is indicated for the treatment of short stature associated with Turner syndrome see Clinical Studies 14 2 Idiopathic Short Stature Humatrope is indicated for the treatment of idiopathic short stature also called non GH deficient short stature defined by height SDS s 2 25 and associated with growth rates unlikely to permit attainment of adult height in the normal range in pediatric patients for whom diagnostic evaluation excludes other causes of short stature that should be observed or treated by other means see Clinical Studies 14 3 SDS standard deviation scores SHOX Deficiency Humatrope is indicated for the treatment of short stature or growth failure in children with short stature homeobox containing gene SHOX deficiency see Clinical Studies 14 4 Small for Gestational Age Humatrope is indicated for the treatment of growth failure in children born small for gestational age SGA who fail to demonstrate catch up growth by age two to four years see Clinical Studies 14 5 1 2 Adult Patients Humatrope is indicated for the replacement of endogenous GH in adults with GH deficiency who meet either of the following two criteria see Clinical Stu
20. allergic reactions may occur Parents patients should be informed that such reactions are possible and that prompt medical attention should be sought if allergic reactions occur 5 14 Laboratory Tests Serum levels of inorganic phosphorus alkaline phosphatase parathyroid hormone and IGF I may increase after somatropin therapy 6 ADVERSE REACTIONS 6 1 Most Serious and or Most Frequently Observed Adverse Reactions This list presents the most serious and or most frequently observed adverse reactions during treatment with somatropin including events observed in patients who received brands of somatropin other than Humatrope Sudden death in pediatric patients with Prader Willi syndrome who had risk factors including severe obesity history of upper airway obstruction or sleep apnea and unidentified respiratory infection see Contraindications 4 2 and Warnings and Precautions 5 2 Intracranial tumors in particular meningiomas in teenagers young adults treated with radiation to the head for a first neoplasm who subsequently receive somatropin see Contraindications 4 3 and Warnings and Precautions 5 3 e Pancreatitis see Warnings and Precautions 5 12 Glucose intolerance including impaired glucose tolerance impaired fasting glucose as well as overt diabetes mellitus see Warnings and Precautions 5 4 Intracranial hypertension see Warnings and Precautions 5 5 Significant diabetic retinopathy see Contraindications 4 4
21. and smaller dose increments should be considered for older patients see Dosage and Administration 2 4 9 DRUG ABUSE AND DEPENDENCE Inappropriate use of somatropin by individuals who do not have indications for which somatropin is approved may result in significant negative health consequences Somatropin is not a drug of dependence 10 OVERDOSAGE Short term Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia Long term Long term overdosage could result in signs and symptoms of gigantism or acromegaly consistent with the known effects of excess endogenous human GH 11 DESCRIPTION Humatrope somatropin rDNA origin for injection is a polypeptide hormone of recombinant DNA origin Humatrope is synthesized in a strain of Escherichia coli that has been modified by the addition of the gene for human GH The peptide is comprised of 191 amino acid residues and has a molecular weight of about 22 125 daltons The amino acid sequence of the peptide is identical to that of human GH of pituitary origin Humatrope is a sterile white lyophilized powder intended for subcutaneous or intramuscular administration after reconstitution to its liquid form Humatrope is a highly purified preparation Phosphoric acid and or sodium hydroxide may have been added to adjust the pH Reconstituted solutions have a pH of approximately 7 5 This product is oxygen sensitive Vial Each vial of Humatrope contains 5 mg somatropi
22. ased on the dosing regimen used in the original adult GH deficiency registration trials the recommended dosage at the start of treatment is not more than 0 006 mg kg 6 g kg daily The dose may be increased according to individual patient requirements to a maximum of 0 0125 mg kg 12 5 g kg daily Clinical response side effects and determination of age and gender adjusted serum IGF I concentrations should be used as guidance in dose titration A lower starting dose and smaller dose increments should be considered for older patients who are more prone to the adverse effects of somatropin than younger individuals In addition obese individuals are more likely to manifest adverse effects when treated with a weight based regimen Estrogen replete women may need higher doses than men Oral estrogen administration may increase the dose requirements in women 3 DOSAGE FORMS AND STRENGTHS Humatrope is a sterile white lyophilized powder available in the following vial and cartridge sizes e 5mg vial and a 5 mL vial of Diluent for Humatrope 6mg cartridge gold and a prefilled syringe of Diluent for Humatrope e 12 mg cartridge teal and a prefilled syringe of Diluent for Humatrope e 24mg cartridge purple and a prefilled syringe of Diluent for Humatrope Humatrope cartridges should be used only with the appropriate corresponding pen device 4 CONTRAINDICATIONS 4 1 Acute Critical Illness Treatment with pharmacologic amounts of somatropin is contrain
23. be injected into the vial of Humatrope by aiming the stream of liquid gently against the vial wall Following reconstitution the vial should be swirled with a GENTLE rotary motion until the contents are completely dissolved DO NOT SHAKE The resulting solution should be clear If the solution is cloudy or contains particulate matter the contents MUST NOT be injected If sensitivity to the diluent should occur the vials may be reconstituted with Bacteriostatic Water for Injection Benzyl Alcohol preserved USP or Sterile Water for Injection USP When Humatrope is reconstituted with Bacteriostatic Water for Injection USP the solution should be kept refrigerated at 36 to 46 F 2 to 8 C and used within 14 days It is important to note that benzyl alcohol used as a preservative in Bacteriostatic Water has been associated with toxicity in newborns Therefore Bacteriostatic Water for Injection must not be used to reconstitute Humatrope for use in a newborn infant When Humatrope is to be administered to a newborn infant it should be reconstituted with the diluent provided or if the infant is sensitive to the diluent Sterile Water for Injection USP When reconstituted with Sterile Water for Injection the solution should be kept refrigerated at 36 to 46 F 2 to 8 C and used within 24 hours Cartridge The Humatrope cartridge has been designed for use only with the Humatrope injection device Each cartridge of Humatrope should be reconstitute
24. bination with insulin and or other hypoglycemic agents other drugs metabolized by CYP450 liver enzymes e g hydrocortisone or other corticosteroids sex steroids anticonvulsants cyclosporine or other hormone replacement therapy Adverse Reactions e Common adverse reactions reported in adult and pediatric patients taking somatropin include injection site reactions hypersensitivity to the diluent and hypothyroidism Additional common adverse reactions in adults include edema arthralgia myalgia carpal tunnel syndrome paresthesias and hyperglycemia For more safety information please see Patient Information and Full Prescribing Information HG HCP ISI 15AUG2014 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use HUMATROPE safely and effectively See full prescribing information for HUMATROPE HUMATROPE somatropin rDNA ORIGIN for injection for Subcutaneous Use Initial U S Approval 1987 manne nn nn nn nnnnnnnnnnnnnnen RECENT MAJOR CHANGES Warnings and Precautions Neoplasms 5 3 07 2014 St a INDICATIONS AND USAGE Humatrope is a recombinant human growth hormone somatropin indicated for Pediatric Patients Treatment of children with short stature or growth failure associated with growth hormone GH deficiency Turner syndrome idiopathic short stature SHOX deficiency and failure to catch up
25. ciency E34 3 L Russell Silver Syndrome Q87 1 MEDICAL ASSESSMENT PLEASE ATTACH SUPPORTING DOCUMENTATION COMPLETING THE SECTION BELOW IS OPTIONAL NEEDED FOR BOTH PEDIATRIC AND ADULT PATIENTS REQUIRED FOR PEDIATRIC PATIENTS ONLY LJ IGF 1 Results Dates LJ Pre treatment Height Velocity _________ cm year Date LI Thyroid Function Test Results Dates LI Bone Age years months Date LI GH Stimulation Test Results Dates LI Open Epiphyses LI Closed Epiphyses Agent ___________ Peak GH Dates L Predicted Adult Height _____ cm Date Agent ____________ Peak GH Dates L Growth Chart Attached Date LI Start Date of GH Treatment For Current Patients Only PRESCRIPTION OPTIONS 16 mg cartridge HumatroPen 6 mg Ll 12 mg cartridge HumatroPen 12mg 24 mg cartridge HumatroPen 24mg 5 mg Vial Kit Cartridge NDC 0002 8147 01 Pen NDC 0002 9560 01 Cartridge NDC 0002 8148 01 Pen NDC 0002 9561 01 Cartridge NDC 0002 8149 01 Pen NDC 0002 9562 01 NDC 0002 7335 11 Dose range 0 025 1 50 mg Dose range 0 05 3 00 mg Dose range 0 10 6 00 mg 5 mg vial diluent 0 025 mg increments 0 05 mg increments 0 10 mg increments amount 1 5 5 mL Needle gauge length Dose ___________mgsc day Dose Frequency times week Days Supply Please order syringes and needle gauges Number of Refills _________________ Needle gauge length 4mm x 32G 5mmx31G 8mmx31G Other ___ for recansttition S
26. control Patients who were randomized to treatment with Humatrope at 12 5 ug kg day achieved a 2 9 greater increase from baseline than control patients in total 15 body bone mineral content BMC 8 1 9 0 vs 5 2 8 2 p 0 02 whereas patients treated with Humatrope at 25 yg kg day had no significant change in BMC These results include data from patients who received less than 2 years of treatment A greater treatment effect was observed for patients who completed 2 years of treatment Increases in lumbar spine BMD and BMC were also statistically significant compared to control with the 12 5 ug kg day dose but not the 25 ug kg day dose Hip BMD and BMC did not change significantly compared to control with either dose The effect of GH treatment on BMC and BMD in transition patients at doses lower than12 5 ug kg day was not studied The effect of Humatrope on the occurrence of osteoporotic fractures has not been studied 14 2 Pediatric Patients with Turner Syndrome One long term randomized open label Canadian multicenter concurrently controlled study two long term open label multicenter historically controlled US studies and one long term randomized US dose response study were conducted to evaluate the efficacy of somatropin treatment of short stature due to Turner syndrome The Canadian randomized study compared near adult height outcomes for Humatrope treated patients to those of a concurrent control group who received no injections T
27. d one or more of the following risk factors severe obesity history of upper airway obstruction or sleep apnea or unidentified respiratory infection Male patients with one or more of these factors may be at greater risk than females Patients with Prader Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin If during treatment with somatropin patients show signs of upper airway obstruction including onset of or increased snoring and or new onset sleep apnea treatment should be interrupted All patients with Prader Willi syndrome treated with somatropin should also have effective weight control and be monitored for signs of respiratory infection which should be diagnosed as early as possible and treated aggressively see Contraindications 4 2 Humatrope is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader Willi syndrome 5 3 Neoplasms In childhood cancer survivors who were treated with radiation to the brain head for their first neoplasm and who developed subsequent GH deficiency and were treated with somatropin an increased risk of a second neoplasm has been reported Intracranial tumors in particular meningiomas were the most common of these second neoplasms In adults it is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor recurrence see Contraindica
28. d using only the diluent syringe that accompanies the cartridge and should not be reconstituted with the Diluent for Humatrope provided with Humatrope vials The reconstituted solution should be clear If the solution is cloudy or contains particulate matter the contents MUST NOT be injected Humatrope cartridges should not be used if the patient is allergic to metacresol or glycerin The somatropin concentrations for the reconstituted Humatrope cartridges are as follows 6 mg cartridge gold 2 08 mg mL 12 mg cartridge teal 4 17 mg mL 24 mg cartridge purple 8 33 mg mL See How Supplied 16 2 and Information for the Patient for comprehensive directions on Humatrope cartridge reconstitution 2 2 General Administration Guidelines For all indications the following general principles for administration should be followed When using the Humatrope vial the septum of the vial should be wiped with an alcoholic antiseptic solution before and after each injection to prevent contamination of the contents by repeated needle insertions Sterile disposable syringes and needles should be used The volume of the syringe should be small enough so that the prescribed dose can be withdrawn from the vial with reasonable accuracy e When using the Humatrope cartridge a sterile disposable needle should be used for each injection e Humatrope should be administered by subcutaneous injection with regular rotation of injection sites to avoid lipoatrophy e For pe
29. diatric patients the calculated weekly Humatrope dosage should be divided into equal doses given either 6 or 7 days per week For adult patients the prescribed dose should be administered daily 2 3 Dosing for Pediatric Patients The Humatrope dosage and administration schedule should be individualized for each patient based on the growth response Failure to increase height velocity particularly during the first year of treatment should prompt close assessment of compliance and evaluation of other causes of poor growth such as hypothyroidism under nutrition advanced bone age and antibodies to recombinant human growth hormone Response to somatropin treatment tends to decrease with time Somatropin treatment for stimulation of linear growth should be discontinued once epiphyseal fusion has occurred The recommended weekly dosages in milligrams mg per kilogram kg of body weight for pediatric patients are Growth hormone deficiency 0 026 to 0 043 mg kg day 0 18 to 0 30 mg kg week Turner syndrome up to 0 054 mg kg day 0 375 mg kg week Idiopathic short stature up to 0 053 mg kg day 0 37 mg kg week SHOX deficiency 0 050 mg kg day 0 35 mg kg week Small for gestational age up to 0 067 mg kg day 0 47 mg kg week Recent literature has recommended initial treatment with larger doses of somatropin e g 0 067 mg kg day especially in very short children i e height SDS lt 3 and or older pubertal children and that a reduction in d
30. dicated in patients with acute critical illness due to complications following open heart surgery abdominal surgery or multiple accidental trauma or those with acute respiratory failure Two placebo controlled clinical trials in non GH deficient adult patients n 522 with these conditions in intensive care units revealed a significant increase in mortality 41 9 vs 19 3 among somatropin treated patients doses 5 3 8 0 mg day compared to those receiving placebo see Warnings and Precautions 5 1 4 2 Prader Willi Syndrome in Children Somatropin is contraindicated in patients with Prader Willi syndrome who are severely obese have a history of upper airway obstruction or sleep apnea or have severe respiratory impairment There have been reports of sudden death when somatropin was used in such patients Humatrope is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader Willi syndrome See Warnings and Precautions 5 2 4 3 Active Malignancy In general somatropin is contraindicated in the presence of active malignancy Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin Somatropin should be discontinued if there is evidence of recurrent activity Since GH deficiency may be an early sign of the presence of a pituitary tumor or rarely other brain tumors the presence of such tumors should be ruled out prior to initiati
31. dies 14 1 Adult Onset AQ Patients who have GH deficiency either alone or associated with multiple hormone deficiencies hypopituitarism as a result of pituitary disease hypothalamic disease surgery radiation therapy or trauma or Childhood Onset CQ Patients who were GH deficient during childhood as a result of congenital genetic acquired or idiopathic causes Patients who were treated with somatropin for GH deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin therapy at the reduced dose level recommended for GH deficient adults According to current standards confirmation of the diagnosis of adult GH deficiency in both groups involves an appropriate GH provocative test with two exceptions 1 patients with multiple other pituitary hormone deficiencies due to organic disease and 2 patients with congenital genetic GH deficiency 2 DOSAGE AND ADMINISTRATION For subcutaneous injection Therapy with Humatrope should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with short stature associated with GH deficiency Turner syndrome idiopathic short stature SHOX deficiency small for gestational age birth or adult patients with either childhood onset or adult onset GH deficiency 2 1 Reconstitution Vial Each 5 mg vial of Humatrope should be reconstituted with 1 5 to 5 mL of Diluent for Humatrope The diluent should
32. e reconstituted vial of Humatrope After Reconstitution with Sterile Water USP Use only one dose per Humatrope vial and discard the unused portion If the solution is not used immediately it must be refrigerated at 2 to 8 C 36 to 46 F and used within 24 hours Cartridges 19 Before Reconstitution Cartridges of Humatrope and Diluent for Humatrope are stable when refrigerated at 2 to 8 C 36 to 46 F Avoid freezing Diluent for Humatrope Expiration dates are stated on the labels After Reconstitution Cartridges of Humatrope are stable for up to 28 days when reconstituted with Diluent for Humatrope and refrigerated at 2 to 8 C 36 to 46 F Store the Humatrope injection device without the needle attached Avoid freezing the reconstituted cartridge of Humatrope Cartridges should be reconstituted only with the supplied diluent Cartridges should not be reconstituted with the Diluent for Humatrope provided with Humatrope vials or with any other solution 17 PATIENT COUNSELING INFORMATION See FDA approved patient labeling Patients being treated with Humatrope and or their parents should be informed about the potential benefits and risks associated with Humatrope treatment and the contents of the Patient Information Insert should be reviewed This information is intended to educate patients and caregivers it is not a disclosure of all possible intended or adverse effects Patients and caregivers who will admini
33. e liver and kidneys In renal cells at least a portion of the breakdown products of somatropin is returned to the systemic circulation In healthy volunteers mean somatropin clearance is 0 14 L hr kg The mean half life of intravenous somatropin is 0 36 hours whereas subcutaneously and intramuscularly administered somatropin have mean half lives of 3 8 and 4 9 hours respectively The longer half life observed after subcutaneous or intramuscular administration is due to slow absorption from the injection site Excretion Urinary excretion of intact Humatrope has not been measured Small amounts of somatropin have been detected in the urine of pediatric patients following replacement therapy Geriatric patients The pharmacokinetics of Humatrope have not been studied in patients greater than 65 years of age Pediatric patients The pharmacokinetics of Humatrope in pediatric patients are similar to those of adults Gender No gender specific pharmacokinetic studies have been performed with Humatrope The available literature indicates that the pharmacokinetics of somatropin are similar in men and women Race No data are available Renal hepatic insufficiency No studies have been performed with Humatrope Table 6 Summary of Somatropin Parameters in Healthy Adult Volunteers Cmax tie AUC Cls VB ng mL hr ngehr mL L kgehr L kg 0 02 mg 0 05 IU kg iv 415 75 0 363 0 053 156 33 0 135 0 0703 Mean
34. e to 1 Year 0 1 0 5 0 7 0 5 0 5 0 3 0 8 0 8 0 5 Baseline to 2 Year 0 2 0 5 1 2 0 7 1 0 0 7 1 3 1 2 0 7 Patients with height SDS gt 2 0 at 2 years 1 4 11 41 8 31 Positive values favor Humatrope gt Statistically significantly different from untreated p lt 0 001 Statistically significantly different from untreated p lt 0 05 14 5 Pediatric Patients Born Small for Gestational Age SGA Who Fail to Demonstrate Catch up Growth by Age 2 4 Years Data from 2 clinical trials demonstrate the effectiveness of Humatrope in promoting linear growth in short children born SGA who fail to demonstrate catch up growth The primary objective of Study 1 was to demonstrate that the increase from baseline in height SDS after 1 year of treatment would be similar when Humatrope is administered according to an individually adjusted dose IAD regimen or a fixed high dose FHD regimen The height increases would be considered similar if the lower bound of the 95 confidence interval Cl for the mean difference between the groups IAD FHD was greater than 0 5 height SDS This 2 year open label multicenter European study enrolled 193 prepubertal non GH deficient children with mean chronological age 6 8 2 4 years range 3 0 to 12 3 Additional study entry criteria included birth weight lt 10th percentile and or birth length SDS lt 2 for gestational age and height SDS for chronological age lt 3 Excl
35. ed and ready to be attached to your pen injection device see the User Manual for your pen injection device If the solution is cloudy or contains particles gently invert the cartridge 10 additional times Let the cartridge sit for 5 more minutes If the solution remains cloudy or contains particles DO NOT USE THE CARTRIDGE Contact your healthcare professional or Lilly If you have questions about preparing your Humatrope cartridge you should contact your Humatrope provider or your healthcare professional e Abdomen above below or either side of the navel e Front of the upper thighs e Upper outer buttocks e Back of the arms above the elbow and below the shoulder Discuss use of the pen injection device the right places to inject and site rotation with your nurse or doctor Literature revised August 1 2011 Marketed by Lilly USA LLC Indianapolis IN 46285 USA www humatrope com RA 119 FSAM 00 1 PA 1686 AMP HUMATROPE Somatropin rDNA origin for Injection INFORMATION FOR THE PATIENT Do not mix reconstitute the drug or inject it until you have been thoroughly trained in the proper techniques by your doctor Use sterile techniques as instructed by your doctor Destroy and discard syringes and or needles after each use Humatrope should be kept refrigerated 36 to 46 F 2 to 8 C before and after reconstitution Do not freeze Reconstituted Humatrope should be used within 14 days Reconstitu
36. ed for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader Willi syndrome e Active Malignancy Somatropin is contraindicated in patients with any evidence of active malignancy Growth hormone deficiency may be an early sign of a pituitary tumor or other intracranial tumor the presence of such a tumor should be excluded before initiation of somatropin treatment e Diabetic Retinopathy Somatropin is contraindicated in patients with active proliferative or severe non proliferative diabetic retinopathy e Closed Epiphyses Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses e Hypersensitivity Humatrope is contraindicated in patients with a known sensitivity to somatropin or the supplied diluent Localized reactions are the most common hypersensitivity reactions Patients with a known sensitivity to either metacresol or glycerin should not receive Humatrope reconstituted with the supplied diluent for Humatrope Warnings and Precautions e Acute Critical Illness Increased mortality in patients with acute critical illness due to complications following open heart surgery abdominal surgery or multiple accidental trauma or those with acute respiratory failure has been reported after treatment with pharmacologic doses of somatropin e Prader Willi Syndrome in Children There have been reports of fatalities after initiating therapy with somatropin in pediatric
37. en in untreated patients with Prader Willi syndrome Physicians should be alert to these abnormalities which may manifest during somatropin therapy 5 11 Otitis Media and Cardiovascular Disorders in Patients with Turner Syndrome Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders as these patients have an increased risk of ear and hearing disorders Somatropin treatment may increase the occurrence of otitis media in patients with Turner syndrome In addition patients with Turner syndrome should be monitored closely for cardiovascular disorders e g hypertension aortic aneurysm or dissection stroke as patients with Turner syndrome are also at increased risk for these conditions 5 12 Pancreatitis Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment with some evidence supporting a greater risk in children compared with adults Published literature indicates that girls who have Turner syndrome may be at greater risk than other somatropin treated children Pancreatitis should be considered in any somatropin treated patient especially a child who develops abdominal pain 5 13 Local and Systemic Reactions When somatropin is administered subcutaneously at the same site over a long period of time tissue atrophy may result This can be avoided by rotating the injection site see Dosage and Administration 2 2 As with any protein local or systemic
38. ent of GH deficient patients with somatropin results in a general reduction of fat stores and decreased serum concentrations of low density lipoprotein LDL cholesterol Mineral Metabolism Administration of somatropin results in an increase in total body potassium and phosphorus and to a lesser extent sodium probably as the result of cell growth Serum concentrations of inorganic phosphate increase in somatropin treated GH deficient children because of the metabolic activities associated with bone growth Although urinary calcium excretion is increased there is a simultaneous increase in calcium absorption from the intestine 13 Consequently serum calcium concentrations generally are not altered although negative calcium balance may occur occasionally during somatropin treatment Associated with the changes in mineral metabolism parathyroid hormone may increase during somatropin treatment 12 3 Pharmacokinetics Absorption Humatrope has been studied following intramuscular subcutaneous and intravenous administration in adult volunteers see Figure 1 The absolute bioavailability of somatropin is 75 and 63 after subcutaneous and intramuscular administration respectively Distribution The volume of distribution of somatropin after intravenous injection is about 0 07 L kg Table 6 Metabolism Extensive metabolism studies have not been conducted The metabolic fate of somatropin involves classical protein catabolism in both th
39. equire adjustment 5 4 Intracranial Hypertension IH Exclude preexisting papilledema IH may develop but is usually reversible after discontinuation or dose reduction 5 5 Fluid Retention e g edema arthralgia carpal tunnel syndrome especially in adults Reduce dose as necessary if such signs develop 5 6 Hypothyroidism Monitor thyroid function periodically as hypothyroidism may first become evident or worsen after initiation of somatropin 5 8 Slipped Capital Femoral Epiphysis SCFE Evaluate any child with onset of a limp or hip knee pain for possible SCFE 5 9 Progression of Preexisting Scoliosis Monitor any child with scoliosis for progression of the curve 5 10 Pancreatitis Consider pancreatitis in patients with abdominal pain especially children 5 12 Common adverse reactions reported in adult and pediatric patients receiving somatropin include injection site reactions hypersensitivity to the diluent and hypothyroidism 6 1 Additional common adverse reactions in adults include edema arthralgia myalgia carpal tunnel syndrome paraesthesias and hyperglycemia 6 1 6 2 To report SUSPECTED ADVERSE REACTIONS contact Eli Lilly and Company at 1 800 LillyRx 1 800 545 5979 or FDA at 1 800 FDA 1088 or www fda gov medwatch macnn nen nn 0 e e DRUG INTERACTIONS Inhibition of 11B Hydroxysteroid Dehydrogenase Type 1 May require the initiation of gluc
40. er and tray the bottom of the Diluent discard DO NOT depress the Note This product is designed Syringe Plunger yet It is okay if a drop for left or right handed use so of fluid is lost It is not necessary you may use whichever hand is to release air from the Diluent most comfortable for you Syringe Hold the cartridge with the PUSH the cartridge STRAIGHT Hold the Diluent Syringe and the Black Triangles toward the in until it stops AND the Black cartridge together with TWO Diluent Syringe Align the Triangles ARE COVERED HANDS Push and release the cartridge and Diluent Syringe in You may hear or feel a click Plunger 2 or 3 times until the a straight line DO NOT insert DO NOT twist the cartridge Diluent is in the cartridge the cartridge at an angle Remove your thumb from the With your thumb OFF the Place the End Cap on a hard Plunger and check that the Plunger pull the cartridge away flat surface Push the Diluent Diluent Syringe is empty it is from the Diluent Syringe Syringe onto the End Cap and normal for small drops of immediately discard the Diluent Diluent to remain in the Diluent Syringe as instructed by your Syringe healthcare professional Mix the cartridge by gently inverting 10 times and let it sit for 3 minutes DO NOT SHAKE Injections can be given in the following areas Inspect the solution The Humatrope solution should be clear If the solution is clear your cartridge is now prepar
41. etabolic New onset type 2 diabetes mellitus in patients Neoplasia Leukemia has been reported in a small number of GH deficient children treated with somatropin somatrem methionylated rhGH and GH of pituitary origin It is uncertain whether these cases of leukemia are related to GH therapy the pathology of GH deficiency itself or other associated treatments such as radiation therapy On the basis of current evidence experts have not been able to conclude that GH therapy per se was responsible for these cases of leukemia The risk for children with GH deficiency if any remains to be established see Contraindications 4 3 and Warnings and Precautions 5 3 In an ongoing post marketing observational study of somatropin treatment in 3 102 GH deficient adults hypertension dyspnea and sleep apnea were reported by 1 to less than 10 of patients after various durations of treatment 7 DRUG INTERACTIONS 7 1 11B Hydroxysteroid Dehydrogenase Type 1 The microsomal enzyme 118 hydroxysteroid dehydrogenase type 1 11BHSD 1 is required for conversion of cortisone to its active metabolite cortisol in hepatic and adipose tissue GH and somatropin inhibit 118HSD 1 Consequently individuals with untreated GH deficiency have relative increases in 11BHSD 1 and serum cortisol 11 Introduction of somatropin treatment may result in inhibition of 118HSD 1 and reduced serum cortisol concentrations As a consequence previously undiagnosed central
42. evel 11 4 15 5 NS Physical mobility 3 1 10 5 p lt 0 01 Social isolation 0 5 4 7 p lt 0 01 Emotional reactions 4 5 5 4 NS Sleep 6 4 3 7 NS Pain 2 8 2 9 NS An improvement in score is indicated by a more negative change in the score To account for multiple analyses appropriate statistical methods were applied and the required level of significance is 0 01 NS not significant o fo Two studies evaluating the effect of Humatrope on bone mineralization were conducted subsequently In a 2 year randomized double blind placebo controlled trial 67 patients with previously untreated adult onset GH deficiency received placebo or Humatrope injections titrated to maintain serum IGF I within the age adjusted normal range In men but not women lumbar spine bone mineral density BMD increased with Humatrope treatment compared to placebo with a treatment difference of approximately 4 p 0 001 There was no significant change in hip BMD with Humatrope treatment in men or women when compared to placebo In a 2 year open label randomized trial 149 patients with childhood onset GH deficiency who had completed pediatric somatropin therapy had attained final height height velocity lt 1 cm yr and were confirmed to be GH deficient as young adults commonly referred to as transition patients were randomized to receive Humatrope 0 0125 mg kg day 12 5 g kg day Humatrope 0 025 mg kg day 25 ug kg day or no injections
43. g the 2 year study period the proportion of patients who had at least one IGF I concentration greater than 2 0 SD above the age and gender appropriate mean was 10 of 27 37 0 for the Humatrope treated group vs 0 of 24 patients 0 0 for the untreated group The proportion of patients who had at least one IGFBP 3 concentration greater than 2 0 SD above the age and gender appropriate mean was 16 of 27 59 3 for the Humatrope treated group vs 7 of 24 29 2 for the untreated group Table 3 Clinically Significant Treatment Emergent Adverse Reactions by Treatment Group in Patients with SHOX Deficiency Adverse Reaction drsetnientiGreup Untreated Humatrope Total Number of Patients 25 27 Patients with at least one event 2 5 Arthralgia 2 8 0 3 11 1 Gynecomastia 0 0 0 1 8 3 Excessive number of cutaneous nevi 0 0 0 2 7 4 Scoliosis 0 0 0 1 3 7 All events were non serious P Events are included only if reported for a greater number of Humatrope treated than Untreated patients Percentage calculated for males only 1 12 Small for Gestational Age Study 1 In a 2 year multicenter randomized study 193 non GH deficient children with short stature born SGA who failed to demonstrate catch up growth were treated with 2 different Humatrope treatment regimens a fixed dose of 0 067 mg kg day FHD group or an individually adjusted dose regimen IAD group starting dose 0 035 mg
44. he Humatrope treated patients received a dosage of 0 3 mg kg week given in divided doses 6 times per week from a mean age of 11 7 years for a mean duration of 4 7 years Puberty was induced with a standardized estrogen regimen initiated at 13 years of age for both treatment groups The Humatrope treated group n 27 attained a mean SD near final height of 146 0 6 2 cm the untreated control group n 19 attained a near final height of 142 1 4 8 cm By analysis of covariance with adjustments for baseline height and mid parental height the effect of somatropin treatment was a mean height increase of 5 4 cm p 0 001 In two of the US studies the effect of long term somatropin treatment 0 375 mg kg week given in divided doses either 3 times per week or daily on adult height was determined by comparing adult heights in the treated patients with those of age matched historical controls with Turner syndrome who received no growth promoting therapy Puberty was induced with a standardized estrogen regimen initiated after 14 years of age in one study in the second study patients treated with early somatropin before 11 years of age were randomized to begin pubertal induction at either age 12 n 26 or 15 n 29 years conjugated estrogens 0 3 mg escalating to 0 625 mg daily those whose somatropin was initiated after 11 years of age began estrogen replacement after 1 year of somatropin Mean height gains from baseline to adult or near adult height ra
45. hould be monitored closely when somatropin therapy is administered e Hypothyroidism Patients treated with somatropin should have periodic thyroid function tests and thyroid hormone replacement therapy should be initiated or appropriately adjusted in cases of unmasked or worsening hypothyroidism e Slipped Capital Femoral Epiphysis in Pediatric Patients Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders and in patients undergoing rapid growth Any pediatric patient with the onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated Progression of Scoliosis in Pediatric Patients Progression of scoliosis can occur in patients who experience rapid growth Somatropin has not been shown to increase the occurrence of scoliosis Otitis Media and Cardiovascular Disorders in Patients with Turner Syndrome Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders as somatropin treatment may increase the occurrence of otitis media in these susceptible patients In addition patients with Turner syndrome should be monitored closely for cardiovascular disorders e g hypertension aortic aneurysm or dissection stroke as they are at increased risk for these conditions Pancreatitis Cases of pancreatitis have been reported rarely in children and adults receiving somatropin Pancreatitis should be considered in any so
46. hyroidism may prevent an optimal response to somatropin in particular the growth response in children Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism In patients with GH deficiency central secondary hypothyroidism may first become evident or worsen during somatropin treatment Therefore patients treated with somatropin should have periodic thyroid function tests performed and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated 5 9 Slipped Capital Femoral Epiphysis in Pediatric Patients 6 Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders including pediatric GH deficiency and Turner syndrome or in patients undergoing rapid growth Any pediatric patient with the onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated 5 10 Progression of Preexisting Scoliosis in Pediatric Patients Progression of scoliosis can occur in patients who experience rapid growth Because somatropin increases growth rate patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis However somatropin has not been shown to increase the occurrence of scoliosis Skeletal abnormalities including scoliosis are commonly seen in untreated patients with Turner syndrome Scoliosis is also commonly se
47. ic transferase were reported significantly more often for Humatrope treated 12 5 than placebo treated patients 0 0 p 0 031 No other events were reported significantly more often for Humatrope treated patients during the placebo controlled phase The following events were reported for at least 5 of patients in either of the 2 treatment groups over the 18 month duration of the study listed in descending order of maximum frequency for either group aspartate aminotransferase increased 13 10 headache 11 edema 9 pain 9 alanine aminotransferase increased 6 asthenia 6 myalgia 6 respiratory disorder 6 Table 5 Treatment Emergent Adverse Reactions with 25 Overall Occurrence in Childhood Onset Growth Hormone Deficient Patients Treated with Humatrope for 18 Months as Compared with 6 Month Placebo and 12 Month Humatrope Exposure 18 Months Exposure 18 Months GH Exposure Adverse Reaction Placebo 6 per a 12 Months ie n n Flu syndrome 8 22 9 5 15 6 AST increased 2 5 7 4 12 5 Headache 4 11 4 3 9 4 Asthenia 1 2 9 2 6 3 Cough increased 0 0 2 6 3 Edema 3 8 6 2 6 3 Hypesthesia 0 0 2 6 3 Myalgia 2 5 7 2 6 3 Pain 3 8 6 2 6 3 Rhinitis 2 5 7 2 6 3 ALT increased 2 5 7 2 6 3 Respiratory disorder 2 5 7 1 3 1 Gastritis 2 5 7 0 0 Pharyngitis 5 14 3 1 3 1 i Abbreviations GH Humatrope N number of patients receiving treatment in the period stated n numbe
48. ich approximately half of the patients received placebo injections while the other half received Humatrope injections The Humatrope dosages for all studies were identical 1 month of treatment at 0 00625 mg kg day 6 25 ug kg day followed by 0 0125 mg kg day 12 5 ug kg day for the next 5 months The 6 month double blind phase was followed by 12 months of open label Humatrope treatment for all patients The primary efficacy measures were body composition lean body mass and fat mass lipid parameters and quality of life as measured by the Nottingham Health Profile a general health related quality of life questionnaire Lean body mass was determined by bioelectrical impedance analysis BIA validated with potassium 40 Body fat was assessed by BIA and sum of skinfold thickness Lipid subfractions were analyzed by standard assay methods in a central laboratory Adult onset patients and childhood onset patients differed by diagnosis organic vs idiopathic pituitary disease body size average vs small mean height and weight and age mean 44 vs 29 years In patients with adult onset GH deficiency Humatrope treatment vs placebo resulted in an increase in mean lean body mass 2 59 vs 0 22 kg p lt 0 001 and a decrease in body fat 3 27 vs 0 56 kg p lt 0 001 Similar changes were seen in childhood onset GH deficient patients These significant changes in lean body mass persisted throughout the 18 month period for both the adult onset and
49. in height after small for gestational age birth 1 1 Adult Patients Treatment of adults with either childhood onset or adult onset GH deficiency 1 2 Humatrope should be administered subcutaneously 2 2 Injection sites should always be rotated regularly to avoid lipoatrophy 2 2 For pediatric patients the recommended weekly dosages in milligrams mg per kilogram kg of body weight given in divided doses 6 to 7 times per week are Pediatric GH deficiency 0 18 to 0 30 mg kg week 2 3 Turner syndrome Up to 0 375 mg kg week 2 3 Idiopathic short stature Up to 0 37 mg kg week 2 3 SHOX deficiency 0 35 mg kg week 2 3 Small for gestational age Up to 0 47 mg kg week 2 3 Adult GH deficiency Either a non weight based or a weight based dosing regimen may be followed with doses adjusted based on treatment response and IGF I concentrations 2 4 Non weight based dosing A starting dose of approximately 0 2 mg day range 0 15 0 30 mg day may be used without consideration of body weight and increased gradually every 1 2 months by increments of approximately 0 1 0 2 mg day 2 4 Weight based dosing The recommended initial daily dose is not more than 0 006 mg kg 6 g kg the dose may be increased to a maximum of 0 0125 mg kg 12 5 ug kg daily 2 4 1 2 22 DOSAGE FORMS AND STRENGTHS 5 mg vial and 5 mL vial of Diluent for Humatrope 3 6 mg gold 12 mg teal and 24 mg
50. ized muscle pain weakness mild hyperglycemia and glucosuria Adult Onset GH Deficiency In the first 6 months of controlled blinded trials during which patients received either Humatrope or placebo adult onset GH deficient adults who received Humatrope experienced a statistically significant increase in edema Humatrope 17 3 vs placebo 4 4 p 0 043 and peripheral edema 11 5 vs 0 respectively p 0 017 In patients with adult onset GH deficiency edema muscle pain joint pain and joint disorder were reported early in therapy and tended to be transient or responsive to dosage titration Two of 113 adult onset patients developed carpal tunnel syndrome after beginning maintenance therapy without a low dose 0 00625 mg kg day lead in phase Symptoms abated in these patients after dosage reduction All treatment emergent adverse events with 25 overall occurrence rate during 12 or 18 months of replacement therapy with Humatrope are shown in Table 4 adult onset patients and in Table 5 childhood onset patients Adult patients treated with Humatrope who had been diagnosed with GH deficiency in childhood reported side effects less frequently than those with adult onset GH deficiency Table 4 Treatment Emergent Adverse Reactions with 25 Overall Occurrence in Adult Onset Growth Hormone Deficient Patients Treated with Humatrope for 18 Months as Compared with 6 Month Placebo and 12 Month Humatrope Exposure
51. kg day which could be increased as early as Month 3 to 0 067 mg kg day based on a validated growth prediction model The most frequently reported adverse events were common childhood infectious diseases Adverse events possibly probably related to Humatrope were otitis media and headaches where there was a suggestion of a modest dose response and slipped capital femoral epiphysis 1 child see Warnings and Precautions 5 9 and Adverse Reactions 6 1 There were no clear cut cases of new onset diabetes mellitus no children treated for hyperglycemia and no children whose fasting blood glucose exceeded 126 mg dL at any time during the study However 6 children 4 in the FHD group and 2 in the IAD group whose dose was increased from 0 035 mg kg day to 0 067 mg kg day one at Month 3 and one at Year 1 manifested impaired fasting glucose at Year 2 Two of these six children displayed impaired fasting glucose during the study as well and one of them was required to discontinue Humatrope at Month 15 as a consequence see Warnings and Precautions 5 4 and Adverse Reactions 6 1 A modestly dose dependent increase in mean serum IGF I SDS concentrations within the reference range was observed of note at study completion 20 25 of these children had serum IGF I SDS values gt 2 Study 2 A 2 year open label single arm study of Humatrope at a dosage of 0 067 mg kg day in 35 non GH deficient children with short stature born SGA who failed to demons
52. ly with an alcohol swab Use a circular motion and work outward from the inside of the circle 3 3 Subcutaneous Injection With the thumb and forefinger stabilize the skin by spreading or pinching up a large area of skin e Holding the syringe at a 90 degree angle to injection site quickly insert the needle all the way into the skin e Slowly inject the solution e Remove the needle quickly and apply pressure over the injection site with a dry gauze pad or cotton ball Rub for several seconds e Destroy needle or needle and syringe after use 4 Intramuscular Injection With the thumb and first 2 fingers press the skin down firmly against a large muscle mass such as the thigh e Holding the syringe at a 90 degree angle to injection site quickly insert the needle all the way into the skin e When the needle is in place slowly pull back on the plunger If blood enters the syringe remove needle discard syringe and drug and prepare another injection e Ifno blood enters the syringe slowly inject the solution e Remove the needle quickly and apply pressure over the injection site with a dry gauze pad or cotton ball Rub for several seconds e Destroy needle or needle and syringe after use If you have any questions consult your doctor Literature revised August 1 2011 Marketed by LILLY USA LLC INDIANAPOLIS IN 46285 USA PA 1686 AMP
53. matropin treated patient especially a child who develops abdominal pain Girls who have Turner syndrome may be at greater risk than other somatropin treated children Local and Systemic Reactions Injection site should be rotated to avoid tissue atrophy Patients should be informed that local or systemic allergic reactions may occur and that prompt medical attention should be sought in such cases e Laboratory Tests Serum levels of inorganic phosphorus alkaline phosphatase parathyroid hormone and IGF I may increase after somatropin therapy e Pregnancy Nursing Mothers Somatropin should be used during pregnancy only if clearly needed and with caution in nursing mothers because it is not known whether somatropin is excreted in human milk e Special Populations The safety and effectiveness of somatropin in patients aged 65 years and over have not been evaluated in clinical studies Elderly patients may be more sensitive to the action of somatropin and may be more prone to adverse reactions e Potential Drug Interactions Somatropin inhibits 11B hydroxysteroid dehydrogenase type 1 11RHSD 1 in adipose hepatic tissue and may significantly impact the metabolism of cortisol and cortisone As a consequence in patients treated with somatropin previously undiagnosed central secondary hypoadrenalism may be unmasked requiring glucocorticoid replacement therapy o Careful monitoring is advisable when growth hormone is administered in com
54. n 15 IU or 225 nanomoles 25 mg mannitol 5 mg glycine and 1 13 mg dibasic sodium phosphate Each vial is supplied in a combination package with an accompanying 5 12 mL vial of diluting solution diluent The diluent contains Water for Injection with 0 3 metacresol as a preservative and 1 7 glycerin Cartridge Cartridges of Humatrope contain either 6 mg 18 IU 12 mg 36 IU or 24 mg 72 IU of somatropin Each Humatrope cartridge contains the following Cartridge 6mg 12 mg 24 mg gold teal purple Component Somatropin 6 mg 12 mg 24 mg Mannitol 18 mg 36 mg 72 mg Glycine 6 mg 12 mg 24 mg res 1 36mg 2 72mg 5 43 mg Each cartridge is supplied in a combination package with an accompanying syringe containing approximately 3 mL of diluting solution diluent The diluent contains Water for Injection 0 3 metacresol as a preservative and 1 7 0 29 and 0 29 glycerin in the 6 12 and 24 mg cartridges respectively 12 CLINICAL PHARMACOLOGY 12 1 Mechanism of Action GH binds to dimeric GH receptors located within the cell membranes of target tissue cells This interaction results in intracellular signal transduction and subsequent induction of transcription and translation of GH dependent proteins including IGF I IGF BP 3 and acid labile subunit GH has direct tissue and metabolic effects including stimulation of chondrocyte differentiation stimulation of lipolysis and stimulation of
55. nged from 5 0 to 8 3 cm depending on age at initiation of somatropin treatment and estrogen replacement Table 8 In the third US study a randomized blinded dose response study patients were treated from a mean age of 11 1 years for a mean duration of 5 3 years with a weekly Humatrope dosage of either 0 27 mg kg or 0 36 mg kg administered in divided doses 3 or 6 times weekly The mean near final height of Humatrope treated patients was 148 7 6 5 cm n 31 When compared to historical control data the mean gain in adult height was approximately 5 cm In summary patients with Turner syndrome total n 181 from the 4 studies above treated to adult height achieved statistically significant average height gains ranging from 5 0 to 8 3 cm Table 8 Summary Table of Efficacy Results Study Group Study Number at Adult GH Estroge GH Adult Height Design Height Age yr n Duration yr Gain cm Age yr Canadian RCT 27 11 7 13 4 7 5 4 US 1 MHT 17 9 1 15 2 7 6 7 4 US 2 AY MHT 29 9 4 15 6 1 8 3 B 26 9 6 12 3 5 6 5 9 c9 51 12 7 13 7 3 8 5 US 3 RDT 31 11 1 8 13 5 5 3 5 Data shown are mean values P RCT randomized controlled trial MHT matched historical controlled trial RDT randomized dose response trial Analysis of covariance vs controls 8 Compared with historical data GH age lt 11 yr estrogen age 15 yr f GH age lt 11 yr estrogen age 12 yr 3 GH age gt 11 yr estrogen at m
56. nt when somatropin therapy is instituted in these patients 5 5 Intracranial Hypertension Intracranial hypertension IH with papilledema visual changes headache nausea and or vomiting has been reported in a small number of patients treated with somatropin products Symptoms usually occurred within the first eight 8 weeks after the initiation of somatropin therapy In all reported cases IH associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose Funduscopic examination should be performed routinely before initiating treatment with somatropin to exclude preexisting papilledema and periodically during the course of somatropin therapy If papilledema is observed by funduscopy during somatropin treatment treatment should be stopped If somatropin induced IH is diagnosed treatment with somatropin can be restarted at a lower dose after IH associated signs and symptoms have resolved Patients with Turner syndrome may be at increased risk for the development of IH 5 6 Fluid Retention Fluid retention during somatropin replacement therapy in adults may frequently occur Clinical manifestations of fluid retention are usually transient and dose dependent 5 7 Hypopituitarism Patients with hypopituitarism multiple pituitary hormone deficiencies should have their other hormonal replacement treatments closely monitored during somatropin treatment 5 8 Hypothyroidism Undiagnosed untreated hypot
57. ocorticoid replacement therapy Patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance doses 7 1 7 2 Glucocorticoid Replacement Should be carefully adjusted 7 2 Cytochrome P450 Metabolized Drugs Monitor carefully if used with somatropin 7 3 Oral Estrogen Larger doses of somatropin may be required in women 7 4 Insulin and or Other Hypoglycemic Agents May require adjustment 7 5 See 17 for PATIENT COUNSELING INFORMATION and FDA approved patient labeling Revised 07 2014 FULL PRESCRIBING INFORMATION CONTENTS 1 INDICATIONS AND USAGE 1 1 Pediatric Patients 1 2 Adult Patients 2 DOSAGE AND ADMINISTRATION 2 1 Reconstitution 2 2 General Administration Guidelines 2 3 Dosing for Pediatric Patients 2 4 Dosing for Patients with Adult Growth Hormone Deficiency 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4 1 Acute Critical Illness 4 2 Prader Willi Syndrome in Children 4 3 Active Malignancy 4 4 Diabetic Retinopathy 4 5 Closed Epiphyses 4 6 Hypersensitivity 5 WARNINGS AND PRECAUTIONS 8 1 Pregnancy 5 1 Acute Critical Illness 8 3 Nursing Mothers 5 2 Prader Willi Syndrome in Children 8 5 Geriatric Use 2 P RAAE 9 DRUG ABUSE AND DEPENDENCE ucose Intolerance and Diabetes Mellitus 5 5 Intracranial Hypertension 10 OVERDOSAGE 5 6 Fluid Retention 11 DESCRIPTION 5 7 Hypopituitarism 12 CLINICAL PHARMACOLOGY 5 8 Hypothyroidism na
58. on of the study and final height SDS minus baseline predicted height SDS were also significantly greater in Humatrope treated patients than in placebo treated patients Tables 9 and 10 In addition the number of patients whose final height was above the 5th percentile of the general population height standard for age and sex was significantly greater in the Humatrope group than the placebo group 41 vs 0 p lt 0 05 as was the number of patients who gained at least 1 SDS unit in height across the duration of the study 50 vs 0 p lt 0 05 Table 9 Baseline Height Characteristics and Effect of Humatrope on Final Height in Placebo Controlled Study Placebo Humatrope Treatment Effect p value n 11 n 22 Mean Mean SD Mean SD 95 Cl Baseline height SDS 2 75 0 6 2 7 0 6 NA 0 77 BPH SDS 2 3 0 8 2 1 0 7 NA 0 53 Final height SDS 2 3 0 6 1 8 0 8 0 51 0 10 0 92 0 017 FH SDS baseline height SDS 0 4 0 2 0 9 0 7 0 51 0 04 0 97 0 034 FH SDS BPH SDS 0 1 0 6 0 3 0 6 0 46 0 02 0 89 0 043 Abbreviations BPH baseline predicted height Cl confidence interval FH final height NA not applicable SDS standard deviation score gt For final height population Between group comparison was performed using analysis of covariance with baseline predicted height SDS as the covariate Treatment effect is expressed as least squares mean 95 Cl The dose response stud
59. on of treatment Somatropin should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor 4 4 Diabetic Retinopathy Somatropin is contraindicated in patients with active proliferative or severe non proliferative diabetic retinopathy 4 5 Closed Epiphyses Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses 4 6 Hypersensitivity Humatrope is contraindicated in patients with a known hypersensitivity to somatropin or diluent Localized reactions are the most common hypersensitivity reactions 5 WARNINGS AND PRECAUTIONS 5 1 Acute Critical Illness Increased mortality in patients with acute critical illness due to complications following open heart surgery abdominal surgery or multiple accidental trauma or those with acute respiratory failure has been reported after treatment with pharmacologic doses of somatropin see Contraindications 4 1 The safety of continuing somatropin treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established Therefore the potential benefit of treatment continuation with somatropin in patients experiencing acute critical illnesses should be weighed against the potential risk 5 2 Prader Willi Syndrome in Children There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with Prader Willi syndrome who ha
60. onth 12 14 3 Pediatric Patients with Idiopathic Short Stature Two randomized multicenter trials 1 placebo controlled and 1 dose response were conducted in pediatric patients with idiopathic short stature also called non GH deficient short stature The diagnosis of idiopathic short stature was made after excluding other known causes of short stature as well as GH deficiency Limited safety and efficacy data are available below the age of 7 years No specific studies have been conducted in pediatric patients with familial short stature The placebo controlled study enrolled 71 pediatric patients 55 males 16 females 9 to 15 years old mean age 12 4 1 5 years with short stature 68 of whom received Humatrope Patients were predominately prepubertal Tanner 16 45 or in early puberty Tanner Il 47 at baseline In this double blind trial patients received subcutaneous injections of either Humatrope 0 222 mg kg week equivalent to 32 yg kg day or placebo given in divided doses 3 times per week until height velocity decreased to lt 1 5 cm year final height Final height measurements were available for 33 subjects 22 Humatrope 11 placebo after a mean treatment duration of 4 4 years range 0 1 9 1 years The Humatrope treated group achieved a mean final height SDS of 1 8 Table 9 whereas placebo treated patients had a mean final height SDS of 2 3 mean treatment difference 0 51 SDS p 0 017 Height gain across the durati
61. osage e g gradually towards 0 033 mg kg day should be considered if substantial catch up growth is observed during the first few years of therapy On the other hand in younger SGA children e g approximately lt 4 years who respond the best in general with less severe short stature i e baseline height SDS values between 2 and 3 consideration should be given to initiating treatment at a lower dose e g 0 033 mg kg day and titrating the dose as needed over time In all children clinicians should carefully monitor the growth response and adjust the somatropin dose as necessary 2 4 Dosing for Patients with Adult Growth Hormone Deficiency Either of two approaches to Humatrope dosing may be followed a non weight based regimen or a weight based regimen Non weight based based on published consensus guidelines a starting dose of approximately 0 2 mg day range 0 15 0 30 mg day may be used without consideration of body weight This dose can be increased gradually every 1 2 months by increments of approximately 0 1 0 2 mg day according to individual patient requirements based on the clinical response and serum insulin like growth factor IGF I concentrations The dose should be decreased as necessary on the basis of adverse events and or serum IGF I concentrations above the age and gender specific normal range Maintenance dosages vary considerably from person to person and between male and female patients Weight based b
62. oxyproline Carbohydrate Metabolism GH has a physiological role in the maintenance of normoglycemia during times of substrate restriction e g fasting via mechanisms such as stimulation of hepatic gluconeogenesis and suppression of insulin stimulated glucose uptake by peripheral tissues Because of these actions GH is considered an insulin antagonist with respect to carbohydrate metabolism Consequently the fasting hypoglycemia that may occur in some children with hypopituitarism may be improved by somatropin treatment As an extension of its physiological actions supraphysiological GH concentrations may increase glucose production sufficiently to stimulate insulin secretion to maintain normoglycemia Large doses of somatropin may impair glucose tolerance if compensatory insulin secretion is inadequate Administration of somatropin to healthy adults and patients with Turner syndrome resulted in increases in mean serum fasting and postprandial insulin concentrations although mean values remained in the normal range In addition mean HbA concentrations and mean fasting and postprandial glucose concentrations remained in the normal range Lipid Metabolism Somatropin stimulates intracellular lipolysis and administration of somatropin leads to an increase in plasma free fatty acids and triglycerides Untreated GH deficiency is associated with increased body fat stores including increased abdominal visceral and subcutaneous adipose tissue Treatm
63. population height standards p NS Table 10 Idiopathic Short Stature Trials Final Height Minus Baseline Predicted Height Placebo controlled Trial Dose Response Trial 3x per week dosing 6x per week dosing Placebo Humatrope Humatrope Humatrope Humatrope 0 22 mg kg 0 24 mg kg 0 24 0 37 mg kg 0 37 mg kg n 10 n 22 n 13 n 13 n 13 FH Baseline PH 0 7 3 6 2 3 2 2 0 4 3 9 5 4 2 8 6 7 4 1 9 2 7 2 4 6 9 8 Mean 95 Cl cm 7 9 Abbreviations FH final height PH predicted height Cl confidence interval cm centimeters 14 4 Pediatric Patients with SHOX Deficiency SHOX deficiency may result either from a deletion of one copy of the short stature homeobox containing SHOX gene or from a mutation within or outside one copy of the SHOX gene that impairs the production or function of SHOX protein A randomized controlled two year three arm open label study was conducted to evaluate the efficacy of Humatrope treatment of short stature in pediatric patients with SHOX deficiency who were not GH deficient 52 patients 17 24 male 28 female with SHOX deficiency 3 0 to 12 3 years of age were randomized to either a Humatrope treated arm 27 patients mean age 7 3 2 1 years or an untreated control arm 25 patients mean age 7 5 2 7 years To determine the comparability of treatment effect between patients with SHOX deficiency and patients with Turner syndrome the third study arm en
64. r of patients reporting each treatment emergent adverse event ALT alanine aminotransferase formerly SGPT AST aspartate aminotransferase formerly SGOT p 0 03 as compared to placebo 6 months ion 6 3 Post Marketing Experience Because these adverse events are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure The adverse events reported during post marketing surveillance do not differ from those listed discussed above in Sections 6 1 and 6 2 in children and adults Other adverse events that have been reported in somatropin treated patients include the following Neurologic Headaches common in children and occasional in adults Skin Increase in size or number of cutaneous nevi especially in patients with Turner syndrome and those with SHOX deficiency see Warnings and Precautions 5 3 Endocrine Gynecomastia Gastrointestinal Pancreatitis Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment with some evidence supporting a greater risk in children compared with adults Published literature indicates that girls who have Turner syndrome may be at greater risk than other somatropin treated children Pancreatitis should be considered in any somatropin treated patient especially a child who develops abdominal pain see Warnings and Precautions 5 12 M
65. rolled 26 patients with Turner syndrome 4 5 to 11 8 years of age mean age 7 5 1 9 years to Humatrope treatment All patients were prepubertal at study entry Patients in the Humatrope treated group s received daily subcutaneous injections of 0 05 mg kg 50 g kg of Humatrope equivalent to 0 35 mg kg week Patients in the untreated group received no injections Patients with SHOX deficiency who received Humatrope had significantly greater first year height velocity than untreated patients 8 7 cm year vs 5 2 cm year p lt 0 001 primary efficacy analysis and similar first year height velocity to Humatrope treated patients with Turner syndrome 8 7 cm year vs 8 9 cm year In addition patients who received Humatrope had significantly greater second year height velocity and first and second year height gain cm and SDS than untreated patients Table 11 Table 11 Summary of Efficacy Results in Patients with SHOX deficiency and Turner Syndrome SHOX Deficiency Turner Syndrome Untreated Humatrope Treatment Humatrope n 24 n 27 Difference n 26 Mean SD Mean SD Mean 95 CI Mean SD Height Velocity cm yr 1 Year 5 2 1 1 8 7 1 6 3 5 2 8 4 2 8 9 2 0 2 Year 5 4 1 2 7 3 1 1 2 0 1 3 2 6 7 0 1 1 Height Gain cm Baseline to 1 Year 5 4 1 2 9 1 1 5 3 7 2 9 4 5 8 9 1 9 Baseline to 2 Year 10 5 1 9 16 4 2 0 5 8 4 6 7 1 15 7 2 7 Height SDS Gain Baselin
66. rse Reactions by Treatment Group in Idiopathic Short Stature Treatment Group Adverse Reaction Placebo Humatrope Total Number of Patients 31 37 Scoliosis 4 12 9 7 18 9 Otitis media 2 6 5 6 16 2 Hyperlipidemia 1 3 2 3 8 1 Gynecomastia 1 3 2 2 5 4 Hip pain 0 1 2 7 Arthralgia 1 3 2 4 10 8 Arthrosis 2 6 5 4 10 8 Myalgia 4 12 9 9 24 3 Hypertension 0 1 2 7 The adverse events observed in the dose response study 239 patients treated for 2 years did not indicate a pattern suggestive of a somatropin dose effect Among Humatrope dose groups mean fasting blood glucose mean glycosylated hemoglobin and the incidence of elevated fasting blood glucose concentrations were similar One patient developed abnormalities of carbohydrate metabolism glucose intolerance and high serum HbA on treatment SHOX Deficiency Clinically significant adverse events adverse events previously observed in association with growth hormone treatment in general were assessed prospectively during the 2 year randomized open label study those observed are presented in Table 3 In both treatment groups the mean fasting plasma glucose concentration at the end of the first year was similar to the baseline value and remained in the normal range No patient developed diabetes mellitus or had an above normal value for fasting plasma glucose at the end of one year of treatment Durin
67. rt Stature In a randomized placebo controlled study of Humatrope treatment 0 22 mg kg week to adult height in patients with idiopathic short stature the adverse events reported in Humatrope treated patients Table 2 were similar to those observed in other pediatric populations treated with Humatrope Mean serum glucose concentration did not change during Humatrope treatment Mean fasting serum insulin concentration increased 10 in the Humatrope treatment group at the end of treatment relative to baseline but remained within the normal reference range For the same duration of treatment the mean fasting serum insulin concentration decreased by 2 in the placebo group The occurrence rates of above range values for glucose insulin and HbA were similar in the Humatrope somatropin and placebo treated groups No patient developed diabetes mellitus Consistent with the known mechanism of growth hormone action Humatrope treated patients had greater mean increases relative to baseline in serum insulin like growth factor I IGF I than placebo treated patients at each study observation However there was no significant difference between the Humatrope and placebo treatment groups in the proportion of patients who had at least one serum IGF I concentration more than 2 0 SD above the age and gender appropriate mean Humatrope 9 of 35 patients 26 placebo 7 of 28 patients 25 Table 2 Non serious Clinically Significant Treatment Emergent Adve
68. s indicated for the treatment of e Children who have growth failure or short stature due to growth hormone GH deficiency Turner syndrome or SHOX deficiency have idiopathic short stature defined by height SDS lt 2 25 associated with growth rates unlikely to result in adult height in the normal range and in whom other causes of short stature have been excluded were born small for gestational age and fail to show catch up growth by 2 to 4 years of age e Adults who have GH deficiency either adult onset as a result of pituitary disease hypothalamic disease surgery radiation therapy or trauma or childhood onset Patients treated for growth hormone deficiency in childhood who have closed epiphyses should be reevaluated to determine if they should continue growth hormone Contraindications e Acute Critical Illness Somatropin should not be used to treat patients with acute critical illness due to complications following open heart surgery abdominal surgery or multiple accidental trauma or those with acute respiratory failure A significant increase in mortality has been reported in such cases e Prader Willi Syndrome in Children Somatropin should not be used in pediatric patients with Prader Willi syndrome who are severely obese have a history of upper airway obstruction or sleep apnea or have severe respiratory impairment There have been reports of sudden death when somatropin was used in such patients Humatrope is not indicat
69. secondary hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with somatropin In addition patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11BHSD 1 7 2 Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth promoting effects of somatropin in children Therefore glucocorticoid replacement dosing should be carefully adjusted in children receiving concomitant somatropin and glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth 7 3 Cytochrome P450 Metabolized Drugs Limited published data indicate that somatropin treatment increases cytochrome P450 CP450 mediated antipyrine clearance in man These data suggest that somatropin administration may alter the clearance of compounds metabolized by CP450 liver enzymes e g corticosteroids sex steroids anticonvulsants cyclosporine Therefore careful monitoring is advised when somatropin is administered in combination with drugs metabolized by CP450 liver enz
70. ster Humatrope should receive appropriate training and instruction on the proper use of Humatrope from the physician or other suitably qualified health care professional A puncture resistant container for the disposal of used needles and syringes should be strongly recommended Patients and or parents should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of needles and syringes This information is intended to aid in the safe and effective administration of the medication Literature revised July 30 2014 Marketed by Lilly USA LLC Indianapolis IN 46285 USA Copyright 1987 2014 Eli Lilly and Company All rights reserved HTR 0001 USPI 20140730 1 RA 119 FSAM 00 INFORMATION AND PATIENT INSTRUCTIONS HUMATROPE Somatropin rDNA origin for Injection CARTRIDGES HUMATROPE CARTRIDGES ARE ONLY TO BE USED WITH HUMATROPEN OR HUMATROPEN 3 INJECTION DEVICES Important Things to Know It is important to learn the names of the parts of the Humatrope Cartridge Kit and how these parts work before injecting yourself or your child Make sure you have been properly trained by your nurse pharmacist or doctor before you mix the drug add the diluent liquid to the dry Humatrope powder or inject it Wash your hands and be careful to follow the instructions given to you by your nurse pharmacist or doctor After mixing throw away the diluent syringe in a puncture resistant container such as the type
71. ting the Vial of Humatrope Reconstitute Humatrope only with Diluent for Humatrope Do not use other solutions for reconstitution unless instructed to do so by your doctor Your doctor will also tell you what size syringe and needle to use and how much diluent to add to the vial of Humatrope Always start by washing your hands 1 Remove and discard plastic caps from tops of vials of diluent and Humatrope Wipe tops of both vials with an alcohol swab Figure 1 Remove needle cover and save Pull back on syringe plunger to draw up an amount of air equal to the amount of diluent your doctor has prescribed Insert needle in stopper of diluent vial and inject air into vial 2 Hold vial upside down and making sure needle tip remains in solution withdraw the amount of diluent your doctor has prescribed Figure 2 After making sure that no air bubbles are in the syringe turn vial upright and holding barrel remove syringe 3 Insert same needle into vial of Humatrope and gently aim needle tip toward wall of vial Slowly inject the diluent by aiming the stream of liquid against the wall of vial Figure 3 Do not aim it at the white 4 2 powder at the bottom of the vial To equalize the pressure withdraw a volume of air equal to the amount of diluent added before removing the syringe from the vial If the needle can be removed from the barrel of the syringe remove destroy and discard the needle If the needle and syringe are made as
72. tions 4 3 Monitor all patients receiving somatropin therapy who have a history of GH deficiency secondary to an intracranial neoplasm for progression or recurrence of the tumor Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies practitioners should thoroughly consider the risks and benefits of starting somatropin in these patients If treatment with somatropin is initiated these patients should be carefully monitored for development of neoplasms Monitor patients receiving somatropin therapy carefully for increased growth or potential malignant changes of preexisting nevi 5 4 Glucose Intolerance and Diabetes Mellitus Treatment with somatropin may decrease insulin sensitivity particularly at higher doses in susceptible patients As a result previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked and new onset type 2 diabetes mellitus has been reported in patients taking somatropin Therefore glucose levels should be monitored periodically in all patients treated with somatropin especially in those with risk factors for diabetes mellitus such as obesity Turner syndrome or a family history of diabetes mellitus Patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during somatropin therapy The doses of antihyperglycemic drugs e g insulin or oral agents may require adjustme
73. trate catch up growth did not reveal further safety data of note Study 3 Additional safety information was obtained from 340 short children born SGA followed in an observational study who received an average Humatrope dosage of 0 041 mg kg day maximum dose 0 084 mg kg day for an average of 3 0 years Type 2 diabetes mellitus apparently precipitated by Humatrope therapy was reported in a single patient but appeared to resolve after discontinuation of Humatrope treatment as the child had a normal oral glucose tolerance test and was receiving no antihyperglycemic medications 9 months after the drug was discontinued One patient manifested carpal tunnel syndrome see Adverse Reactions 6 1 and another developed an exacerbation of preexisting scoliosis see Warnings and Precautions 5 10 and Adverse Reactions 6 1 which may have been related to Humatrope treatment In both Study 1 and Study 2 after treatment with Humatrope bone maturation did not accelerate excessively and the timing of puberty was age appropriate in boys and girls 9 Therefore it can be concluded that no novel adverse events potentially related to treatment with Humatrope were reported in either short term study or were apparent after a review of the post marketing observational safety database Adult Patients In clinical studies in which high doses of Humatrope were administered to healthy adult volunteers the following events occurred infrequently headache local
74. uggested Pharmacy optional Phone and dosing Suggested Pharmacy can be completed only by a member of the office staff PRESCRIBER CERTIFICATIONS By signing below certify that the therapy is medically necessary and that this information is accurate to the best of my knowledge also represent that am disclosing this information for purposes of treatment payment and or healthcare operations and otherwise have consent to disclose this information as well as other medical information that may be disclosed including medical records of the patient to Eli Lilly and Company and Lilly USA LLC and its agents for the purpose of assessing whether the patient qualifies for any reimbursement benefits through the duration of the patient s therapy also certify that the patient is aware and has consented to my disclosure of their information to Lilly so that Lilly may contact the patient to further enable these services Prescriber Name NPI DEA License Tax ID Dispense as written No stamps allowed Please see Indications for Use and Phone Fax Important Safety Information on the back of this form and accompanying Name of Contact Person Contact Phone Full Prescribing Information and Patient Information Prescriber Signature e See Full Pen User Manual that accompanies the HumatroPen 6 mg 12 mg 24 mg Date Important Safety Information for Humatrope INDICATIONS FOR HUMATROPE Humatrope i
75. usion criteria included syndromal conditions e g Turner syndrome chronic disease e g diabetes mellitus and tumor activity Children were randomized to either a FHD 0 067 mg kg day 0 47 mg kg week n 99 or an IAD treatment group n 94 The initial Humatrope dosage in the IAD treatment group was 0 035 mg kg day 0 25 mg kg week The dosage was increased to 0 067 mg kg day in those patients in the IAD group whose 1 year height gain predicted at Month 3 was lt 0 75 height SDS n 40 or whose actual height gain measured at Year 1 was lt 0 75 height SDS n 11 Approximately 85 of the randomized patients completed 2 years of therapy At baseline the FHD and IAD treatment groups had comparable height SDS mean 3 9 Table 12 Although the mean 1 year height increase in the IAD group was statistically significantly lower than that observed in the FHD group the study achieved its primary objective by demonstrating that the increase from baseline in height SDS in the IAD group was clinically similar non inferior to that in the FHD group mean between group difference 0 3 SDS 95 CI 0 4 0 2 SDS The mean changes from baseline in height SDS at the end of the 2 year study were 1 4 and 1 6 SDS in the IAD 18 and FHD groups respectively The results were similar when children who entered puberty during the study were removed from the analysis Table 12 Study 1 Results for Height SDS and Change from Baseline in Height SDS at Year
76. y included 239 pediatric patients 158 males 81 females 5 to 15 years old mean age 9 8 2 3 years Mean SD baseline characteristics included height SDS 3 21 0 70 predicted adult height SDS 2 63 1 08 and height velocity SDS 1 09 1 15 All but 3 patients were prepubertal Patients were randomized to one of three Humatrope treatment groups 0 24 mg kg week equivalent to 34 yg kg day 0 24 mg kg week for 1 year followed by 0 37 mg kg week equivalent to 53 yg kg day and 0 37 mg kg week The primary hypothesis of this study was that treatment with Humatrope would increase height velocity during the first 2 years of therapy in a dose dependent manner Additionally after completing the initial 2 year dose response phase of the study 50 patients were followed to final height Patients who received the Humatrope dosage of 0 37 mg kg week had a significantly greater increase in mean height velocity after 2 years of treatment than patients who received 0 24 mg kg week 4 04 vs 3 27 cm year p 0 003 The mean difference between final height and baseline predicted height was 7 2 cm for patients who received Humatrope 0 37 mg kg week and 5 4 cm for patients who received 0 24 mg kg week Table 10 While no patient had height above the 5th percentile in any dosage group at baseline 82 of the patients who received 0 37 mg kg week and 47 of the patients who received 0 24 mg kg week achieved final heights above the 5th percentile of the general
77. ymes However formal drug interaction studies have not been conducted 7 4 Oral Estrogen Because oral estrogens may reduce the serum IGF I response to somatropin treatment girls and women receiving oral estrogen replacement may require greater somatropin dosages see Dosage and Administration 2 4 7 5 Insulin and or Other Hypoglycemic Agents Patients with diabetes mellitus who receive concomitant treatment with somatropin may require adjustment of their doses of insulin and or other hypoglycemic agents see Warnings and Precautions 5 4 8 USE IN SPECIFIC POPULATIONS 8 1 Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with Humatrope It is not known whether Humatrope can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity Humatrope should be given to a pregnant woman only if clearly needed 8 3 Nursing Mothers There have been no studies conducted with Humatrope in nursing mothers It is not known whether this drug is excreted in human milk Because many drugs are excreted in human milk caution should be exercised when Humatrope is administered to a nursing woman 8 5 Geriatric Use The safety and effectiveness of Humatrope in patients aged 65 years and over has not been evaluated in clinical studies Elderly patients may be more sensitive to the action of somatropin and therefore may be more prone to development of adverse reactions A lower starting dose

Humatrope Statement of Medical Necessity form

Contents

Download Pdf Manuals

Related Search

Related Contents