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PRODUCT MONOGRAPH - Eli Lilly Canada

1. HUMATROPE may cause intracranial hypertension increased For more information please contact your healthcare pressure within the skull Call the doctor if the patient has a professional or pharmacist first or Eli Lilly Canada Inc at headache that doesn t go away or is severe or has headaches 1 888 545 5972 or visit the website at www lilly ca that become more frequent problems with vision nausea feeling sick in the stomach or vomiting The information in this document is current as of the last revision date shown below For the most current information HUMATROPE Product Monograph Page 53 of 58 IMPORTANT PLEASE READ please visit our website or contact us directly HUMATROPE and HUMATROPEN are trademarks owned or licensed by Eli Lilly and Company its subsidiaries or affiliates This leaflet was prepared by Eli Lilly Canada Inc Toronto Ontario MIN 2E8 Last Revised August 19 2013 HUMATROPE Product Monograph Page 34 of 58 Reconstitution Instructions for HUMATROPE Cartridges Plunger Humatrope Cartridge Diluent Syringe White Tip Cap Only use parts from this kit to prepare the drug cartridge Diluent Needle Cover Note The liquid is coloriess ht is shown here as blue for illustration purposes only HUMATROPE Product Monograph Page 55 of 58 Preparing Your New Cartridge Remove ALL contents from the tray Grasp Needle Cover which is at Remove Ne
2. IAD Group FHD Group Between Group Initial dose 0 035 mg kg day 0 067 mg kg day Difference Mean SD Mean SD IAD FHD 0 0 0 1 n 86 n 93 Baseline 0 2 0 2 3 9 0 6 3 9 0 7 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 4 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 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 gt Only children with actual height measurements were included in the Year 1 and Year 2 analyses Initial dose 0 035 mg kg day increased at 3 months to 0 067 mg kg day for 40 patients 11 additional patients increased dosage at 12 months DETAILED PHARMACOLOGY Somatropin recombinant DNA derived biosynthetic human growth hormone has been shown to promote growth of skeletal and soft tissue and to influence the metabolism of carbohydrate fat HUMATROPE Product Monograph Page 38 of 58 and protein Somatropin influences intestinal calcium transport by affecting the metab
3. WARNINGS AND PRECAUTIONS Serious Warnings and Precautions A doctor trained in hormone and growth disorders must examine the patient to decide if it is safe to use HUMATROPE After the HUMATROPE powder has been dissolved it must be water clear and free of particles This medicine has been prescribed for you Do not pass it on to others It may harm them even if their symptoms seem the same as yours When medicine is injected into the same place over a long time it can cause loss of fat tissue under the skin It is therefore important to keep changing the injection site and the doctor or nurse can tell you how Before using HUMATROPE the patient or caregiver should tell the doctor e ifthe patient has an active brain tumour or any other tumour either benign or cancerous However the doctor may prescribe HUMATROPE if the patient has HUMATROPE Product Monograph Page 51 of 58 IMPORTANT PLEASE READ had a brain tumour and needs no more anti tumour treatment for it The patient should be re examined frequently to make sure that the tumour has not come back or started to grow e ifthe patient is a survivor of childhood cancer e ifthe patient is very ill after a serious operation or after being treated for multiple injuries from an accident or if the patient has sudden serious breathing problems e ifthe patient has diabetes because more or less insulin may be needed when taking HUMATROPE e fa member
4. equivalent to 0 25 mg kg week The dosage was increased to 0 067 mg kg day for those patients whose predicted 1 year height gain assessed at 3 months was lt 0 75 SDS n 40 or whose actual height gain measured at Year 1 was lt 0 75 SDS n 11 Patients whose dose was increased at 3 months were approximately 2 years older at baseline than those who remained on the lower dose a greater proportion of girls had their dosage increased than boys 38 vs 43 respectively One year efficacy data available for 179 patients FHD n 93 IAD n 86 demonstrated that the individually adjusted regimen was statistically non inferior to the fixed dosage regimen 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 noninferior 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 and FHD groups respectively Efficacy results of this study are summarized in Table 16 Table 16 Results from Study GDGB for Height SDS and Change from Baseline in Height SDS at Year 1 and Year 2 After HUMATROPE Treatment of Short Children Born SGA Who Fail to Demonstrate Catch up Growth
5. Progression of pre existing scoliosis curvature of the spine can occur in children who have rapid growth HUMATROPE has not been shown to increase the occurrence of scoliosis If the patient has hypopituitarism and is receiving standard hormone replacement therapy the doctor should monitor the hormone replacement therapy closely during HUMATROPE treatment If the patient has a growth disorder associated with being born small for gestational age the blood sugar and insulin levels should be checked before starting treatment and regularly during treatment Patients over 65 years of age may be more sensitive to HUMATROPE and may require lower dose of HUMATROPE INTERACTIONS WITH THIS MEDICATION Tell the doctor if the patient is taking any of the following drugs e Steroid medications such as glucocorticoids e g cortisone or prednisone e Medications known to be metabolized by certain liver enzymes e g cyclosporine some anticonvulsants and hormones such as estrogen and birth control pills e Insulin and anti hyperglycemic agents Because HUMATROPE may affect how some hormones such as cortisol and cortisone are processed in the body people may discover that they have an underactive adrenal gland after starting HUMATROPE therapy In these cases glucocorticoid replacement therapy would need to be started If already on glucocorticoid therapy dosage may need to be adjusted PROPER USE OF THIS MEDICATION Be sure to
6. Year 2 Two of these six children had impaired fasting glucose during the study as well and one of them was required to discontinue HUMATROPE at Month 15 as a consequence A modestly dose dependent increase in mean serum IGF I concentrations within the reference range was observed of note 20 25 depending on treatment group of the children who had IGF I results available at study completion had serum IGF I values above the upper limit of the normal range for age and sex above 2 SDS Eight children in the FHD group and 2 in the IAD group required somatropin dose reduction due to high IGF I above 2 5 SDS or the combination of IGF I above 0 5 SDS and IGFBP 3 below 0 5 SDS Table 4 presents adverse drug reactions reported at a frequency of gt 1 in Study GDGB listed in descending order of frequency within system organ class Table 4 Adverse Drug Reactions with Frequency gt 1 in Study GDGB FHD IAD Total System Organ Class Preferred Term N 99 N 94 N 193 n n n Ear and labyrinth disorders Vertigo 11 11 2 1 Endocrine disorders Hypothyroidism 2 2 2 2 4 2 A aU 2 2 10 30 sal isor ers and administration site Injection site pain 20 10 30 Edema 0 0 2 2 2 1 Blood insulin increased 4 4 3 3 7 4 Investigations Low density lipoprotein decreased pe 36 1 1 4 2 Si e nae Pain in extremity 3 3 6 6 9 5 on os eletal and connective tissue Arthralgia 10
7. clinical literature has demonstrated no relationship between somatropin therapy and central nervous system CNS tumour recurrence e In adults it is unknown whether there is any relationship between somatropin therapy and CNS tumour recurrence Second neoplasm in survivors of childhood cancer In childhood cancer survivors an increased risk of a second neoplasm benign and malignant has been reported in patients treated with somatropin Intracranial tumours in particular meningiomas in patients treated with radiation to the head for their first neoplasm were the most common of these second neoplasms However in childhood cancer survivors no increased risk of primary cancer recurrence has been reported in patients treated with somatropin Congenital Disorders Prader Willi Syndrome e Lilly has not studied the use of somatropin in patients with Prader Willi syndrome therefore HUMATROPE is not indicated in patients who have Prader Willi syndrome without a diagnosis of growth hormone deficiency e There have been reports of sleep apnea and fatalities after initiating therapy with somatropin in pediatric patients with Prader Willi syndrome who had one or more of the following risk factors e severe obesity e history of upper airway obstruction or sleep apnea or e unidentified i e previously undiagnosed mildly symptomatic respiratory infection Male patients with one or more of these risk factors may be at greater risk than fema
8. disturbance should be ruled out before starting HUMATROPE treatment for children with idiopathic short stature ISS HUMATROPE treatment for ISS should be prescribed only for those patients whose epiphyses are not closed and should be managed by physicians who have sufficient knowledge of ISS and the efficacy safety profile of HUMATROPE Small for Gestational Age In short children born small for gestational age SGA other medical reasons or treatments that could explain growth disturbance should be ruled out before starting treatment with somatropin HUMATROPE Experience with SGA patients with Silver Russell syndrome is limited as is experience in initiating treatment in SGA patients near onset of puberty In short children born SGA it is recommended that IGF I concentrations should be measured before initiation of treatment and monitored regularly thereafter If on repeated measurements IGF I concentrations exceed 2 SD compared to references for age and pubertal status the IGF I IGFBP 3 ratio could be taken into account to consider dose adjustment Adult Patients Patients with ephiphyseal closure who were treated with somatropin therapy in childhood should be re evaluated according to the criteria provided in INDICATIONS AND CLINICAL USE before continuation of somatropin therapy at the reduced dose level required for growth hormone deficient adults Experience with prolonged treatment in adults is limited Adverse events such as periphe
9. 95 CI 1 3 to 0 7 In addition patients who received Humatrope had significantly greater second year height velocity and first and second year height gain than untreated patients Table 12 At the end of the 2 year study period 41 of HUMATROPE treated subjects with SHOX deficiency and 31 of subjects with Turner syndrome had achieved height within the normal range for age and gender gt 2 0 SDS HUMATROPE Product Monograph Page 35 of 58 Table 14 Summary of Efficacy Results in Patients with SHOX deficiency and Turner Syndrome Turner SHOX Deficiency Syndrome Untreated HUMATROPE Treatment EUMATROPE n 24 n 27 Difference n 26 z Mean 95 CD a Height Velocity cm yr 1 Year Mean SD 5 2 1 1 3 5 2 8 4 2 8 9 2 0 2 Y ear Mean SD 5 4 1 2 2 0 1 3 2 6 7 0 1 1 Height change cm Baseline to 1s Year Mean SD 5 4 1 2 9 1 1 5 3 7 2 9 4 5 8 9 1 9 Baseline to 2ndYear Mean SD 10 5 1 9 16 4 2 0 5 8 4 6 7 1 15 7 2 7 Height SDS change Baseline to 1s Year Mean SD 0 1 0 5 0 5 0 3 0 8 0 8 0 5 Baseline to 2ndYear Mean SD 0 2 0 5 1 0 0 7 1 3 1 2 0 7 Patients with height SDS gt 2 0 1 4 11 41 8 31 at 2 years Positive values favor HUMATROPE P Statistically significantly different from untreated with p lt 0 001 Statistically significantly different from untreated with p lt 0 05 Effect of HUMATROPE on Pediatric
10. HUMATROPE Product Monograph Page 15 of 58 Growth Hormone deficient Pediatric Patients As with all protein pharmaceuticals a small percentage of patients may develop antibodies to the protein During the first six months of HUMATROPE somatropin therapy in 314 naive patients only 1 6 developed specific antibodies to HUMATROPE binding capacity gt 0 02 mg L and none had antibody concentrations that exceeded 2 mg L Over the course of 8 years of this study 2 patients 0 6 had an antibody binding capacity of gt 2 mg L It has been reported that growth attenuation from pituitary derived growth hormone may occur when antibody concentrations are gt 1 5 mg L however neither patient demonstrated a decrease in growth velocity at or near the time of increased antibody production In studies with growth hormone deficient pediatric patients injection site pain was reported infrequently Mild and transient edema either localized or generalized was observed in 2 5 of patients during the course of treatment in the study described above Leukemia has been reported in a small number of pediatric patients who have been treated with growth hormone including growth hormone of pituitary origin and recombinant somatrem and somatropin The relationship 1f any between leukemia and growth hormone is uncertain Growth Hormone deficient Adult Patients In the first 6 months of placebo controlled blinded trials adult onset growth hormone deficient pati
11. Patients Born Small for Gestational Age Data from 2 clinical trials one randomized one single arm and one observational study demonstrated the efficacy of HUMATROPE treatment of growth failure in children born SGA The primary objective of Study GDGB 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 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 0 for gestational age and height SDS for chronological age lt 3 0 Exclusion criteria included syndromal conditions e g Turner syndrome chronic disease e g diabetes mellitus and tumour activity Study 0908 was an open label multicenter single arm study conducted in France during which 35 prepubertal nonGH 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 0 or lt 3rd percentile for gestational age and height SDS for chronological age lt 2 0 Exclusion criteria HUMATROPE Product Monograph Page 36 o
12. breathing with swelling of the hands feet or Keep out of reach of children face REPORTING SUSPECTED SIDE EFFECTS Children treated with HUMATROPE may have an increased risk of developing an inflammation of the pancreas called You can report any suspected adverse reactions associated with the pancreatitis If your child develops severe abdominal pain use of health products to the Canada Vigilance Program by one of the contact your doctor following 3 ways It is also important to have blood glucose checked if the patient e Report online at www healthcanada gc ca medeffect has diabetes or a family history of diabetes Call toll free at 1 866 234 2345 e Complete a Canada Vigilance Reporting Form and Fax toll free to 1 866 678 6789 or Mail to Canada Vigilance Program HUMATROPE may affect the way the body handles sugars from food and drink The doctor may need to check the amount Heal ealth Canada of sugar in the urine or blood Postal Locator 0701D Ottawa Ontario HUMATROPE can affect the amount of thyroid hormone in the K1A 0K9 blood so patients must have thyroid function tests from time to Postage paid labels Canada Vigilance Reporting Form and the time If the thyroid is not working properly HUMATROPE adverse reaction reporting guidelines are available on the may not work as well as it should MedEffect Canada website at www healthcanada gc ca medeffect NOTE Should you require information related to the ma
13. change the injection site frequently to help prevent lipoatrophy loss of fat tissue under the skin In general HUMATROPE should be injected in the evening or before bedtime HUMATROPE Product Monograph Page 52 of 58 IMPORTANT PLEASE READ Usual dose Other possible side effects include headaches muscle or joint The doctor will instruct you on what is the best dose of pains in hips or knees swelling associated with tingling HUMATROPE for you or your child based on individual sensations in the hands feeling weak rarely high blood needs Use HUMATROPE exactly as the doctor tells you to pressure shortness of breath and sleep apnea pauses in breathing during sleep If the headaches are bad or frequent Reconstitution Instructions and accompanied by sickness or vision problems tell the doctor Please refer to the enclosed reconstitution instructions immediately Overdose For patients with Turner syndrome HUMATROPE therapy Long term overdosage or using HUMATROPE after the growth may increase the already high frequency of ear infections Your plates in the long bones have closed hardened may result in child should see her doctor if you think she has an ear infection joint pain and continued growth of fingers toes nose ears or jaw If you think this is happening tell the doctor This is not a complete list of side effects If any of the side effects gets serious or if you notice any unexpected side Overdose may change bl
14. deficiency Turner syndrome idiopathic short stature SHOX short stature homeobox containing gene deficiency or being born small for gestational age HUMATROPE is also used in some adults who had growth hormone deficiency when they were children and still have growth hormone deficiency after they finish growing or who do not make enough growth hormone as adults for some other reason What it does HUMATROPE is used to increase growth hormone levels It stimulates bone growth in children unless the ends of the bones have hardened closed epiphyses In both adults and children with growth hormone deficiency it also increases the growth of muscle and reduces body fat When it should not be used Treatment should not be started e in children to promote growth when the ends of the long bones have hardened closed epiphyses Treatment should be stopped when adult height is reached Reevaluation to find out whether the patient still has growth hormone deficiency will determine if continued treatment with HUMATROPE at a lower dose would be beneficial e inpatients with any evidence of an active cancer either newly diagnosed or recurrent e while patients have a serious illness following heart or abdominal surgery or in patients who have just had a serious accident or those with acute respiratory failure low level of oxygen in the blood or high level of carbon dioxide in the blood e inpatients with Prader Willi syndrome who are
15. 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 There is no available information regarding IGF I concentrations at the recommended dose of 0 37 mg kg week Table 2 Nonserious Clinically Significant Treatment Emergent Adverse Events by Treatment Group in Idiopathic Short Stature Adverse Event HUMATROPE Total Number of Patients 37 31 Scoliosis 7 18 9 4 12 9 Otitis media 6 16 2 2 6 5 Hyperlipidemia 3 8 1 1 3 2 Gynecomastia 2 5 4 1 3 2 Hypothyroidism 0 2 6 5 Aching joints 0 1 3 2 Hip pain 1 2 7 0 Arthralgia 4 10 8 1 3 2 Arthosis 4 10 8 2 6 5 Myalgia 9 24 3 4 12 9 Hypertension 1 2 7 0 Coding of adverse events was performed using the Medical Dictionary for Regulatory Activities MedDRA 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 occurrence rates of elevated fasting blood glucose concentrations were similar One patient developed abnormalities of carbohydrate metabolism glucose intolerance and slightly elevated HbA on treatment which resolved when treatment was discontinued HUMATROPE Product Monograph Page 17 of 58 Five patients discontinued
16. powder Sterile Water for Injection USP may be used to dissolve the HUMATROPE supplied in vials not cartridges Refer to How to Store It section for storage instructions If the patient has Turner syndrome and develops an ear infection or headaches her doctor should be told about these problems If the patient is growth hormone deficient and also has Prader Willi syndrome a genetic disorder the doctor should examine the patient for breathing problems and airway infections before starting HUMATROPE treatment especially if the patient is overweight has previously experienced severe breathing problems especially during sleep or suffered infection of the lungs or airways If during treatment the patient has signs of breathing problems snoring treatment should be interrupted and the cause assessed by the doctor Treatment with HUMATROPE can change blood sugar levels The doctor should check the patient s blood sugar regularly while taking HUMATROPE especially if there are risk factors for diabetes Patients who have diabetes or impaired glucose tolerance should have their blood sugar closely monitored during HUMATROPE therapy Leukemia has been reported in a small number of pediatric patients who have been treated with growth hormone including growth hormone of pituitary origin and man made growth hormone products such as somatrem and somatropin The relationship if any between leukemia and growth hormone is uncertain
17. very obese or have severe breathing problems There have been reports of deaths in children with Prader Willi syndrome who were treated with growth hormone and had one or more of the following risk factors severe obesity breathing problems colds or lung infections Treatment should not be started e inpatients known to be allergic to somatropin the active substance in HUMATROPB or to any of the ingredients in the powder or the diluent listed below e inpatients who have undergone kidney transplant until one year post transplant e inpatients with diabetic retinopathy a complication of diabetes that results from damage to the blood vessels of the light sensitive tissue at the back of the eye retina What the medicinal ingredient is Somatropin recombinant human growth hormone What the important nonmedicinal ingredients are The HUMATROPE powder contains freeze dried somatropin dibasic sodium phosphate glycine and mannitol The diluent solution for dissolving somatropin contains metacresol and glycerin Phosphoric acid and or sodium hydroxide may have been added at the time of manufacture to adjust the acidity of the liquid What dosage forms it comes in HUMATROPE is supplied as follows Vial 5 mg vial plus 5 mL diluent Cartridges 6 mg 12 mg or 24 mg cartridges each with 3 15 mL of diluent HUMATROPE cartridges require the use of a HumatroPen to inject the drug HumatroPens are supplied separately
18. week E TARER OR Daily equivalent dose of 0 043 aes mg kg day GH deficient Initiate at not more than Should be titrated Aui patents 000 mk day e adverse effects increasing age or Maximum 0 0125 mg kg day sc 2 eyes e to maintain IGF I lt upper limit of normal for age and sex Patients with Up to 0 375 mg kg week Divide into equal doses given Turner Daily equivalent dose of up to 0 054 sc e daily OR syndrome mg kg day e on 3 alternate days Patients with idiopathic short Up to 0 37 mg kg week Divided into equal doses given 6 to 7 times Daily equivalent dose of 0 053 SC er week stature P mg kg day Patients with SHOX 0 35 mg kg week Divided into equal doses given 6 to 7 times deficiency Daily equivalent dose of 0 050 SC per week mg kg day Patients born small for Up ae AS Divided into equal doses given 6 to 7 times A Daily equivalent dose of 0 067 SC gestational per week age mg kg day Tt is recommended that treatment be initiated 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 A reduction in dosage e g to 0 035 mg kg day should be considered if substantial catch up growth is observed during the first few years of therapy HUMATROPE Product Monograph Page 23 of 58 In younger SGA children approximately lt 4 years of age with less severe short stature 1 e baseline height SDS values bet
19. 20 30 Limb deformity 2 2 0 0 2 1 HUMATROPE Product Monograph Page 19 of 58 FHD IAD Total System Organ Class Preferred Term N 99 N 94 N 193 n n n Neoplasms benign malignant and unspecified including cysts and polyps Melanocytic nevus 2 2 0 0 2 1 Headache 9 9 3 3 12 6 Nervous system disorders Psychomotor hyperactivity 10 36 40 Psychiatric disorders Aggression 11 11 2 1 Pree thoracic and mediastinal Adenoidal hypertrophy 0 0 3 3 3 2 N total number in treatment group n number for whom event was reported FHD fixed high dosage 0 067 mg kg day IAD individually adjusted dosage 0 035 to 0 067 mg kg day Terms designated by investigator as related to study drug in at least one patient In Study 0908 treatment emergent adverse events TEAEs were reported for 30 35 86 of study participants Because of the size of this study all events were reported at a frequency of gt 1 The most frequently reported non serious TEAEs were typical childhood illnesses such as nasopharyngitis 29 and bronchitis gastroenteritis influenza and vomiting 14 for each event Gynecomastia was reported for 13 of males In addition the following events were each reported for 11 of study patients arthralgia headache injection site pain pyrexia the following events were reported for 9 of patients asthenia cough eczema pharyngitis pharyngolaryng
20. FORMATION Concomitant glucocorticoid therapy at supraphysiologic doses may inhibit the response to somatropin Glucocorticoid replacement dosing should be carefully adjusted in children receiving concomitant somatropin and glucocorticoid treatments to avoid both hypocortisolism and glucocorticoid excess with an inhibitory effect on growth see DRUG INTERATIONS Drug Drug Interactions Carcinogenesis and Mutagenesis Long term animal studies for carcinogenicity with somatropin have not been performed There is no evidence of somatropin induced mutagenicity Leukemia has been reported in a small number of growth hormone deficient patients treated with growth hormone including growth hormone of pituitary origin as well as of recombinant DNA origin somatrem and somatropin Based on the current evidence experts cannot conclude that growth hormone therapy is responsible for these occurrences HUMATROPE Product Monograph Page 6 of 58 Neoplasia has been identified as a potential risk for treatment with HUMATROPE Patients who develop neoplasia should be reported to the Health Products and Food Branch HPFB by the treating physician Pre existing tumours or growth hormone deficiency secondary to an intracranial tumour Patients with pre existing tumours or with growth hormone deficiency secondary to an intracranial tumour should be examined routinely for progression or recurrence of the underlying disease process e In pediatric patients
21. MATROPE Treatment in Children with Growth Hormone Deficiency Studies conducted to assess efficacy and safety of somatropin HUMATROPE in pediatric patients with growth hormone deficiency were open label multi national trials with a combined population of 239 patients assessed in three groups naive patients in USA and Canada n 158 naive patients in countries outside North America n 29 and previously treated patients n 52 Each patient served as their own control comparing height velocity before and after treatment Patients were administered 0 18 mg kg week of HUMATROPE either by subcutaneous or intramuscular injections at a frequency of 3 to 7 times week Page 30 of 58 HUMATROPE Product Monograph Growth rates at 1 3 and 6 month time points were significantly greater p lt 0 001 than pretreatment growth rates for all three groups Table 9 shows the increase in height velocity from pretreatment compared to the patient s last visit Table 9 Mean Growth Rates cm year at Baseline Pretreatment and Last Visit Mean Age at Mean Height Velocity cm year Study Entry E years Pretreatment Last visit Naive patients in USA and Canada n 158 8 3 3 51 10 27 Naive patients in countries outside North 8 8 3 79 9 05 America n 29 Previously treated patients n 52 12 3 3 34 8 74 Effect of HUMATROPE Treatment in Adults with Growth Hormone Deficiency Two multicenter trials in adult onset growth
22. NS e Severe cases of generalized allergy including anaphylactic reaction may be life threatening see CONTRAINDICATIONS e Ifany serious hypersensitivity or allergic reaction occurs somatropin therapy should be discontinued immediately and appropriate therapy initiated Antibody production e A small percentage of patients treated with somatropin may develop antibodies during treatment that could potentially reduce treatment response see ADVERSE REACTIONS e Patients who have demonstrated an allergic reaction to other somatropin products may demonstrate an allergic reaction to HUMATROPE Intracranial Hypertension Intracranial hypertension with papilledema visual changes headache nausea and or vomiting has been reported in a small number of patients treated with somatropin Symptoms usually occurred within the first eight weeks of initiation of somatropin therapy In all reported cases signs and symptoms of intracranial hypertension resolved after discontinuation of therapy or a reduction of somatropin dose see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS Funduscopic examination is recommended at the initiation and periodically during the course of somatropin therapy see Monitoring and Laboratory Tests Musculoskeletal Musculoskeletal discomfort pain swelling and or stiffness may occur during treatment with somatropin see ADVERSE REACTIONS These symptoms may resolve spontaneously with analgesic therapy or after re
23. O G sia A A AA EE E 40 REFERENCES aula ra 42 PART III CONSUMER INFORMATION csccscsssssssssssssssscssscesssssessesssssssssessessessessesseees 51 HUMATROPE Product Monograph Page 2 of 58 HUMATROPE somatropin for injection PART I HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Dosage Form Strength Clinically Relevant Administration Non medicinal Ingredients Sterile lyophilized powder in Supplied with diluent that Vial 5 mg contains metacresol and Cartridges 6 mg glycerin 12 mg 24 mg For a complete listing see DOSAGE FORMS COMPOSITION and PACKAGING section Subcutaneous DESCRIPTION HUMATROPE somatropin is a polypeptide hormone of recombinant DNA origin The amino acid sequence is identical to that of human growth hormone of pituitary origin HUMATROPE is synthesized in a strain of E coli that has been modified by the addition of the gene for human growth hormone INDICATIONS AND CLINICAL USE Pediatric Patients Growth Hormone Deficiency HUMATROPE somatropin is indicated for the long term treatment of pediatric patients who have growth failure due to an inadequate secretion of normal endogenous growth hormone and whose epiphyses are not closed Turner Syndrome HUMATROPE is indicated for the treatment of short stature associated with Turner syndrome in patients whose epiphyses are not closed Idiopathic Short Stature ISS HUMATROPE is indicated for the long
24. PE somatropin Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug Adverse drug reaction information from clinical trials is useful for identifying drug related adverse events and for approximating rates Table 1 Adverse Reactions from All Clinical Trial Sources by Body System Body System Adverse Reactions Frequency Body as a whole Injection site reaction gt 1 and lt 10 Hypersensitivity to diluent gt 1 and lt 10 Localized muscle pain gt 0 01 and lt 0 1 pediatric gt 1 and lt 10 Benign intracranial hypertension adults lt 0 1 Endocrine Hypothyroidism gt 10 Metabolic Edema gt 1 and lt 10 pediatric gt 10 adults Hyperglycemia lt 1 pediatric gt 1 and lt 10 adults Musculoskeletal Arthralgia gt 10 adults Progression of scoliosis gt 1 and lt 10 pediatric Nervous Carpal tunnel syndrome gt 1 and lt 10 adults Paresthesias gt 1 and lt 10 adults Healthy Adult Volunteers In clinical studies in which high doses of HUMATROPE were administered to healthy adult volunteers the following events occurred infrequently headache localized muscle pain weakness mild hyperglycemia and glucosuria
25. PRODUCT MONOGRAPH HUMATROPE somatropin for injection Biosynthetic Human Growth Hormone of Recombinant DNA Origin 5 mg vial 6 12 24 mg cartridges Sterile Lyophilized Powder and Diluent Lilly Standard Growth Stimulant ELILILLY CANADA INC Date of Revision 3650 Danforth Avenue August 19 2013 Toronto Ontario MIN 2E8 1 888 545 5972 www lilly ca Control No 165627 HUMATROPE Product Monograph Page l of 58 Table of Contents PART I HEALTH PROFESSIONAL INFORMATION csccssssssssssssssssscsssssssssssssesssssesess 3 SUMMARY PRODUCT INFORMATION cssssetsssicctcesscsseoseseesonsorssensoviceserauecansennsoacens 3 INDICATIONS AND CLINICAL US Bo aiii ii 3 CONTRAINDICATIONS viinivininndic n ici s ta da At 4 WARNINGS AND PRECAUTIONS re damon a id 5 ADVERSEREA CONS IO A I naka 15 DRUG INTERACTON Sua AE O A ATAR 21 DOSAGE AND ADMINISTRATION 050 00 ciccccsscessecresscodseosassoveossorsessessevsdsanevonssecesivaedvenvs 22 OVERDOSAGE ti E A in shu ds AA A E AAA 25 ACTION AND CLINICAL PHARMACOLOGY ennccciccnccconacanonncnnananananinnncanonanonnncananinen 26 STORAGE AND STABILILY a A A 27 DOSAGE FORMS COMPOSITION AND PACKAGING coocociccccnconcnoncnnacanananoniniananinan 28 PART II SCIENTIFIC INFORMATION essesesesessesoroeseserceeesoroesesesoeeesoroeseseroseesoroeseseeoeeesoroee 30 PHARMACEUTICAL INFORMATION cocinar afbutedededsnasted 30 CLINICAL TRIALS oia ai 30 DETAILED PHARMACOL OG iaa 38 TORIC OV
26. Tanner II 46 5 at baseline In this double blind trial patients received subcutaneous injections of either HUMATROPE 0 222 mg kg wk or placebo Study drug was 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 the GH treated group had achieved a mean final height 0 51 SDS greater than the placebo treated group ANCOVA GH 1 8 SDS vs placebo 2 3 SDS p 0 017 this difference translates to approximately 3 7 cm range 2 8 5 0 cm see Table 12 Height gain across the duration 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 Table 12 and 13 In addition the number of patients who achieved a final height above the 5 percentile of the general population standards 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 in height across the duration of the study 50 vs 0 p lt 0 05 HUMATROPE Product Monograph Page 33 of 58 Table 12 Baseline Height Characteristics and Effect of HUMATROPE on Final Height HUMATROPE Placebo Treatment Effect n 22 n 11 Mean Mean SD Mean SD 95 CD FH SDS baseline heigh
27. The mean difference between final height and baseline predicted height was 7 2 cm for patients receiving 0 37 mg kg wk and 5 4 cm for patients receiving 0 24 mg kg wk Table 13 While no patient had height above the 5 percentile in any dose group at baseline 82 of the patients receiving 0 37 mg kg wk and 47 of the patients receiving 0 24 mg kg wk achieved a final height above the se percentile of the general population height standards p NS HUMATROPE Product Monograph Page 34 of 58 Table 13 Final Height Minus Baseline Predicted Height Idiopathic Short Stature Trials Placebo controlled Trial Dose Response Trial 3x per week dosing 6x per week dosing HUMATROPE HUMATROPE HUMATROPE HUMATROPE Placebo 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 2 2 6 7 7 2 Mean cm 95 CI 3 6 2 3 0 4 3 9 4 1 9 2 4 6 9 8 Abbreviations PH predicted height FH final height CI confidence interval Total weekly dosage Effect of HUMATROPE Treatment in Patients with SHOX Deficiency SHOX deficiency may result either from a deletion of one copy of the short stature homeobox containing gene SHOX or from a mutation within or outside one copy of the SHOX gene that impairs the production or function of SHOX protein The SHOX gene is located on the pseudoautosomal region of the X chromosome Haploinsufficiency of the SHOX gene causes short stature analogous to the short
28. UTIONS Serious Warnings and Precautions A doctor trained in hormone and growth disorders must examine the patient to decide if it is safe to use HUMATROPE After the HUMATROPE powder has been dissolved it must be water clear and free of particles This medicine has been prescribed for you Do not pass it on to others It may harm them even if their symptoms seem the same as yours When medicine is injected into the same place over a long time it can cause loss of fat tissue under the skin It is therefore important to keep changing the injection site and the doctor or nurse can tell you how Before using HUMATROPE the patient or caregiver should tell the doctor e ifthe patient has an active brain tumour or any other tumour either benign or cancerous However the HUMATROPE Product Monograph Page 44 of 58 IMPORTANT PLEASE READ doctor may prescribe HUMATROPE if the patient has had a brain tumour and needs no more anti tumour treatment for it The patient should be re examined frequently to make sure that the tumour has not come back or started to grow e ifthe patient is a survivor of childhood cancer e ifthe patient is very ill after a serious operation or after being treated for multiple injuries from an accident or if the patient has sudden serious breathing problems e ifthe patient has diabetes because more or less insulin may be needed when taking HUMATROPE e fa member of the patient s fa
29. act your healthcare professional or pharmacist first or Eli Lilly Canada Inc at 1 888 545 5972 or visit the website at www lilly ca The information in this document is current as of the last revision date shown below For the most current information please visit our website or contact us directly HUMATROPE is a trademark owned or licensed by Eli Lilly and Company its subsidiaries or affiliates This leaflet was prepared by Eli Lilly Canada Inc Toronto Ontario MIN 2E8 Last revised August 19 2013 HUMATROPE Product Monograph Page 50 of 58 IMPORTANT PLEASE READ PART III CONSUMER INFORMATION PHUMATROPE Cartridges somatropin for injection pronounced HYOO mah trope This leaflet is for patients and caregivers It is Part III of a three part Product Monograph published when HUMATROPE was approved for sale in Canada This leaflet is a summary and will not tell you everything about HUMATROPE Contact your doctor or pharmacist if you have any questions about the drug Please read this information carefully before you start to take your medicine even if you have just refilled your prescription Some of the information may have changed Keep this pamphlet since you may need to refer to it after starting treatment with HUMATROPE ABOUT THIS MEDICATION What the medication is used for HUMATROPE is used to treat children and teenagers who are short or growing too slowly due to a medical condition such as growth hormone
30. andomized 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 During 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 There were no discontinuations due to adverse events in this study No serious adverse events were reported for patients with SHOX Deficiency Table 3 Clinically Significant Treatment Emergent Adverse Events by Treatment Group in Patients with SHOX Deficiency A Treatment Group HUMATROPE Total Number of Patients 27 Patients with at least one event 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 gt Events are included only if reported for a greater n
31. approximately 5 cm The HUMATROPE efficacy data of these studies in patients with Turner syndrome is summarized in Table 11 Analysis of covariance includes adjustments for baseline height relative to age and for mid parental height HUMATROPE Product Monograph Page 32 of 58 Table 11 Summary Table of Efficacy Results Number of Adult HUMATROPE HUMATROPE Estrogen HUMATROPE Height Study Study treated at Age Age Duration Gain Group Design Adult Height yr yr y cm ERGA RCT 27 11 7 13 4 7 5 4 GDCI RDT 31 11 1 8 13 5 5 3 5 RCT randomized controlled trial RDT randomized dose response trial gt Mean age at initiation of study drug Analysis of covariance vs controls d Compared with historical data Effect of HUMATROPE Treatment in Pediatric Patients with Idiopathic Short Stature Two randomized multicenter trials 1 placebo controlled and 1 open label dose response were conducted in pediatric patients with idiopathic short stature The diagnosis of idiopathic short stature was made after excluding other known causes of short stature as well as growth hormone deficiency Limited safety and efficacy data are available below the age of 7 years The placebo controlled study enrolled 71 pediatric patients 55 males 16 females 9 to 15 years old mean age 12 38 1 51 years with short stature 68 of whom received study drug Patients were predominately prepubertal or in early puberty Tanner stage I 45 1 and
32. apy at the reduced dose level required for growth hormone deficient adults 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 A lower starting dose may be necessary in obese patient 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 HUMATROPE Product Monograph Page 22 of 58 HUMATROPE dosage Recommended Dose and Dosage Adjustment The dosage and administration schedule for HUMATROPE somatropin should be individualized for each patient and the condition for which he or she is being treated and should be determined based on guidance of a physician experienced in the care of patients with growth hormone deficiency and growth disorders see Table 7 Clinicians should carefully monitor the growth response in all children and adjust the HUMATROPE dose as necessary Table 7 Recommended Dose and Administration Schedule for HUMATROPE eee Recommended dose Indication mg kg body weight Route Comments GH deficient 0 18 mg kg week pediatric Daily equivalent dose of 0 026 Divide into equal doses given on pargas mg kg day e 3 alternate days OR SC Maximum 0 3 mg kg
33. d or needles after each use When the vial has been prepared with the supplied diluent it may be stored in the refrigerator at 2 8 C 36 46 F and MUST be used within 21 DAYS Do NOT freeze Reconstituting 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 ZN 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 HUMATROPE Product Monograph Page 48 of 58 IMPORTANT PLEASE READ 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 powder at the bottom
34. ducing the dosage see DOSAGE AND ADMINISTRATION Swelling of the hands and feet may occur during treatment with somatropin and may lead to carpal tunnel syndrome which may be improved by decreasing the dosage of somatropin Somatropin has not been shown to increase the occurrence of scoliosis However identification of a new scoliosis or progression of pre existing scoliosis can occur in pediatric patients who experience rapid growth Therefore because somatropin increases growth rate patients should be initially screened for presence of a scoliosis and patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis HUMATROPE Product Monograph Page 10 of 58 e Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders including pediatric growth hormone deficiency Turner syndrome and hypothyroidism 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 see Monitoring and Laboratory Tests Renal Hepatic Biliary Pancreatic Impairments e Somatropin should be discontinued from the time of renal transplantation until one year post transplant see CONTRAINDICATIONS Somatropin requirements may need to be adjusted in patients with renal and or hepatic and or biliary and or pancreatic impairments Reproduction Studies e No ad
35. e Administration of somatropin to healthy adults or 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 fasting and postprandial glucose and hemoglobin A concentrations remained in the normal range 4 Lipid Metabolism In growth hormone deficient patients long term administration of human growth hormone of pituitary origin has resulted in lipid mobilization reduction in body fat stores and an increase in plasma fatty acids 5 Mineral Metabolism HUMATROPE Product Monograph Page 26 of 58 Retention of sodium potassium and phosphorus is induced by human growth hormone of pituitary origin Serum concentrations of inorganic phosphate increased in patients with growth hormone deficiency after therapy with HUMATROPE or human growth hormone of pituitary origin Serum calcium is not significantly altered in patients treated with either human growth hormone of pituitary origin or HUMATROPE HUMATROPE stimulates linear growth in pediatric patients who lack adequate normal endogenous growth hormone and in children with short stature in association with Turner syndrome idiopathic short stature SHOX deficiency and failure to catch up in height after small of gestational age birth Treatment of growth hormone deficient pediatric patients and patients with Turner syndrome with HUMATROPE produces increased growth rat
36. e and IGF I concentrations similar to those seen in therapy with human growth hormone of pituitary origin As a result of replacement therapy in growth hormone deficient adults body composition improved HDL cholesterol values normalized and health related quality of life measures concerning physical mobility and social isolation improved in placebo controlled clinical trials Exercise capacity improved as compared to placebo Pharmacokinetics In vitro preclinical and clinical testing have demonstrated that HUMATROPE is therapeutically equivalent to human growth hormone of pituitary origin with equivalent pharmacokinetics in normal adults Absorption HUMATROPE has been studied following intramuscular subcutaneous and intravenous administration in adult volunteers 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 Metabolism Extensive metabolism studies have not been conducted The metabolic fate of somatropin involves classical protein catabolism in both the liver and kidneys In renal cells at least a portion of the breakdown products of somatropin is returned to the systemic circulation In normal volunteers mean clearance is 0 14 L hr kg The mean half life of intravenous somatropin is 0 36 hours whereas subcutaneously and intramuscularly administered somatro
37. e to HUMATROPE treatment can be found dosage adjustment or discontinuation of treatment should be considered In pediatric patients with non growth hormone deficient growth disorders receiving HUMATROPE for improvement of linear growth consideration should be given to discontinuation of treatment when growth is nearly complete as evidenced by e Height velocity less than 2 0 cm per year e Bone age of 14 years or greater in girls or 16 years or greater in boys Reconstitution and Specific Precautions A puncture resistant container should be used for the disposal of used needles and syringes Patients and or caregivers should be thoroughly instructed in the importance of proper needle disposal and cautioned against the reuse of needles and syringes HUMATROPE Vials Reconstitute each vial of HUMATROPE with 1 5 to 5 mL of diluent for HUMATROPE Inject the diluent for HUMATROPE metacresol and glycerin solution into the vial of HUMATROPE aiming the stream of liquid against the glass wall Following reconstitution swirl the vial with a GENTLE ROTARY motion until the contents are completely dissolved DO NOT SHAKE The resulting solution should be clear without particulate matter If the solution is cloudy or contains particulate matter the contents MUST NOT be injected HUMATROPE Product Monograph Page 24 of 58 Before and after injections the septum of the vial should be wiped with rubbing alcohol or another alcoholic antiseptic sol
38. eal pain rhinitis the following events were reported for 6 of patients appendicitis ear infection hyperthermia hypothyroidism joint sprain lymphadenopathy tracheitis tracheobronchitis No patient was reported to have discontinued the study because of an adverse event In the observational study GDFC non serious TEAEs were reported for 76 of 379 20 children with a study entry diagnosis of short stature due to small for gestational age birth who were naive to treatment at study entry and had at least one post baseline visit The majority of these events were typical childhood illnesses or injuries unlikely to have been related to HUMATROPE treatment Less Common Clinical Trial Adverse Drug Reactions lt 1 The following list provides the adverse events reported with a frequency of lt 1 in studies GDGB and GDFC that were designated by the investigators as possibly related to the study drug or for which no designation was made abnormal behaviour back pain blood thyroid stimulating hormone increased cardiovascular disorder carpal tunnel syndrome contusion eyelid edema epiphysiolysis slipped capital femoral epiphysis hyperinsulinemia hypertension impaired fasting glucose injection site bruising injection site hematoma injection site induration injection site pain injection site vesicles mood altered muscle mass nervousness periorbital edema precocious puberty puberty tonsillar hypertrophy type 2 diabetes mellitu
39. edle Cover Hold cartridge Black Triangles PUSH the cartridge Note This product is designed for left the bottom of the Diluent Syringe and discard DO NOT towards the Diluent Syringe STRAIGHT in or right handed use Please feel free depress Plunger yet Itis Align the cartridge and Diluent until it stops AND the to use whichever hand is most okay if a drop of fluid is Syringe in a straight line DO Black Triangles ARE comfortable for you lost It is not necessary to NOT insert the cartridge at an COVERED release angle You may hear or feel a air from the Diluent click DO NOT twist the Syringe cartridge HUMATROPE Product Monograph Page 56 of 58 Hold the Diluent Syringe and the Remove thumb from the Plunger With thumb OFF the Place the End Cap on a hard cartridge together with TWO HANDS and check that the Diluent Syringe plunger pull the cartridge flat surface Push the Diluent Push and release the Plunger 2 or 3 is empty it is normal for away from the Syringe onto the End Cap and times until the small drops of Diluent to remain in Diluent Syringe immediately discard the Diluent Diluent is in the cartridge the Diluent Syringe Syringe as instructed by your healthcare professional HUMATROPE Product Monograph Page 57 of 58 Mix the cartridge by gently inverting10 times and let sit for 3 minutes DO NOT SHAKE Inspect the solution The HUMATROPE solution should be clear If the solution is clear your cartrid
40. efore by increasing the activity of CYP3A4 somatropin could potentially decrease serum cortisol concentration In patients treated with somatropin previously undiagnosed secondary central hypoadrenalism may be unmasked and may require glucocorticoid replacement therapy In addition patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses If glucocorticoid replacement therapy is required for newly diagnosed or preexisting hypoadrenalism dosage and compliance should be monitored carefully to avoid either inhibition of growth promoting effects of somatropin or adrenal insufficiency increases in maintenance or stress doses of glucocorticoids may be required after initiation of somatropin Because somatropin may both inhibit 11BHSD 1 and induce activity of CYP3A4 careful monitoring of serum cortisol concentrations is required for all patients receiving concomitant glucocorticoid and somatropin therapy HUMATROPE Product Monograph Page 21 of 58 Therapeutic Class Effects Clinical comments Cytochrome P450 Metabolized Drugs Insulin and Anti hyperglycemic Agents Somatropin can increase cytochrome P450 CYP liver enzyme activity and CYP3A mediated antipyrine clearance in humans and may result in reduced plasma concentrations and decreased effectiveness of drugs metabolized by CYP3A suc
41. ents who received somatropin HUMATROPE experienced a statistically significant increase in edema HUMATROPE 17 3 vs placebo 4 4 p 0 043 and peripheral edema relative to patients who received placebo injections 11 5 vs 0 respectively p 0 017 In patients with adult onset growth hormone deficiency edema muscle pain and 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 In growth hormone deficient adults treatment emergent adverse events reported after 18 months of therapy which were possibly related to replacement therapy but were not statisticall y significant during the first 6 months included carpal tunnel syndrome edema arthralgia paresthesia hypesthesia myalgia peripheral edema back pain headache and joint disorder Adult patients treated with somatropin following diagnosis of growth hormone deficiency in childhood reported side effects less frequently than those with adult onset growth hormone deficiency Patients with Turner Syndrome Patients with Turner syndrome have an increased risk of ear or hearing disorders In a randomized concurrently controlled clinical trial patients who received somatropin HUMATROPE had statist
42. equate and well controlled studies with HUMATROPE on reproductive function have been performed see Special Populations Pregnant Women Sensitivity Sensitivity to diluent metacresol or glycerin e For patients with a known sensitivity to the diluent for HUMATROPE and those who develop sensitivity to either metacresol or glycerin HUMATROPE should not be reconstituted with the supplied diluent for HUMATROPE see CONTRAINDICTIONS DOSAGE AND ADMINISTRATION Reconstitution and Specific Precautions e Only if sensitivity to the supplied diluent is present or develops HUMATROPE in vials may be reconstituted with Sterile Water for Injection USP When reconstituted with Sterile Water for Injection the solution should be kept refrigerated at 2 8 C and used within 24 hours HUMATROPE in cartridges must be reconstituted ONLY with the supplied diluent Patients who have or develop allergic reactions to HUMATROPE in cartridges should discontinue use of this product Information for Patients Patients and or their parents caregivers should be informed about potential advantages and disadvantages of HUMATROPE therapy including the possible side effects Patients should also be offered instructions for use of injection devices storage travelling and other pertinent information see PART III CONSUMER INFORMATION Female patients should be advised to inform their doctor if they are or become pregnant or are contemplating pregnancy Careful monitori
43. er for Injection USP may be used to dissolve the HUMATROPE supplied in vials not cartridges Refer to How to Store It section for storage instructions If the patient has Turner syndrome and develops an ear infection or headaches her doctor should be told about these problems If the patient is growth hormone deficient and also has Prader Willi syndrome a genetic disorder the doctor should examine the patient for breathing problems and airway infections before starting HUMATROPE treatment especially if the patient is overweight has previously experienced severe breathing problems especially during sleep or suffered infection of the lungs or airways If during treatment the patient has signs of breathing problems snoring treatment should be interrupted and the cause assessed by the doctor Treatment with HUMATROPE can change blood sugar levels The doctor should check the patient s blood sugar regularly while taking HUMATROPE especially if there are risk factors for diabetes Patients who have diabetes or impaired glucose tolerance should have their blood sugar closely monitored during HUMATROPE therapy Leukemia has been reported in a small number of pediatric patients who have been treated with growth hormone including growth hormone of pituitary origin and man made growth hormone products such as somatrem and somatropin The relationship if any between leukemia and growth hormone is uncertain Progression of pre e
44. es were seen in childhood onset growth hormone deficient patients These significant changes in lean body mass persisted throughout the 18 month period as compared to baseline for both groups and for fat mass in the childhood onset group Total cholesterol decreased short term first 3 months although the changes did not persist However the low HDL cholesterol concentrations observed at baseline 31 0 mg dL 0 803 mM and 33 9 mg dL 0 878 mM in adult onset and childhood onset patients respectively normalized by the end of 18 months of therapy a change of 13 7 mg dL 0 354 mM and 11 1 mg dL 0 287 mM for the adult onset and childhood onset groups respectively p lt 0 001 for within group change In patients with adult onset growth hormone deficiency those who received HUMATROPE treatment had significantly greater improvements than patients who received placebo injections for 2 of the 6 domains of the Nottingham Health Profile physical mobility and social isolation Table 10 Patients with childhood onset growth hormone deficiency failed to demonstrate HUMATROPE Product Monograph Page 31 of 58 improvements in Nottingham Health Profile outcomes Table 10 Changes in Nottingham Health Profile Scores in Adult Onset Growth Hormone Deficient Patients Outcome Measure Placebo 6 Months HUMATROPE Therapy Significance 6 months Physical Mobility a sien es cites a e An improvement in score is indicated by a more
45. evels and patients may effects while taking HUMATROPE contact your doctor or experience symptoms of hypoglycemia low blood sugar such healthcare professional as feeling shaky dizzy and unwell or hyperglycemia high blood sugar such as increased urination or thirst HOW TO STORE IT In case of drug overdose contact a health care practitioner hospital emergency department or regional Poison Control Centre immediately even if there are no symptoms Before it has been reconstituted mixed Store HUMATROPE vial and diluent in the refrigerator at 2 8 C 36 46 F Missed Dose Contact your physician or pharmacist if you have missed a dose After it has been reconstituted mixed When the vial is prepared with the supplied diluent it may be stored in the refrigerator at 2 8 C 36 46 F and MUST be used SIDE EFFECTS AND WHAT TO DO ABOUT THEM within 21 DAYS Do NOT freeze Some people may be allergic to the diluent liquid used to mix with the HUMATROPE powder If there is any pain or redness When the vial is prepared with Sterile Water for Injection USP at the injection site or if there is any swelling tell your doctor it should be used immediately Although not recommended it may be stored in the refrigerator at 2 8 C 36 46 F but must Rarely more severe allergic reactions may occur Seek be used within 24 HOURS Do NOT freeze immediate medical help if you or your child experience any sudden trouble
46. evere breathing problems There have been reports of deaths in children with Prader Willi syndrome who were treated with growth hormone and had one or more of the following risk factors severe obesity breathing problems colds or lung infections Treatment should not be started e in patients known to be allergic to somatropin the active substance in HUMATROPE or to any of the ingredients in the powder or the diluent listed below e inpatients who have undergone kidney transplant until one year post transplant e inpatients with diabetic retinopathy a complication of diabetes that results from damage to the blood vessels of the light sensitive tissue at the back of the eye retina What the medicinal ingredient is Somatropin recombinant human growth hormone What the important nonmedicinal ingredients are The HUMATROPE powder contains freeze dried somatropin dibasic sodium phosphate glycine and mannitol The diluent solution for dissolving somatropin contains metacresol and glycerin Phosphoric acid and or sodium hydroxide may have been added at the time of manufacture to adjust the acidity of the liquid What dosage forms it comes in HUMATROPE is supplied as follows Vial 5 mg vial plus 5 mL diluent Cartridges 6 mg 12 mg or 24 mg cartridges each with 3 15 mL of diluent HUMATROPE cartridges require the use of a HumatroPen to inject the drug HumatroPens are supplied separately WARNINGS AND PRECA
47. f 58 included syndromal conditions e g Turner syndrome chronic disease e g diabetes mellitus and any active disease Additional safety information was obtained from 379 short children born SGA followed in an observational study Study GDFC 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 Table 15 Summary of Patient Demographics for Clinical Trials in Pediatric Patients Born Small for Gestational Age Mean age Range 6 8 years 3 0 12 3 Study subjects N number 200 patients entered 193 received at least 1 dose of drug 175 completed 2 years Dosage frequency route of ra 3 Gender administration and duration Trial design Phase 3b multi center randomized open label 2 arm non inferiority study of individually adjusted IAD versus fixed high dose FHD regimen FHD 0 067 mg kg d for 2 years IAD 0 035 mg kg d for 3 months increased to 0 067 mg kg d if predicted or actual 1 year height gain was lt 0 75 SDS Daily subcutaneous 0 47 mg kg wk Daily subcutaneous Initial treatment period was 2 yrs followed by 2 years of untreated observation Phase 3b randomized open label multi centre 35 patients entered 18 completed 9 3 years 6 7 10 8 Phase 4 open label observational multi center Dosage regimen and duration of treatment are at the discretion of investigator mean dose 429 pa
48. f reconstituted HUMATROPE to refrigerator and use within 21 days Dispose of needle or the needle and syringe after use Injecting HUMATROPE l 2 Gently tap injection site several times with fingers Wipe the area thoroughly with an alcohol swab Use a circular motion and work outward from the inside of the circle 3 Subcutaneous Injection With the thumb and forefinger stabilize the skin by spreading or pinching up a large area of skin HUMATROPE Product Monograph Page 49 of 58 IMPORTANT PLEASE READ 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 Dispose of needle or the 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 If no blood enters the syringe slowly inject the solution e Dispose of needle or the needle and syringe after use as per your doctor s instructions For more information please cont
49. from the clinical trials because of adverse events One patient discontinued from the placebo controlled study following diagnosis of Stage 3B Hodgkin disease after 19 weeks of HUMATROPE treatment It was subsequently determined on the basis of clinical radiographic and laboratory findings that subclinical Hodgkin disease was likely present at study entry One placebo treated patient discontinued the study after an accidental injury One patient in the dose response study discontinued following diagnosis of a desmoplastic small round cell tumour after 6 4 years of HUMATROPE treatment and died 4 years later It was subsequently determined that the tumour had an abnormal karyotype typically associated with this type of tumour Neither case of neoplasia in the ISS studies was considered causally related to HUMATROPE exposure Two additional patients discontinued from the dose response study due to adverse events one patient discontinued after diagnosis of a slipped capital femoral epiphysis following trauma one patient was withdrawn from the study due to decreased glucose tolerance Both events have been previously reported in patients receiving somatropin The impact of ethnicity was not evaluated in the clinical trials for idiopathic short stature Patients with 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 r
50. ge is now prepared and ready to be attached to your HUMATROPEN see the User Manual for your HUMATROPEN After the cartridge has been reconstituted mixed with the supplied diluent it may be stored in the refrigerator at 2 8 36 46 F and MUST be used within 28 DAYS Do NOT freeze 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 For more information please contact your healthcare professional or pharmacist first or Eli Lilly Canada Inc at 1 888 545 5972 or visit the website at www lilly ca The information in this document is current as of the last revision date shown below For the most current information please visit our website or contact us directly HUMATROPE and HUMATROPEN are trademarks owned or licensed by Eli Lilly and Company its subsidiaries or affiliates This leaflet was prepared by Eli Lilly Canada Inc Toronto Ontario M1N 2E8 Last revised August 19 2013 HUMATROPE Product Monograph Page 58 of 58
51. h as sex steroids for example estrogen or oral contraceptives cyclosporine and some anticonvulsants Patients with diabetes mellitus who receive concomitant somatropin may require adjustment of their doses of insulin and or other anti hyperglycemic agents Careful monitoring is advised when somatropin is administered in combination with drugs metabolized by CP450 liver enzymes Because somatropin may induce a state of insulin resistance patients who receive somatropin should be monitored for evidence of abnormal glucose metabolism and or diabetes mellitus New onset type 2 diabetes mellitus has been reported in children and adults receiving somatropin Drug Food Interactions Interactions with food have not been established Drug Herb Interactions Interactions with herbal products have not been established Drug Laboratory Tests Interactions For interactions between HUMATROPE and laboratory tests see WARNINGS AND PRECAUTIONS Monitoring and Laboratory Tests subsection DOSAGE AND ADMINISTRATION Dosing Considerations The patient s medical history for hypersensitivity reactions should be carefully evaluated prior to HUMATROPE administration see WARNINGS AND PRECAUTIONS Sensitivity Adult Patients Patients with epiphyseal closure who were treated with somatropin therapy in childhood should be re evaluated according to the criteria in INDICATIONS AND CLINICAL USE before continuation of somatropin ther
52. h 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 aggressivel y see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS Congenital Disorders HUMATROPE Product Monograph Page 13 of 58 Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders before and during treatment with somatropin because these patients have an increased risk of ear and hearing disorders see ADVERSE REACTIONS Patients with Turner syndrome are at risk for cardiovascular disorders e g hypertension stroke and aortic dilatation aneurysm and dissection and these patients should be monitored closely for development or worsening of these conditions before and during treatment with somatropin Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease Therefore these patients should have periodic thyroid function tests performed and be treated appropriately see Endocrine and Metabolism Because somatropin may induce a state of insulin resistance patients should be closely monitored during somatropin therapy for evidence of glucose intolerance see Endocrine and Metabolism In patients with hypopituitarism standard hormonal replacement therapy should be monitored closely when somatropin therapy is administered see Endocrine and Metabolism Because inadequate trea
53. hether somatropin is excreted in human milk Due to its large molecular weight it is unlikely that somatropin would be passed intact into human breast milk and absorption of intact protein from the gastrointestinal tract of the infant is also unlikely However secretion of breakdown products of somatropin in breast milk has not been studied Therefore somatropin should be used with caution in nursing women Geriatrics gt 65 years of age The safety and effectiveness of somatropin have not been established in patients aged gt 65 years Older patients may be at greater risk of adverse reactions A lower starting dose and smaller dose increments should be considered for older patients Obese patients Obese individuals are more likely to manifest adverse effects when treated with a weight based regimen see DOSAGE AND ADMINISTRATION Monitoring and Laboratory Tests It is recommended that insulin like growth factor I IGF I concentrations be monitored regularly and maintained within the normal range for age and sex see WARNINGS AND PRECAUTIONS General Patients with Prader Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin If a somatropin treated patient shows signs of upper airway obstruction including onset of or increased snoring and or new onset of sleep apnea treatment should be interrupted All patients with Prader Willi syndrome treated wit
54. hormone deficiency n 98 and two studies in childhood onset growth hormone deficiency n 67 were designed to assess the effects of replacement therapy with HUMATROPE The primary efficacy measures were body composition lean body mass and fat mass lipid parameters and the Nottingham Health Profile The Nottingham Health Profile is a general health related quality of life questionnaire These four studies each included a 6 month randomized blinded placebo controlled phase followed by 12 months of open label therapy for all patients The HUMATROPE dosages for all four studies were identical 1 month of therapy at 0 00625 mg kg day followed by the maintenance dose of 0 0125 mg kg day Adult onset patients and childhood onset patients differed by diagnosis proportion of patients with organic vs idiopathic pituitary disease body size average vs small for mean height and weight and mean age 44 vs 29 years 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 Serum lipid subfractions were analyzed by standard assay methods in a central laboratory Significantly greater increases in lean body mass and decreases in percent body fat were observed for HUMATROPE treated adult onset patients compared with placebo treated patients lean body mass 2 59 vs 0 22 kg p lt 0 001 percent body fat 3 60 vs 0 19 p lt 0 001 Similar chang
55. ically significantly greater rates of otitis media 43 vs 26 ear disorders 18 vs 5 and surgical procedures 45 vs 27 than patients who received no treatment see WARNINGS AND PRECAUTIONS Congenital Disorders HUMATROPE Product Monograph Page 16 of 58 Patients with Idiopathic Short Stature In a placebo controlled study there were no significant differences between the HUMATROPE treated 0 222 mg kg week and placebo treated groups for any of the non serious clinically significant treatment emergent adverse events see Table 2 Mean serum glucose concentration did not change during HUMATROPE treatment Mean fasting serum insulin concentrations increased 10 in the HUMATROPE treatment group at the end of treatment relative to baseline values 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 of above range values for glucose insulin and HbA were similar in the HUMATROPE 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
56. icity of the reconstituted solutions Reconstituted solutions have a pH of approximately 7 5 HUMATROPE Product Monograph Page 28 of 58 Table 8 HUMATROPE Dosage Forms and Packaging Dosage Form Combination Packages HUMATROPE Diluent Vial 5 mg 5 mL y 6 mg Cartridges for use with HumatroPen 12 mg POME 24 mg The HumatroPen family of injection devices each with a HumatroPen User Manual is available separately HUMATROPE Product Monograph Page 29 of 58 PART II SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION Drug Substance Somatropin recombinant human growth hormone rhGH is a polypeptide hormone of recombinant DNA origin Somatropin has 191 amino acid residues and a molecular weight of about 22 125 daltons The amino acid sequence is identical to that of human growth hormone of pituitary origin Somatropin is synthesized in a strain of E coli that has been modified by the addition of the gene for somatropin production Proper name somatropin recombinant human growth hormone rhGH Common name Molecular formula 191 amino acid residues Molecular mass 22 125 daltons Structure human growth hormone figure 1 Ml Product Characteristics HUMATROPE somatropin is a sterile white lyophilized powder of highly purified somatropin intended for subcutaneous or intramuscular administration after reconstitution with the supplied diluent CLINICAL TRIALS Effect of HU
57. id the development of carpal tunnel syndrome see ADVERSE REACTIONS Intracranial hypertension has been recognized as a complication early in somatropin treatment The diagnosis is made on the basis of clinical symptoms such as severe persistent or recurrent HUMATROPE Product Monograph Page 14 of 58 headache visual problems nausea and or vomiting papilledema and temporal relationship to somatropin Physicians and parents should be attentive to these symptoms Funduscopic examination should be performed routinely before initiating treatment with somatropin to exclude pre existing papilledema and should be repeated if there is any clinical suspicion of intracranial hypertension If papilledema is confirmed by funduscopy somatropin treatment should be stopped Intracranial hypertension usually resolves rapidly when somatropin treatment is withdrawn If symptoms and signs of intracranial hypertension resolve somatropin treatment can be restarted at a lower dose If somatropin treatment is restarted careful monitoring for symptoms of intracranial hypertension is necessary and treatment should be discontinued if intracranial hypertension recurs At present there is insufficient evidence to guide clinical decision making in patients with resolved intracranial hypertension ADVERSE REACTIONS Adverse Drug Reaction Overview The data presented below reflect the findings from clinical trials and post marketing experience of treatment with HUMATRO
58. in turn results in a relative increase in serum cortisol Somatropin treatment may inhibit 11BHSD 1 resulting in relative reduction of serum cortisol concentrations In addition somatropin may enhance the activity of CYP3A4 a cytochrome P450 enzyme involved in glucocorticoid catabolism Therefore by increasing the activity of CYP3A4 somatropin could potentially decrease serum cortisol concentration Because somatropin may both inhibit 11BHSD 1 an enzyme required for production of cortisol and induce activity of CYP3A4 an enzyme involved in cortisol breakdown careful monitoring of serum cortisol concentrations is required for all patients receiving concomitant glucocorticoid and somatropin therapy As a consequence of its actions on enzymes involved in cortisol metabolism somatropin treatment may unmask previously undiagnosed central secondary hypoadrenalism and glucocorticoid replacement may be required In addition patients treated with glucocorticoids for previously diagnosed hypoadrenalism primary or secondary may require adjustments of their maintenance or stress doses following initiation of somatropin treatment this may be especially true for patients treated with cortisone acetate and prednisone because conversion of these drugs to their biologically active metabolites is dependent on the activity of 11BHSD 1 see Monitoring and Laboratory Tests Fluid Retention Fluid retention during somatropin replacement therapy in adults
59. ion stroke and aortic dilatation aneurysm and dissection and these patients should be monitored closely for development or worsening of these conditions before and during treatment with somatropin e Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease Therefore these patients should have periodic thyroid function tests performed and be treated appropriately see Endocrine and Metabolism Skeletal abnormalities including scoliosis are commonly seen in untreated patients with Turner syndrome Dependence Tolerance Somatropin is not a drug of dependence Potential for Misuse Inappropriate use of somatropin by individuals who do not have conditions for which there is an approved indication for somatropin may result in clinically significant negative health consequences Drug Interactions see DRUG INTERACTIONS Endocrine and Metabolism Patients with diabetes mellitus or glucose intolerance should be monitored closely during therapy with somatropin as an adjustment of their antidiabetic therapy may be required see Monitoring and Laboratory Tests Treatment with somatropin may decrease insulin sensitivity particularly at higher doses in patients with risk factors for diabetes mellitus such as obesity Turner syndrome or a family history of diabetes mellitus those receiving high dose corticosteroid therapy and patients with impaired glucose tolerance or pre existing diabetes me
60. les e Patients with Prader Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin see Monitoring and Laboratory Tests e If asomatropin treated patient shows signs of upper airway obstruction including onset of or increased snoring and or new onset of sleep apnea somatropin treatment should be interrupted and the patient should be treated for upper airway obstruction and or sleep apnea e 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 HUMATROPE Product Monograph Page 7 of 58 and Monitoring and Laboratory Tests Turner Syndrome e Patients with Turner syndrome may be at increased risk for development of intracranial hypertension Therefore these patients should be evaluated for signs and symptoms of intracranial hypertension and 1f present this condition should be treated before initiation of treatment with somatropin e Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders before and during treatment with somatropin because these patients have an increased risk of ear and hearing disorders see ADVERSE REACTIONS e Patients with Turner syndrome are at risk for cardiovascular disorders e g hypertens
61. llitus As a result previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked during somatropin treatment Therefore patients who receive somatropin should be monitored for evidence of abnormal glucose metabolism and or diabetes mellitus New onset type 2 diabetes mellitus has been reported in children and adults receiving somatropin In patients with hypopituitarism standard hormonal replacement therapy should be monitored closely when somatropin therapy is administered see Monitoring and Laboratory Tests HUMATROPE Product Monograph Page amp of 58 Somatropin can increase the extrathyroidal conversion of thyroxine T4 to triiodothyronine T3 and may unmask incipient hypothyroidism Because inadequate treatment of hypothyroidism may prevent optimal response to somatropin thyroid function should be evaluated before starting somatropin therapy and should be monitored regularly during treatment not less frequently than annually see Monitoring and Laboratory Tests Notes Regarding Potential Effects of Somatropin on Glucocorticoid Metabolism The microsomal enzyme 11B hydroxysteroid dehydrogenase type 1 11f8HSD 1 is required for conversion of cortisone to its active metabolite cortisol in hepatic and adipose tissue Endogenous growth hormone and exogenous somatropin inhibit the activity of 11BHSD 1 Therefore growth hormone deficiency is associated with a relative increase in 11BHSD 1 activity which
62. may occur frequently Clinical manifestations of fluid retention are usually transient and dose dependent Immune Local allergic reactions e Patients receiving somatropin treatment may experience redness swelling pain inflammation or itching at the site of injection see ADVERSE REACTIONS e Most of these minor reactions usually resolve in a few days to a few weeks Such reactions may occur if the injection is given incorrectly irritants in the skin cleansing agent or poor injection technique or if the patient is allergic to somatropin or any non medicinal ingredient see CONTRAINDICATIONS e Rarely subcutaneous administration of somatropin can result in lipoatrophy or lipohypertrophy Regular rotation of the injection site may help reduce or prevent these reactions HUMATROPE Product Monograph Page 9 of 58 e Patients should be advised to consult their doctor if they notice any of the conditions described above e Onrare occasions injection site reactions may require discontinuation of somatropin therapy Systemic allergic reactions e As with any protein local or systemic 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 e These reactions may be characterized by a generalized rash with pruritus shortness of breath wheezing angioneurotic edema and drop in blood pressure see ADVERSE REACTIO
63. mily has diabetes e ifthe patient is taking a steroid medication glucocorticoid such as cortisone or prednisone This is because the combination may reduce the success of the HUMATROPE treatment or because more of the steroid medication may be needed when the patient is also taking HUMATROPE e ifthe patient is taking a medication known to be metabolized by certain liver enzymes e g cyclosporine some anticonvulsants and hormones such as estrogen and birth control pills This is because the treatment with HUMATROPE may reduce the effectiveness of these drugs e if the patient especially a child develops abdominal pain e if the patient is or plans to become pregnant or is breast feeding e ifthe patient has hypothyroidism low levels of thyroid hormone because HUMATROPE may reduce the levels of thyroid hormone The patient may require a change in dosage of his or her thyroid hormone medication e ifthe patient suffers from a bad headache or frequent headaches or from problems with eyesight vomiting or feeling sick Very rarely swelling of the brain may develop and the doctor may want to examine the patient to look for signs of brain swelling If this occurs it may be necessary to stop HUMATROPE treatment e ifthe patient develops a limp or has hip or knee pain while being treated with HUMATROPE If the patient is sensitive to any component of the diluent the liquid used to mix with the HUMATROPE powder Sterile Wat
64. nagement of side effects contact your health care professional The Canada Vigilance Program does not provide medical advice Any child who begins to limp must be examined by a doctor HUMATROPE may cause intracranial hypertension increased pressure within the skull Call the doctor if the patient has a headache that doesn t go away or is severe or has headaches MORE INFORMATION that become more frequent problems with vision nausea feeling sick in the stomach or vomiting For more information please contact your healthcare HUMATROPE Product Monograph Page 46 of 58 IMPORTANT PLEASE READ professional or pharmacist first or Eli Lilly Canada Inc at 1 888 545 5972 or visit the website at www lilly ca The information in this document is current as of the last revision date shown below For the most current information please visit our website or contact us directly HUMATROPE and HUMATROPEN are trademarks owned or licensed by Eli Lilly and Company its subsidiaries or affiliates This leaflet was prepared by Eli Lilly Canada Inc Toronto Ontario M N 2E8 Last Revised August 19 2013 HUMATROPE Product Monograph Page 47 of 58 IMPORTANT PLEASE READ Reconstitution Instructions for HUMATROPE Vials 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 Discard syringes an
65. ndrome idiopathic short stature SHOX short stature homeobox containing gene deficiency or being born small for gestational age HUMATROPE is also used in some adults who had growth hormone deficiency when they were children and still have growth hormone deficiency after they finish growing or who do not make enough growth hormone as adults for some other reason What it does HUMATROPE is used to increase growth hormone levels It stimulates bone growth in children unless the ends of the bones have hardened closed epiphyses In both adults and children with growth hormone deficiency it also increases the growth of muscle and reduces body fat When it should not be used Treatment should not be started e in children to promote growth when the ends of the long bones have hardened closed epiphyses Treatment should be stopped when adult height is reached Reevaluation to find out whether the patient still has growth hormone deficiency will determine if continued treatment with HUMATROPE at a lower dose would be beneficial e inpatients with any evidence of an active cancer either newly diagnosed or recurrent e while patients have a serious illness following heart or abdominal surgery or in patients who have just had a serious accident or those with acute respiratory failure low level of oxygen in the blood or high level of carbon dioxide in the blood e inpatients with Prader Willi syndrome who are very obese or have s
66. ne supplementation on adult height in Turner syndrome results of the Canadian randomized controlled trial J Clin Endocrinol Metab 90 3360 3366 Winegrad AJ Shaw WH Lukens FD et al 1959 Effect of growth hormone in vitro on the metabolism of glucose on rat adipose tissue J Biol Chem 234 1922 1928 Wit JM Rekers Mombarg LTM Cutler GB et al 2005 Growth hormone GH treatment to final height in children with idiopathic short stature evidence for a dose effect J Pediatr 146 45 53 HUMATROPE Product Monograph Page 43 of 58 IMPORTANT PLEASE READ PART II CONSUMER INFORMATION HUMATROPE Vials somatropin for injection pronounced HYOO mah trope This leaflet is for patients and caregivers It is Part III of a three part Product Monograph published when HUMATROPE was approved for sale in Canada This leaflet is a summary and will not tell you everything about HUMATROPE Contact your doctor or pharmacist if you have any questions about the drug Please read this information carefully before you start to take your medicine even if you have just refilled your prescription Some of the information may have changed Keep this pamphlet since you may need to refer to it after starting treatment with HUMATROPE ABOUT THIS MEDICATION What the medication is used for HUMATROPE is used to treat children and teenagers who are short or growing too slowly due to a medical condition such as growth hormone deficiency Turner sy
67. negative change in the score gt To account for multiple analyses appropriate statistical methods were applied and the required level of significance was 0 01 NS not significant Effect of HUMATROPE Treatment in Patients with Turner Syndrome One long term randomized open label multicenter concurrently controlled study and one long term randomized dose response study were conducted to evaluate the efficacy of HUMATROPE for the treatment of patients with short stature due to Turner syndrome In the randomized study GDCT comparing HUMATROPE treated patients to a concurrent control group who received no somatropin the HUMATROPE treated patients who received a dose of 0 3 mg kg wk given 6 times per week from a mean age of 11 7 years for a mean duration of 4 7 years attained a mean near final height of 146 0 6 2 cm n 27 mean SD as compared to the control group who attained a near final height of 142 1 4 8 cm n 19 By analysis of covariance the effect of HUMATROPE therapy was a mean height increase of 5 4 cm p 0 001 In a randomized blinded dose response study GDCI patients were treated from a mean age of 11 1 years for a mean duration of 5 3 years with a weekly HUMATROPE dose of either 0 27 mg kg or 0 36 mg kg administered 3 or 6 times weekly The mean near final height of patients who received HUMATROPE was 148 7 6 5 cm n 31 When compared to historical control data the mean gain in adult height was
68. ng is essential in pregnant patients see WARNINGS AND PRECAUTIONS Special Populations and PART HI CONSUMER INFORMATION Special Populations Pediatric Patients see INDICATIONS AND CLINICAL USE Children who have endocrine disorders including growth hormone deficiency may develop slipped capital femoral epiphyses more frequently than children in the general population Any pediatric patient with onset of a limp during somatropin therapy should be evaluated HUMATROPE Product Monograph Page 11 of 58 Somatropin has not been shown to increase the occurrence of scoliosis However identification of a new scoliosis or progression of pre existing scoliosis can occur in pediatric patients who experience rapid growth Therefore because somatropin increases growth rate patients should be initially screened for presence of a scoliosis and patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis Children treated with somatropin may have an increased risk of developing pancreatitis compared to adults Although rare pancreatitis should be considered in somatropin treated children who develop abdominal pain see ADVERSE REACTIONS Some of the height gain obtained with somatropin treatment may be lost if treatment is stopped before final height is reached Turner Syndrome see Congenital Disorders Idiopathic Short Stature Other medical reasons or treatments that could explain growth
69. ns be monitored regularly and maintained within the normal range for age and sex see Monitoring and Laboratory Tests A significant increase in mortality was reported among somatropin treated adult patients who received high somatropin doses of 5 3 to 8 0 mg day with acute critical illnesses in intensive care units due to complications following open heart surgery or abdominal surgery multiple accidental trauma or acute respiratory failure compared with those who received placebo injections see CONTRAINDICATIONS The safety of continuing somatropin 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 suffering from acute critical illnesses should be weighed against the potential risk The subcutaneous injection site should be rotated to minimize the risk of lipoatrophy To avoid transmission of disease somatropin HUMATROPE cartridges must not be used by more than one person Instructions for appropriate use should be provided to patients and or their caregivers Patients being treated with somatropin should be informed of the potential benefits and risks associated with treatment Patients should be instructed to contact their physician should they experience any side effects or discomfort during treatment with somatropin see Information for Patients and Part II CONSUMER IN
70. nsport by influencing the metabolism of vitamin D Cholecalciferol vitamin D3 was administered with and without somatropin treatment 5 The inactive form of vitamin D cholecalciferol and somatropin administered separately had no significant effect on calcium transport Simultaneous administration of both substances however caused significant elevation in intestinal calcium transport HUMATROPE Product Monograph Page 39 of 58 TOXICOLOGY The toxicity safety of somatropin has been studied in five animal species after single or repeated parenteral injection by the subcutaneous intramuscular and intravenous routes The tests involved young healthy animals In vitro tests were performed to investigate possible genetic toxicity of somatropin and to determine the compatibility of somatropin and diluent vehicles for injection with whole blood Acute Toxicity Studies Single doses of somatropin have been studied in mice rats dogs and rhesus monkeys using subcutaneous and intravenous administration Mice and rats received a single subcutaneous or intravenous dose of 12 5 mg kg of body weight This dose is approximately 200 fold the expected human clinical daily dose for the treatment of dwarfism These animals appeared normal within two hours after dosing Table 17 Acute Toxicity Studies Species Animals Duration of Study Administration Dose Signs of M F Days mg kg Toxicity SC 12 5 None IV 12 5 None SC 12 5 None IV 12 5 Leg
71. nt with somatropin should be discontinued at the time of renal transplantation see WARNINGS AND PRECAUTIONS Renal Hepatic Biliary Pancreatic Impairment WARNINGS AND PRECAUTIONS Serious Warnings and Precautions e HUMATROPE therapy should be directed by physicians experienced in the diagnosis and management of patients with growth hormone deficiency Turner syndrome idiopathic short stature small for gestational age SHOX deficiency or adult patients with either childhood onset or adult onset growth hormone deficiency see INDICATIONS AND CLINICAL USE e Any change in brand of somatropin products should be made cautiously and only under medical supervision see WARNINGS AND PRECAUTIONS Immune Antibody Production e Reconstituted HUMATROPE must only be used if the solution is water clear and contains no particles see DOSAGE AND ADMINISTRATION Reconstitution and Specific Precautions HUMATROPE Product Monograph Page 5 of 58 e There have been reports of fatalities associated with the use of somatropin in pediatric patients with Prader Willi syndrome who have one or more of the following risk factors severe obesity history of respiratory impairment or sleep apnea or unidentified i e previously undiagnosed mildly symptomatic respiratory infections see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS Congenital Disorders General It is recommended that insulin like growth factor I IGF I concentratio
72. nts must have somatotropin deficiency syndrome either alone or associated with multiple hormone deficiencies hypopituitarism as a result of pituitary disease hypothalamic disease surgery radiation therapy or trauma or 2 Childhood Onset Patients who were growth hormone deficient during childhood as a result of congenital genetic acquired or idiopathic causes Confirmation of the diagnosis of adult growth hormone deficiency in both groups by appropriate growth hormone stimulation test is usually required However confirmatory growth hormone stimulation testing may not be required in patients with congenital genetic growth hormone deficiency or multiple pituitary hormone deficiencies due to organic disease CONTRAINDICATIONS Somatropin should not be initiated in patients with acute critical illness due to complications following cardiac or abdominal surgery or multiple accidental trauma or to patients who have acute respiratory failure Clinical studies demonstrated that high doses of somatropin were associated with a significantly increased morbidity and mortality in those patients see WARNINGS AND PRECAUTIONS General HUMATROPE Product Monograph Page 4 of 58 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 patient
73. of the patient s family has diabetes e ifthe patient is taking a steroid medication glucocorticoid such as cortisone or prednisone This is because the combination may reduce the success of the HUMATROPE treatment or because more of the steroid medication may be needed when the patient is also taking HUMATROPE e ifthe patient is taking a medication known to be metabolized by certain liver enzymes e g cyclosporine some anticonvulsants and hormones such as estrogen and birth control pills This is because the treatment with HUMATROPE may reduce the effectiveness of these drugs e ifthe patient especially a child develops abdominal pain e if the patient is or plans to become pregnant or is breast feeding e ifthe patient has hypothyroidism low levels of thyroid hormone because HUMATROPE may reduce the levels of thyroid hormone The patient may require a change in dosage of his or her thyroid hormone medication e if the patient suffers from a bad headache or frequent headaches or from problems with eyesight vomiting or feeling sick Very rarely swelling of the brain may develop and the doctor may want to examine the patient to look for signs of brain swelling If this occurs it may be necessary to stop HUMATROPE treatment e if the patient develops a limp or has hip or knee pain while being treated with HUMATROPE If the patient is sensitive to any component of the diluent the liquid used to mix with the HUMATROPE
74. 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 and discard the needle If the needle and syringe are made as 1 unit discard the entire unit 4 Swirl the vial with a gentle rotary motion until contents are completely dissolved Figure 4 Do not shake Preparing the Injection l Ze a 8 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 Return unused portion o
75. olism of vitamin D and has an anabolic effect on bone metabolism Somatropin has a positive influence on the wound healing process of surgically induced full thickness dermal wounds and heat induced full thickness dermal burns in rodents Studies conducted with somatropin have established that the biologic activities of recombinant DNA derived hGH are identical to those produced by pituitary sourced hGH When a growing rat is hypophysectomized it stops gaining weight and growing in length The bioactivity and biopotency of all somatropin preparations have been determined in a ten day assay using hypophysectomized rats to measure increased proximal tibial cartilage width and body weight gain Somatropin 6 25 mg rat day for seven days administered subcutaneously induced elevations in general protein and collagen synthesis within the skin While collagen synthesis was significantly increased collagen content was reduced and the percentage of total collagen that was determined to be Type III Collagen was significantly reduced in somatropin treated rats Somatropin treatment induced a significant increase in general protein content protein DNA and RNA DNA in the skin of hypophysectomized rats Elevations in these parameters are indicators of increased protein synthesis and cell size The composite of these studies indicates that somatropin either alone or acting through other mediators insulin like growth factors somatomedins significantly c
76. ontributed to the synthesis and turnover of skin proteins The changes induced in collagen metabolism are similar to the changes that occur during skin maturation In the absence of insulin like growth factors somatomedins as in the case of incubation medium without serum present somatropin had no direct effect on general protein or collagen synthesis in vitro Therefore somatropin exerts its pharmacologic effects in vivo through the production of insulin like growth factors somatomedins The Effect of Somatropin on Bone Metabolism in Rats Growth hormone acting through the insulin like growth factors is a major stimulus to new bone formation and has been demonstrated to cause epiphyseal cartilage proliferation The anabolic effects of somatropin on bone metabolism were tested in adult male rats Somatropin 400 mg kg administered by subcutaneous injection twice daily for 28 days caused significant increases in bone mineral content BMC and bone density BMC BW without causing increased bone width BW as measured by single I photon absorptiometry Confirmation of increased BMC was determined by bone ashing techniques Somatropin treatment also induced significant body weight gain and bone hydroxyproline content The data reported are consistent with the hypothesis that growth hormone has anabolic effects on bone metabolism The Effect of Somatropin on Intestinal Calcium Transport Growth hormone influences intestinal calcium tra
77. ood sugar levels and patients may effects while taking HUMATROPE contact your doctor or experience symptoms of hypoglycemia low blood sugar such healthcare professional as feeling shaky dizzy and unwell or hyperglycemia high blood sugar such as increased urination or thirst HOW TO STORE IT In case of drug overdose contact a health care practitioner hospital emergency department or regional Poison Control Centre immediately even if there are no symptoms Before it has been reconstituted mixed Store HUMATROPE cartridges and diluent in the refrigerator at 2 8 C 36 46 F Missed Dose Contact your physician or pharmacist if you have missed a dose After it has been reconstituted mixed When the cartridge is prepared with the supplied diluent it may be stored in the refrigerator at 2 8 C 36 46 F and MUST be SIDE EFFECTS AND WHAT TO DO ABOUT THEM used within 28 DAYS Do NOT freeze Some people may be allergic to the diluent liquid used to mix with the HUMATROPE powder If there is any pain or redness Keep out of reach of children at the injection site or if there is any swelling tell your doctor Rarely more severe allergic reactions may occur Seek REPORTING SUSPECTED SIDE EFFECTS immediate medical help if you or your child experience any HT oe or a sudden trouble breathing with swelling of the hands feet or You can report any suspected adverse reactions associated with the face use of heal
78. owth hormone deficiency The measurable increase in body length height after administration of either HUMATROPE or human growth hormone of pituitary origin results from an effect on the growth plates of long bones Serum concentrations of IGF I play a role in skeletal growth Serum IGF 1 concentrations are low in growth hormone deficient pediatric patients but increase during treatment with HUMATROPE Elevations in mean serum alkaline phosphatase concentrations are also seen b Cell Growth It has been shown that there are fewer skeletal muscle cells in short statured pediatric patients who lack endogenous growth hormone as compared to normal pediatric populations Treatment with human growth hormone of pituitary origin has been reported to increase both the number and the size of muscle cells 2 Protein Metabolism Linear growth is facilitated in part by increased cellular protein synthesis Nitrogen retention as demonstrated by decreased urinary nitrogen excretion and serum urea nitrogen follows the initiation of therapy with human growth hormone of pituitary origin Treatment with HUMATROPE results in a similar decrease in serum urea nitrogen 3 Carbohydrate Metabolism Pediatric patients with hypopituitarism sometimes experience fasting hypoglycemia which is improved by treatment with HUMATROPE Large doses of somatropin may impair glucose tolerance Untreated patients with Turner syndrome have an increased incidence of glucose intoleranc
79. owth hormone Genetic Toxicity Somatropin did not produce any mutagenic effects and is unlikely to pose a genotoxic hazard in human chemotherapy HUMATROPE Product Monograph Page 41 of 58 REFERENCES 1 10 11 Blum Werner F Crowe BJ Quigley Charmian A Jung Heike Cao Dachuang Ross Judith L Braun LeeAnn and Rappold Gudrun for the SHOX Study Group 2007 Growth Hormone Is Effective in Treatment of Short Stature Associated with Short Stature Homeobox Containing Gene Deficiency Two Year Results of a Randomized Controlled Multicenter Trial The Journal of Clinical Endocrinology amp Metabolism 92 1 219 228 Crowe BJ Rekers Mombarg LTM Robling K et al 2006 Effect of growth hormone dose on bone maturation and puberty in children with idiopathic short stature J Clin Endocrinol Metab 91 1 169 175 Evans HM Simpson ME Marx W et al 1943 Bioassay of pituitary growth hormone width of the proximal epiphyseal cartilage of the tibia in hypophysectomized rats Endocrinology 32 13 16 Finkelstein JD and Schachter D 1962 Active transport of calcium by intestine effects of hypophysectomy and growth hormone Am J Physiol 203 873 880 Frigeri LG Peterson SM and Lewis UJ 1979 The 20 000 Dalton structural variant of human growth hormone lack of some early insulin like effects Biochem Biophys Res Commun 91 778 782 Greenspan FS Li CH Simpson ME and Evans HM 1949 Bioassay of hypophyseal growth ho
80. particulate matter If the solution is cloudy or contains particulate matter the contents MUST NOT be injected If the solution is clear the cartridge is ready to be attached to the HumatroPen For complete instructions on the reconstitution of HUMATROPE cartridges please refer to the reconstitution instruction leaflet provided with all HUMATROPE cartridges The diluent syringe is for single use only Discard it after use in a puncture resistant container HUMATROPE cartridges are designed for use only with the HumatroPen family of pens A sterile needle should be used for each administration of somatropin For complete instructions on the use of the HumatroPen see the relevant HumatroPen Instruction Manual OVERDOSAGE For management of a suspected drug overdose contact your regional Poison Control Centre Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia Long term overdosage could result in signs and symptoms of gigantism or acromegaly consistent with the known effects of excess endogenous human growth hormone See Recommended Dose and Dosage Adjustments Table 7 HUMATROPE Product Monograph Page 25 of 58 ACTION AND CLINICAL PHARMACOLOGY Mechanism of Action The following actions have been demonstrated for HUMATROPE somatropin and or human growth hormone of pituitary origin 1 Tissue Growth a Skeletal Growth Somatropin stimulates skeletal growth in pediatric patients with gr
81. pin 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 STORAGE AND STABILITY HUMATROPE Product Monograph Page 27 of 58 Before Reconstitution Vials of HUMATROPE somatropin HUMATROPE cartridges for use with the HumatroPen and the supplied diluent for HUMATROPE are stable when stored at 2 to 8 C Avoid freezing the diluent for HUMATROPE Expiration dates are stated on the labels After Reconstitution When reconstituted with the supplied diluent and stored at 2 to 8 C e HUMATROPE vials are stable for up to 21 days and e HUMATROPE cartridges for use with the HumatroPen are stable for up to 28 days e Avoid freezing the reconstituted vials and cartridges of HUMATROPE If HUMATROPE vials are reconstituted with Sterile Water for Injection USP they should be used immediately after reconstitution Although not recommended the solution can be stored refrigerated 2 to 8 C but must be used within 24 hours Discard any unused portion Light Protect from light DOSAGE FORMS COMPOSITION AND PACKAGING HUMATROPE somatropin is a sterile white lyophylized powder of highly purified rhGH which is intended for s
82. ral edema myalgia arthralgia and paresthesiae have been reported during post marketing studies see ADVERSE REACTIONS Growth hormone deficiency in the adult is a lifelong condition and should be treated accordingly Experience with patients over sixty years of age is limited HUMATROPE Product Monograph Page 12 of 58 Based on assessment of clinical trial data post marketing data and spontaneous reports carpal tunnel syndrome appears to occur more frequently in patients over 40 years of age than in younger patients In almost half of the reported cases the recommended maximum somatropin dose had been exceeded In the majority of cases the condition resolved spontaneously or with a decrease in dosage interruption of treatment or discontinuation of treatment The maximum recommended dosage should not be exceeded Pregnant women There are no adequate and well controlled studies of HUMATROPE treatment in pregnant women Therefore the safety of HUMATROPE has not been established in this subpopulation It is not known whether HUMATROPE can cause fetal harm when administered to a pregnant woman HUMATROPE should be given to a pregnant woman only if the benefits clearly outweigh the risks and only under medical supervision Female patients should be advised to inform their doctor if they are or become pregnant or are contemplating pregnancy Nursing women There are no studies of HUMATROPE treatment in nursing women It is not known w
83. rmone the tibia test Endocrinology 45 455 463 Hollander DM Devereux DF Marafino BJ and Hoppe H 1984 Increased wound breaking strength in rats following treatment with synthetic human growth hormone Surgical Forum 35 612 614 Leschek EW Rose SR Yanovski JA et al 2004 Effect of growth hormone treatment on adult height in peripubertal children with idiopathic short stature a randomized double blind placebo controlled trial J Clin Endocrinol Metab 89 7 3140 3148 Mardh G and Lindberg A 1995 Growth hormone replacement therapy in adult Hypopituitary patients with growth hormone deficiency Combined clinical safety data from clinical trials in 665 patients Endocrinology and Metabolism Vol 2 B 11 16 Marx W Simpson ME and Evans HM 1942 Bioassay of the growth hormone of the anterior pituitary Endocrinology 30 1 10 Parlow AF Wilhelmi AE and Reichert LE 1965 Further studies on the fractionation of human pituitary glands Endocrinology 77 1126 1134 HUMATROPE Product Monograph Page 42 of 58 12 13 14 15 16 17 18 19 20 21 22 Quigley CA Crowe BJ Anglin DG Chipman JJ and the US Turner Syndrome Study Group 2002 Growth hormone and low dose estrogen in Turner syndrome results of a United States multi center trial to near final height J Clin Endocrinol Metab 87 2033 2041 Quigley CA Gill AM Crowe BJ et al 2005 Safety of growth hormone treatment in pediatric patients
84. s HUMATROPE is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader Willi syndrome see SERIOUS WARNINGS AND PRECAUTIONS Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses Treatment of pediatric growth disorders with somatropin should be discontinued when the patient has reached satisfactory adult height or the epiphyses are closed Somatropin should not be used or should be discontinued when there is any evidence of neoplastic activity including intracranial tumour Anti tumour therapy must be completed with evidence of remission prior to the institution of somatropin therapy Patients should be examined frequently for progression or recurrence of the underlying process Somatropin should be discontinued if there is evidence of recurrent tumour growth see WARNINGS AND PRECAUTIONS Carcinogenesis and Mutagenesis Somatropin should not be administered to patients with active proliferative or severe non proliferative diabetic retinopathy For patients with a known sensitivity to either metacresol or glycerin HUMATROPE should not be reconstituted with the supplied diluent for HUMATROPE If sensitivity to the supplied diluent should occur HUMATROPE in vials may be reconstituted with Sterile Water for Injection USP see WARNINGS AND PRECAUTIONS Sensitivity and DOSAGE AND ADMINISTRATION Reconstitution and Specific Precautions Treatme
85. s and visual disturbance In study 0908 there were no events reported with a frequency of lt 1 due to study size n 35 Post Marketing Adverse Drug Reactions In addition to the Clinical Trial Adverse Reactions listed in Table 1 the Adverse Reactions shown in Table 5 have been noted in post marketing studies HUMATROPE Product Monograph Page 20 of 58 Table 5 Adverse Reactions from Post Marketing Studies by Body System Body System Adverse Reactions Frequency Respiratory Dyspnea gt 1 and lt 10 adults Sleep apnea gt 1 and lt 10 adults Vascular Hypertension gt 1 and lt 10 adults Metabolic Type 2 diabetes mellitus gt 0 1 and lt 1 pediatric Adult cases of type 2 diabetes mellitus were reported spontaneously DRUG INTERACTIONS Drug Drug Interactions Potential drug interactions are tabulated below Table 6 Table 6 Established or Potential Drug Drug Interactions with HUMATROPE somatropin Therapeutic Class Effects Clinical comments Glucocorticoids Inhibition of 11B hydroxysteroid dehydrogenase type 1 11BHSD 1 Somatropin inhibits the liver enzyme 11BHSD 1 which is required for conversion of administered cortisone and prednisone to their active metabolites cortisol and prednisolone respectively In addition somatropin may enhance the activity of CYP3A4 a cytochrome P450 enzyme involved in glucocorticoid catabolism Ther
86. site frequently to help prevent lipoatrophy loss of fat tissue under the skin In general HUMATROPE should be injected in the evening or before bedtime HUMATROPE Product Monograph Page 45 of 58 IMPORTANT PLEASE READ Usual dose Other possible side effects include headaches muscle or joint The doctor will instruct you on what is the best dose of pains in hips or knees swelling associated with tingling HUMATROPE for you or your child based on individual sensations in the hands feeling weak rarely high blood needs Use HUMATROPE exactly as the doctor tells you to pressure shortness of breath and sleep apnea pauses in breathing during sleep If the headaches are bad or frequent Reconstitution Instructions and accompanied by sickness or vision problems tell the doctor Please refer to the enclosed reconstitution instructions immediately Overdose For patients with Turner syndrome HUMATROPE therapy Long term overdosage or using HUMATROPE after the growth may increase the already high frequency of ear infections Your plates in the long bones have closed hardened may result in child should see her doctor if you think she has an ear infection joint pain and continued growth of fingers toes nose ears or jaw If you think this is happening tell the doctor This is not a complete list of side effects If any of the side effects gets serious or if you notice any unexpected side Overdose may change blood sugar l
87. stature seen in patients who have Turner syndrome since these patients also lack one copy of the SHOX gene due to absence or structural alterations of the second sex chromosome 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 Fifty two patients 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 enrolled 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 of HUMATROPE 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 least squares mean difference 0 5 cm year
88. t SDS For final height population gt 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 CI One placebo treated patient was not included in this analysis because baseline bone age X ray was not available Abbreviations FH final height SDS standard deviation score BPH baseline predicted height CI confidence interval NA not applicable The dose response study included 239 pediatric patients 158 males 81 females 5 to 15 years old mean age 9 8 2 3 years Mean baseline characteristics included height SDS of 3 21 0 70 predicted adult height SDS of 2 63 1 08 and height velocity SDS of 1 09 1 15 All but 3 patients were Tanner stage I prepubertal Patients were randomized to one of three HUMATROPE treatment groups 0 24 mg kg wk 0 24 mg kg wk for 1 year followed by 0 37 mg kg wk and 0 37 mg kg wk 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 receiving 0 37 mg kg wk had a significantly greater increase in mean height velocity after 2 years of treatment than patients receiving 0 24 mg kg wk 4 04 vs 3 27 cm year p 0 003
89. term treatment of idiopathic short stature defined by HUMATROPE Product Monograph Page 3 of 58 e normal birth weight e careful diagnostic evaluation that excludes other known causes of short stature that should be either observed or treated by other means e height at least 2 25 standard deviation scores SDS below the mean for age and sex e height velocity below the 25 percentile for bone age and sex over 12 months of observation and unlikely to permit attainment of adult height in the expected range HUMATROPE treatment for idiopathic short stature should be prescribed only for those patients whose epiphyses are not closed and should be managed by physicians who have sufficient knowledge of idiopathic short stature and the efficacy safety profile of HUMATROPE Short Stature Homeobox containing Gene SHOX Deficiency HUMATROPE is indicated for the treatment of short stature or growth failure in children with SHOX short stature homeobox containing gene deficiency whose epiphyses are not closed Small for Gestational Age SGA HUMATROPE is indicated for the treatment of growth failure in children born small for gestational age birth weight and or length below 2 SD and who fail to achieve catch up growth by 2 to 4 years or later Adult Patients HUMATROPE is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who meet either of the following two criteria 1 Adult Onset Patie
90. th products to the Canada Vigilance Program by one of the following 3 ways Children treated with HUMATROPE may have an increased risk of developing an inflammation of the pancreas called e Report online at www healthcanada gc ca medeffect pancreatitis If your child develops severe abdominal pain Call toll free at 1 866 234 2345 contact your doctor e Complete a Canada Vigilance Reporting Form and Fax toll free to 1 866 678 6789 or Mail to Canada Vigilance Program It is also important to have blood glucose checked if the patient Health Canada has diabetes or a family history of diabetes Postal Locator 0701D Ottawa Ontario HUMATROPE may affect the way the body handles sugars KIA 0K9 from food and drink The doctor may need to check the amount Postage paid labels Canada Vigilance Reporting Form and the of sugar in the urine or blood adverse reaction reporting guidelines are available on the MedEffect Canada website at www healthcanada gc ca medeffect HUMATROPE can affect the amount of thyroid hormone in the blood so patients must have thyroid function tests from time to time If the thyroid is not working properly HUMATROPE may not work as well as it should NOTE Should you require information related to the management of side effects contact your health care professional The Canada Vigilance Program does not provide medical advice Any child who begins to limp must be examined by a doctor MORE INFORMATION
91. tients entered 379 patients 8 4 years 0 1 16 0 post marketing 0 29 mg kg wk Typically daily subcutaneous naive to treatment and had at least one post baseline visit Duration Median duration of treatment 2 3 yrs range 0 1 to 15 4 Abbreviations FHD fixed high dosage 0 067 mg kg day AD individually adjusted dosage 0 035 to 0 067 mg kg day Ongoing study data as of 2009 Study 0908 showed that after 2 years of Humatrope treatment mean height SDS increased from a baseline value of 2 7 0 5 to 1 5 0 6 The primary objective of Study GDGB was to demonstrate that HUMATROPE given according to an individually adjusted dosage IAD regimen would result in a 1 year height SDS increase not inferior to that achieved with a fixed high dosage FHD regimen The non inferiority margin was 0 5 SDS that is the height increase for the IAD group would be considered non inferior if the lower bound of the 95 confidence interval CI for the mean difference between the groups IAD FHD was greater than 0 5 height SDS In this open label study 193 children with mean HUMATROPE Product Monograph Page 37 of 58 age 6 8 2 4 years range 3 to 12 were randomized to either a fixed dosage group 0 067 mg kg day 67 ug kg day equivalent to 0 47 mg kg week or an individually adjusted dosage group and received at least 1 dose of study drug The initial HUMATROPE dosage for the IAD group was 0 035 mg kg day 35 ug kg day
92. tment of hypothyroidism may prevent optimal response to somatropin thyroid function should be evaluated before starting somatropin therapy and should be monitored regularly during treatment not less frequently than annually see Endocrine and Metabolism Bone age should be monitored periodically during somatropin administration Patients with growth hormone deficiency secondary to an intracranial lesion should be examined frequently for progression or recurrence of the underlying disease process Patients with an intra or extra cranial neoplasm in remission who are receiving treatment with somatropin should be examined carefully and at regular intervals by the physician Patients who develop neoplasia should be reported to Health Canada by the treating physician For patients receiving somatropin therapy physicians should be aware of the potential for development of neoplasia or for recurrence of a previous neoplasm Treatment should be discontinued if a new tumour or signs of relapse are detected In short children born SGA it is recommended that IGF I concentrations should be measured before initiation of treatment and monitored regularly thereafter If on repeated measurements IGF I concentrations exceed 2 SD compared to references for age and pubertal status the IGF I IGFBP 3 ratio could be taken into account to consider dose adjustment In case of persistent edema or severe paraesthesia the dosage should be decreased in order to avo
93. ubcutaneous or intramuscular use after reconstitution with the supplied diluent HUMATROPE is available as a vial and cartridges Table 8 HUMATROPE Vials Each vial of HUMATROPE contains 5 mg of somatropin for injection in addition to mannitol glycine and dibasic sodium phosphate Phosphoric acid and or sodium hydroxide may have been used for pH adjustment Each vial of HUMATROPE is supplied in a combination pack with an accompanying vial of diluting solution The diluent for HUMATROPE contains water for injection with 1 7 glycerin and 0 3 metacresol as a preservative At a concentration of 2 mg HUMATROPE per mL diluent the 1 7 glycerin makes the reconstituted product nearly isotonic Reconstituted solutions have a pH of approximately 7 5 HUMATROPE Cartridges Each cartridge of HUMATROPE for use with the HumatroPen contains 6 mg 12 mg or 24 mg of somatropin for injection The cartridge also contains mannitol glycine and dibasic sodium phosphate Phosphoric acid and or sodium hydroxide may have been added at the time of manufacture to adjust the pH Each cartridge is supplied in a combination package with an accompanying syringe containing 3 15 mL of diluting solution The diluent for 6 mg cartridges contains water for injection 0 3 metacresol as a preservative and 1 7 glycerin The diluent for 12 and 24 mg cartridges contains water for injection 0 3 metacresol and 0 29 glycerin Glycerin is added to the diluent to modify ton
94. umber of HUMATROPE treated than Untreated patients Percentage calculated for males only 1 12 HUMATROPE Product Monograph Page 18 of 58 Patients Born Small for Gestational Age The safety of HUMATROPE treatment in children born small for gestational age was assessed in 2 clinical trials Study GDGB and Study 0908 and one observational study Study GDFC see CLINICAL TRIALS Effects of HUMATROPE on Pediatric Patients Born Small for Gestational Age In Study GDGB a randomized open label study 4 patients discontinued due to adverse events 3 from the Fixed High Dose FHD 0 067 mg kg day group 1 patient each for impaired fasting glucose mood alteration and pain in extremity and 1 patient from the Individually Adjusted Dose IAD 0 035 mg kg day then increased to 0 067 mg kg day group focal glomerulosclerosis Adverse events possibly or probably related to HUMATROPE are provided in Table 4 The most frequently reported of these adverse drug reactions was headache for which there was a suggestion of a modest dose response FHD 9 IAD 3 There were no clear cut cases of new onset diabetes mellitus no children treated for hyperglycemia and no children whose fasting blood glucose exceeded 7 mmol L 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
95. ution to prevent contamination of the contents by repeated needle insertions HUMATROPE should be administered using sterile disposable syringes and needles The syringes should be of small enough volume that the prescribed dose can be drawn from the vial with reasonable accuracy If intramuscular injection is intended the needle should be of sufficient length usually 1 inch or more to ensure that the injection reaches the muscular layer If sensitivity to the diluent should occur HUMATROPE in vials may be reconstituted with Sterile Water for Injection USP When reconstituted with Sterile Water for Injection USP the solution should be used immediately after reconstitution and the unused portion discarded Although not recommended the solution can be stored refrigerated 2 to 8 C but must be used within 24 hours HUMATROPE Cartridges Each HUMATROPE cartridge for use with the HumatroPen should be reconstituted using the accompanying diluent syringe To reconstitute attach the cartridge to the pre filled diluent syringe according to the instructions provided with the HUMATROPE Cartridge Kit and slowly inject the entire contents of the pre filled diluent syringe into the cartridge The diluent needle aims the stream of liquid against the wall of the cartridge Following reconstitution gently invert the cartridge up and down 10 times until the contents are completely dissolved DO NOT SHAKE The resulting solution should be clear without
96. weakness IV 0 125 No effects on BP rapid infusion 1 25 heart and 3 125 respiratory rates SC 6 25 None Abbreviations M male F female SC subcutaneous IV intravenous BP blood pressure Subacute Toxicity Somatropin was administered daily for 30 days by intravenous and subcutaneous routes at doses of 0 125 0 625 and 3 125 mg kg There were no deaths and there were no toxicologically significant treatment related changes in clinical signs hematology clinical chemistry urinalysis or organ weight parameters Rhesus monkeys received somatropin administered intramuscularly daily for 5 weeks at doses of 0 125 0 375 and 1 25 mg kg up to 20 fold the anticipated daily human clinical dose All of the monkeys survived and there were no treatment related abnormalities observed in clinical signs body weight food consumption hematology or urinalysis parameters Antibodies were not produced against somatropin or possible E coli polypeptide components that could have been produced as a result of production by recombinant technology In contrast when monkeys were treated with methionyl growth hormone under similar study conditions antibodies to the hormone were observed HUMATROPE Product Monograph Page 40 of 58 Reproduction Studies Standard reproduction and teratology studies in laboratory animals have not been conducted with somatropin The value of such studies is questionable considering the compound is identical to human gr
97. ween 2 and 3 consideration should be given to initiating treatment with a lower dose e g 0 035 mg kg day then titrating the dose as needed SC subcutaneous SDS standard deviation score SHOX short stature homeobox containing gene It is recommended that IGF I concentrations be monitored regularly and maintained within the normal range for age and sex When IGF I concentrations are higher than the normal range a dose reduction should be considered Administration HUMATROPE should be administered subcutaneously and the injection site should be rotated to minimize the risk of lipoatrophy HUMATROPE treatment for improvement of linear growth in childhood should be administered to pediatric patients whose epiphyses have not closed For patients whose height velocity in the first year of treatment does not improve by at least 50 above the pre treatment height velocity consideration should be given to the following e Is the patient receiving the correct dosage and frequency of the medication e Is the growth disorder diagnosis correct e Does the patient have a coexistent condition that may impair growth such as hypothyroidism a gastrointestinal disorder or severe psychological disturbance e Is the patient receiving adequate nutrition e Is the patient receiving a concomitant medication that may impair response to HUMATROPE such as systemic glucocorticoids or stimulant medications If no underlying reason for a suboptimal respons
98. with idiopathic short stature J Clin Endocrinol Metab 90 9 5188 5196 Rappold G Blum WF Shavrikova EP Crowe BJ Roathe R Quigley CA Ross JL Niesler B 2006 Genotypes and phenotypes in children with short stature clinical indicators of SHOX haploinsufficiency J Med Genet 2007 44 306 313 Rappold GA Fukami M Niesler B Schiller S Zumkeller W Bettendorf M Heinrich U Vlachopapadoupoulou E Reinehr T Onigata K Ogata T 2002a Deletions of the homeobox gene SHOX Short Stature Homeobox are an important cause of growth failure in children with short stature J Clin Endocrinol Metab 87 1402 1406 Rappold G Ross J Blaschke J and Blum W 2002b Understanding SHOX deficiency and its role in growth disorders a reference guide Oxfordshire UK TMG Health Care Communications Ltd 121 p Shaar CJ Grinnan EL Short WG et al 1986 Hyperglycemic activity in dogs of recombinant DNA derived 20 000 Dalton variant of methionyl human growth hormone Endocrine Research 12 21 35 Rosilio M Carel JC Ecosse E Chaussain JL on behalf of the 0908 Lilly Study Group 2005 Adult height of prepubertal short children born small for gestational age treated with GH Eur J Endocrinol 152 6 835 843 Takala J Ruokonen E Webster NR et al 1999 Increased mortality associated with growth hormone treatment in critically ill adults New England Journal Med 341 785 792 The Canadian Growth Hormone Advisory Committee 2005 Impact of growth hormo
99. xisting scoliosis curvature of the spine can occur in children who have rapid growth HUMATROPE has not been shown to increase the occurrence of scoliosis If the patient has hypopituitarism and is receiving standard hormone replacement therapy the doctor should monitor the hormone replacement therapy closely during HUMATROPE treatment If the patient has a growth disorder associated with being born small for gestational age the blood sugar and insulin levels should be checked before starting treatment and regularly during treatment Patients over 65 years of age may be more sensitive to HUMATROPE and may require lower dose of HUMATROPE INTERACTIONS WITH THIS MEDICATION Tell the doctor if the patient is taking any of the following drugs e Steroid medications such as glucocorticoids e g cortisone or prednisone e Medications known to be metabolized by certain liver enzymes e g cyclosporine some anticonvulsants and hormones such as estrogen and birth control pills e Insulin and anti hyperglycemic agents Because HUMATROPE may affect how some hormones such as cortisol and cortisone are processed in the body people may discover that they have an underactive adrenal gland after starting HUMATROPE therapy In these cases glucocorticoid replacement therapy would need to be started If already on glucocorticoid therapy dosage may need to be adjusted PROPER USE OF THIS MEDICATION Be sure to change the injection

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