HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`OMNITROPE® safely and effectively. See full prescribing information
`for OMNITROPE®.
`
`OMNITROPE® [somatropin (rDNA origin) injection], for
`SUBCUTANEOUS use.
`Initial U.S. Approval: 1987
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`Indications and Usage (1.1)
`
` Prader-Willi Syndrome
` Small for Gestational Age
`
`
`Dosage and Administration (2.1)
`
` Prader-Willi Syndrome
` Small for Gestational Age
`
`
`•
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`OMNITROPE® is a recombinant human growth hormone indicated for:
`
`•
`Pediatric: Treatment of children with growth failure due to growth
`
`hormone deficiency (GHD), Prader-Willi Syndrome, Small for
`Gestational Age (1.1)
`Adult: Treatment of adults with either adult onset or childhood onset
`GHD (1.2)
`
`
`
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`OMNITROPE® should be administered subcutaneously (2).
`
`
`•
`
`
`
`
`
`
`
`
`Pediatric GHD: 0.16 to 0.24 mg/kg//week, divided into 6 - 7 daily
`injections, (2.1)
`Prader-Willi Syndrome: 0.24 mg/kg/week, divided into 6 - 7 daily
`injections, (2.1)
`Small for Gestational Age: Up to 0.48 mg/kg/week, divided into 6 - 7
`
`daily injections, (2.1)
`Adult GHD: not more than 0.04 mg/kg/week (divided into daily
`injections) to be increased as tolerated to not more than 0.08
`mg/kg/week); to be increased gradually every 1 - 2 months (2.2)
`
`OMNITROPE® Cartridges 5 mg/1.5 mL and 10 mg/1.5 mL must be
`
`
`used with the corresponding OMNITROPE® Pen 5 and Pen 10 delivery
`
`
`system, respectively (2.3)
`Injection sites should always be rotated to avoid lipoatrophy (2.3)
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`• OMNITROPE® Cartridge 5 mg/1.5 mL (15 IU) is a prefilled sterile
`
`
`solution in a glass cartridge ready to be administered with the
`Omnitrope® Pen 5. (3.1).
`
`OMNITROPE® Cartridge 10 mg/1.5 mL (30 IU) is a prefilled sterile
`
`solution in a glass cartridge ready to be administered with the
`Omnitrope® Pen 10. (3.1).
`
`OMNITROPE® for injection 1.5 mg/vial is supplied with two vials, one
`containing somatropin as a powder and the other vial containing the
`diluent (3.2).
`OMNITROPE® for injection 5.8 mg/vial is supplied with two vials, one
`containing somatropin as a powder and the other vial containing diluent
`(3.3).
`
`
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`• Acute Critical Illness (4.1, 5.1)
`
`•
`
`Children with Prader-Willi syndrome who are severely obese or have
`severe respiratory impairment - reports of sudden death (4.2)
`
`
`
`
`Active Malignancy (4.3)
`
`Active Proliferative or Severe Non-Proliferative Diabetic Retinopathy
`
`(4.4)
`Children with closed epiphyses (4.5)
`Known hypersensitivity to somatropin or excipients (4.6)
`Formulations containing benzyl alcohol (5 mg/1.5 mL Omnitrope
`Cartridges and the Bacteriostatic Water for Injection diluent for the 5.8
`mg/vial Omnitrope) should not be used in premature babies or neonates
`(4.7)
`
`•
`
`•
`
`
`•
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`• Acute Critical Illness: Potential benefit of treatment continuation should
`
`be weighed against the potential risk (5.1)
`
`Prader-Willi Syndrome in children: Evaluate for signs of upper airway
`obstruction and sleep apnea before initiation of treatment. Discontinue
`treatment if these signs occur (5.2).
`Neoplasm: Monitor patients with preexisting tumors for progression or
`
`
`recurrence. Increased risk of a second neoplasm in childhood cancer
`
`survivors treated with somatropin - in particular meningiomas in patients
`
`treated with radiation to the head for their first neoplasm (5.3).
`Impaired Glucose Tolerance and Diabetes Mellitus: May be unmasked.
`Periodically monitor glucose levels in all patients. Doses of concurrent
`antihyperglycemic drugs in diabetics may require adjustment (5.4).
`
`Intracranial Hypertension: Exclude preexisting papilledema. May
`develop and is usually reversible after discontinuation or dose reduction
`
`(5.5).
`Fluid Retention (i.e., edema, arthralgia, carpal tunnel syndrome ­
`
`especially in adults): May occur frequently. Reduce dose as necessary
`
`(5.6).
`Hypo pituitarism: Closely monitor other hormone replacement therapies
`
`(5.7)
`Hypothyroidism: May first become evident or worsen (5.8)
`
`Slipped Capital Femoral Epiphysis: May develop. Evaluate children
`
`with the onset of a limp or hip/knee pain (5.9)
`
`Progression of Preexisting Scoliosis: May develop (5.10)
`
`
`•
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`Other common somatropin-related adverse reactions include injection site
`reactions/rashes and lipoatrophy (6.1) and headaches (6.3).
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at
`
`1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
`
`
`------------------------------DRUG INTERACTIONS------------------------------­
`
`•
`
`
`
`
`
`
`Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1: May require
`
`
`the initiation of glucocorticoid replacement therapy. Patients treated with
`glucocorticoid replacement for previously diagnosed hypoadrenalism
`
`may require an increase in their maintenance doses (7.1, 7.2).
`
`
`Glucocorticoid Replacement: Should be carefully adjusted (7.2)
`
`Cytochrome P450-Metabolized Drugs: Monitor carefully if used with
`somatropin (7.3)
`
`Oral Estrogen: Larger doses of somatropin may be required in women
`(7.4)
`Insulin and/or Oral Hypoglycemic Agents: May require adjustment (7.5)
`
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1. INDICATIONS AND USAGE
`
`1.1 Pediatric Patients
`1.2 Adult Patients
`2. DOSAGE AND ADMINISTRATION
`
`2.1 Dosing of Pediatric Patients
`2.2 Dosing of Adult Patients
`2.3 Preparation and Administration
`3. DOSAGE FORMS AND STRENGTHS
`
`4. CONTRAINDICATIONS
`
`4.1 Acute Critical Illness
`
`
`4.2 Prader-Willi Syndrome in Children
`4.3 Active Malignancy
`
`4.4 Diabetic Retinopathy
`4.5 Closed Epiphyses
`4.6 Hypersensitivity
`4.7 Benzyl Alcohol Sensitivity
`
`5. WARNINGS AND PRECAUTIONS
`5.1 Acute Critical Illness
`
`5.2 Prader-Willi Syndrome in Children
`5.3 Neoplasms
`
`
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`

`5.4 Glucose Intolerance
`5.5 Intracranial Hypertension (IH)
`
`5.6 Fluid Retention
`
`5.7 Hypopituitarism
`
`5.8 Hypothyroidism
`
`5.9 Slipped Capital Femoral Epiphysis in Pediatric Patients
`5.10 Progression of Preexisting Scoliosis in Pediatric Patients
`5.11 Confirmation of Childhood Onset Adult GHD
`5.12 Local and Systemic Reactions
`5.13 Laboratory Tests
`
`6. ADVERSE REACTIONS
`
`6.1 Most Serious and/or Most Frequently Observed Adverse Reactions
`6.2 Clinical Trials Experience
`6.3 Post-Marketing Surveillance
`7. DRUG INTERACTIONS
`
`7.1 Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-1)
`
`7.2 Glucocorticoid Replacement
`7.3 Cytochrome P450-Metabolized Drugs
`
`7.4 Oral Estrogen
`7.5 Insulin and/or Oral Hypoglycemic Agents
`8. USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`8.5 Geriatric Use
`10. OVERDOSAGE
`
`Short-Term
`
`
`Long-Term
`
`11. DESCRIPTION
`
`12. CLINICAL PHARMACOLOGY
`
`12.1 Mechanism Of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13. NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility
`
`14. CLINICAL STUDIES
`
`14.1 Pediatric Growth Hormone Deficiency (GHD)
`
`
`14.2 Adult Growth Hormone Deficiency (GHD)
`14.3 Prader-Willi Syndrome (PWS)
`
`14.4 Pediatric Patients Born Small for Gestational Age (SGA) Who Fail to
`Manifest Catch-up Growth by Age 2
`16. HOW SUPPLIED/STORAGE AND HANDLING
`
`Storage
`16.1 OMNITROPE® Cartridge 5 mg/1.5 mL
`
`
`16.2 OMNITROPE® Cartridge 10 mg/1.5 mL
`
`
`16.3 OMNITROPE® (somatropin [rDNA origin]) for injection 1.5 mg/vial
`16.4 OMNITROPE® (somatropin [rDNA origin]) for injection 5.8 mg/vial
`17. PATIENT COUNSELING INFORMATION
`
`OMNITROPE® PEN 5 INSTRUCTIONS FOR USE
`
`OMNITROPE® PEN 10 INSTRUCTIONS FOR USE
`
`
`INSTRUCTIONS FOR OMNITROPE® 1.5 MG/VIAL
`
`
`INSTRUCTIONS FOR OMNITROPE® 5.8 MG/VIAL
`
`
`
`*Sections or subsections omitted from the full prescribing information are not listed
`
`
`FULL PRESCRIBING INFORMATION
`
`1. INDICATIONS AND USAGE
`
`1.1 Pediatric Patients
`Omnitrope® [somatropin (rDNA origin) injection] is indicated for the treatment of children with growth failure due to
`inadequate secretion of endogenous growth hormone (GH).
`Omnitrope® [somatropin (rDNA origin) injection] is indicated for the treatment of pediatric patients who have growth
`failure due to Prader-Willi Syndrome (PWS). The diagnosis of PWS should be confirmed by appropriate genetic testing
`
`[see CONTRAINDICATIONS (5.2)].
`Omnitrope® [somatropin (rDNA origin) injection] is indicated for the treatment of growth failure in children born small
`for gestational age (SGA) who fail to manifest catch-up growth by age 2 years.
`
`1.2 Adult Patients
`Omnitrope® [somatropin (rDNA origin) injection] is indicated for the replacement of endogenous GH in adults with
`growth hormone deficiency (GHD) who meet either of the following two criteria:
`• Adult Onset (AO): Patients who have GHD, either alone or associated with multiple hormone deficiencies
`
`(hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or
`
`
`• Childhood Onset (CO): Patients who were GH deficient during childhood as a result of congenital, genetic, acquired,
`
`or idiopathic causes.
`Patients who were treated with somatropin for growth hormone deficiency in childhood and whose epiphyses are closed
`
`should be reevaluated before continuation of somatropin therapy at the reduced dose level recommended for growth
`hormone deficient adults. Confirmation of the diagnosis of adult growth hormone deficiency in both groups involves an
`appropriate growth hormone provocative test with two exceptions: (1) patients with multiple other pituitary hormone
`
`
`deficiencies due to organic disease; and (2) patients with congenital/genetic growth hormone deficiency.
`
`
`2. DOSAGE AND ADMINISTRATION
`The weekly dose should be divided into 6 or 7 daily subcutaneous injections.
`
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`Therapy with Omnitrope® should be supervised by a physician who is experienced in the diagnosis and management of
`pediatric patients with short stature associated with GHD, Prader-Willi Syndrome (PWS), those who were born small for
`gestational age (SGA), and adult patients with either childhood onset or adult onset GHD.
`
`2.1 Dosing of Pediatric Patients
`
`General Pediatric Dosing Information
`The Omnitrope® dosage and administration schedule should be individualized based on the growth response of each
`patient.
`Response to somatropin therapy in pediatric patients tends to decrease with time. However, in pediatric patients, the
`failure to increase growth rate, particularly during the first year of therapy, indicates the need for close assessment of
`compliance and evaluation for other causes of growth failure, such as hypothyroidism, under nutrition, advanced bone age
`and antibodies to recombinant human GH (rhGH).
`Treatment with Omnitrope® for short stature should be discontinued when the epiphyses are fused.
`
`Pediatric Growth Hormone Deficiency (GHD)
`Generally, a dosage of 0.16 - 0.24 mg/kg body weight/week, divided into 6 - 7 daily doses, is recommended.
`
`
`Prader-Willi Syndrome (PWS)
`Generally, a dosage of 0.24 mg/kg body weight/week, divided into 6 - 7 daily doses, is recommended.
`
`Small for Gestational Age (SGA)
`Generally, a dosage of up to 0.48 mg/kg body weight/week, divided into 6 - 7 daily doses, is recommended.
`
`
`2.2 Dosing of Adult Patients
`
`Adult Growth Hormone Deficiency (GHD)
`Based on the weight-based dosing utilized in clinical studies with another somatropin product, the recommended dosage
`
`at the start of therapy is not more than 0.04 mg/kg/week given as a daily subcutaneous injection. The dose may be
`increased at 4- to 8-week intervals according to individual patient requirements to not more than 0.08 mg/kg/week.
`Clinical response, side effects, and determination of age- and gender-adjusted serum IGF-I levels may be used as guidance
`in dose titration.
`
`Alternatively, taking into account recent literature, a starting dose of approximately 0.2 mg/day (range, 0.15-0.30 mg/day)
`
`may be used without consideration of body weight. This dose can be increased gradually every 1-2 months by increments
`
`
`of approximately 0.1-0.2 mg/day, according to individual patient requirements based on the clinical response and serum
`
`IGF-I concentrations. During therapy, the dose should be decreased if required by the occurrence of adverse events and/or
`
`serum IGF-I levels above the age- and gender-specific normal range. Maintenance dosages vary considerably from person
`to person.
`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. In order to reach the defined treatment goal, estrogen-replete women
`may need higher doses than men. Oral estrogen administration may increase the dose requirements in women.
`
`2.3 Preparation and Administration
`
`Omnitrope® Cartridge 5 mg/1.5 mL and Cartridge 10 mg/1.5 mL
`
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`
`
` Each cartridge of Omnitrope® must be inserted into its corresponding Omnitrope® Pen 5 or Omnitrope® Pen 10 delivery
`system. Instructions for delivering the dosage are provided in the Omnitrope® INSTRUCTIONS FOR USE booklet
`enclosed with the Omnitrope® drug and the Omnitrope® Pens.
`
`Omnitrope® for injection 1.5 mg/vial and 5.8 mg/vial
`
`Instructions for delivering the dosage are provided in the INSTRUCTIONS FOR USE leaflets enclosed with the
`Omnitrope® drug.
`Once the diluent is added to the lyophilized powder, swirl gently; do not shake. Shaking may cause denaturation of the
`
`
`active ingredient.
`
`
`Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to
`administration, whenever solution and container permit. Omnitrope® MUST NOT BE INJECTED if the solution is
`
`cloudy or contains particulate matter. Use it only if it is clear and colorless. Omnitrope must be refrigerated at 2° to 8°C
`
`(36° to 46°F).
`
`Patients and caregivers who will administer Omnitrope® in medically unsupervised situations should receive appropriate
`
`training and instruction on the proper use of Omnitrope® from the physician or other suitably qualified health
`professional.
`The dosage of Omnitrope® must be adjusted for the individual patient. The dose should be given daily by subcutaneous
`
`
`injections (administered preferably in the evening). Omnitrope® may be given in the thigh, buttocks, or abdomen.
`
`Injection sites should always be rotated to avoid lipoatrophy.
`
`3. DOSAGE FORMS AND STRENGTHS
`Omnitrope® Cartridges and vials (for injection) are available:
`
`• 5 mg/1.5 mL Cartridge is a prefilled sterile somatropin solution containing benzyl alcohol in a glass cartridge ready to
`
`
`
`
`be administered with the Omnitrope® Pen 5.
`• 10 mg/1.5 mL Cartridge is a prefilled sterile somatropin solution in a glass cartridge ready to be administered with the
`
`Omnitrope® Pen 10.
`• 1.5 mg/vial is supplied with two vials, one containing somatropin as a powder and the other vial containing the diluent
`
`(Sterile Water for Injection).
`• 5.8 mg/vial is supplied with two vials, one containing somatropin as a powder and the other vial containing diluent
`
`
`
`(Bacteriostatic Water for Injection containing benzyl alcohol as a preservative).
`
`
`4. CONTRAINDICATIONS
`
`4.1 Acute Critical Illness
`Treatment with pharmacologic amounts of somatropin is contraindicated in patients with acute critical illness due to
`complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute
`respiratory failure. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with
`these conditions in intensive care units revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin-
`treated patients (doses 5.3-8 mg/day) compared to those receiving placebo [see WARNINGS AND PRECAUTIONS
`(5.1)].
`
`4.2 Prader-Willi Syndrome in Children
`
`Somatropin is contraindicated in patients with Prader-Willi syndrome who are severely obese, have a history of upper
`airway obstruction or sleep apnea, or have severe respiratory impairment. There have been reports of sudden death when
`somatropin was used in such patients [see WARNINGS AND PRECAUTIONS (5.2)].
`
`
`
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`

`4.3 Active Malignancy
` In general, somatropin is contraindicated in the presence of active malignancy. Any preexisting malignancy should be
`
`
`inactive and its treatment complete prior to instituting therapy with somatropin. Somatropin should be discontinued if
`there is evidence of recurrent activity. Since GHD may be an early sign of the presence of a pituitary tumor (or, rarely,
`
`other brain tumors), the presence of such tumors should be ruled out prior to initiation of treatment. Somatropin should
`not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor.
`
`4.4 Diabetic Retinopathy
`Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.
`
`
`4.5 Closed Epiphyses
`Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses.
`
`4.6 Hypersensitivity
`Omnitrope® is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. Localized
`reactions are the most common hypersensitivity reactions.
`
`4.7 Benzyl Alcohol Sensitivity
`Benzyl alcohol, a preservative in Omnitrope Cartridge 5 mg/1.5 mL and in Bacteriostatic Water for Injection, has been
`associated with toxicity in newborns.
`Omnitrope® Cartridge 5 mg/1.5 mL and Omnitrope® for Injection 5.8 mg/vial must not be given to premature babies or
`neonates.
`
`5. WARNINGS AND PRECAUTIONS
`
`5.1 Acute Critical Illness
`
`Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal
`
`surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with
`pharmacologic amounts of somatropin [see CONTRAINDICATIONS (4.1)]. The safety of continuing somatropin
`treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has
`not been established. Therefore, the potential benefit of treatment continuation with somatropin in patients experiencing
`acute critical illnesses should be weighed against the potential risk.
`
`5.2 Prader-Willi Syndrome in Children
`There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with Prader-Willi
`
`Syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep
`apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than
`females. Patients with Prader-Willi Syndrome should be evaluated for signs of upper airway obstruction (including onset
`
`of or increased snoring) and sleep apnea before initiation of treatment with somatropin. If, during treatment with
`somatropin, patients show signs of upper airway obstruction (including onset of or increased snoring) and/or new onset
`sleep apnea, treatment should be interrupted. All patients with Prader-Willi Syndrome treated with somatropin should also
`
`have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as
`possible and treated aggressively [see CONTRAINDICATIONS (4.2)].
`
`5.3 Neoplasms
`
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`
`Patients with preexisting tumors or GHD secondary to an intracranial lesion should be monitored routinely for progression
`or recurrence of the underlying disease process. In pediatric patients, clinical literature has revealed no relationship
`between somatropin replacement therapy and central nervous system (CNS) tumor recurrence or new extracranial tumors.
`However, in childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients treated with
`
`somatropin after their first neoplasm. Intracranial tumors, in particular meningiomas, in patients treated with radiation to
`the head for their first neoplasm, were the most common of these second neoplasms. In adults, it is unknown whether
`
`
`there is any relationship between somatropin replacement therapy and CNS tumor recurrence.
`Patients should be monitored carefully for potential malignant transformation of skin lesions, i.e. increased growth of
`preexisting nevi.
`
`5.4 Glucose Intolerance
`Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a
`
`result, previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked during
`somatropin treatment. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin,
`especially in those with risk factors for diabetes mellitus, such as obesity, Turner syndrome, or a family history of diabetes
`mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored
`closely during somatropin therapy. The doses of antihyperglycemic drugs (i.e., insulin or oral agents) may require
`adjustment when somatropin therapy is instituted in these patients. [See Drug Interactions (7.5)].
`
`
`5.5 Intracranial Hypertension (IH)
`Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a
`small number of patients treated with somatropin products. Symptoms usually occurred within the first eight (8) weeks
`
`after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after
`cessation of therapy or a reduction of the somatropin dose.
`
`Funduscopic examination should be performed routinely before initiating treatment with somatropin to exclude
`
`preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed by
`
`funduscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment
`with somatropin can be restarted at a lower dose after IH-associated signs and symptoms have resolved. Patients with
`Prader-Willi Syndrome may be at increased risk for the development of IH.
`
`5.6 Fluid Retention
`Fluid retention during somatropin replacement therapy in adults may frequently occur. Clinical manifestations of fluid
`
`retention are usually transient and dose dependent.
`
`5.7 Hypopituitarism
`
`Patients with hypopituitarism (multiple pituitary deficiencies) should have their other hormonal replacement treatments
`closely monitored during somatropin treatment.
`
`5.8 Hypothyroidism
`Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response
`
`in children. Patients with an inherently increased risk of developing autoimmune thyroid disease and primary
`
`hypothyroidism should have their thyroid function checked prior to initiation of somatropin therapy. In patients with
`
`GHD, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Therefore,
`
`
`patients treated with somatropin should have periodic thyroid function tests and thyroid hormone replacement therapy
`
`should be initiated or appropriately adjusted when indicated.
`
`5.9 Slipped Capital Femoral Epiphysis in Pediatric Patients
`
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`

` Slipped capital femoral epiphysis may occur more frequently in patients undergoing rapid growth. Any pediatric patient
`
`with the onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated.
`
`5. 10 Progression of Preexisting Scoliosis in Pediatric Patients
`
`Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases
`growth rate, patients with a history of scoliosis who are treated with somatropin should be monitored for
`progression of scoliosis. However, somatropin has not been shown to increase the occurrence of scoliosis.
`Scoliosis is commonly seen in untreated patients with Prader-Willi Syndrome. Physicians should be alert to
`these abnormalities, which may manifest during somatropin therapy.
`
`5.11 Confirmation of Childhood Onset Adult GHD
`
`Patients with epiphyseal closure who were treated with somatropin replacement therapy in childhood should be
`reevaluated according to the criteria in INDICATIONS AND USAGE (1.2) before continuation of somatropin therapy at
`
`the reduced dose level recommended for GH deficient adults.
`
`5.12 Local and Systemic Reactions
`When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result.
`This can be avoided by rotating the injection site [see DOSAGE AND ADMINISTRATION (2.3)].
`
`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.
`
`5.12/13 Laboratory Tests
`Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and IGF-I may increase after
`
`somatropin therapy.
`
`6. ADVERSE REACTIONS
`
`6.1 Most Serious and/or Most Frequently Observed Adverse Reactions
`This list presents the most seriousb and/or most frequently observeda adverse reactions during treatment with somatropin:
`
`•
`
`
`bSudden death in pediatric patients with Prader-Willi syndrome with risk factors including severe obesity, history of upper airway
`
`
`
`obstruction or sleep apnea and unidentified respiratory infection [see CONTRAINDICATIONS (4.2) and WARNINGS AND
`
`
`PRECAUTIONS (5.2)]
`bIntracranial tumors, in particular meningiomas, in teenagers/young adults treated with radiation to the head as children for a first
`
`
`
`
`
`neoplasm and somatropin [see CONTRAINDICATIONS (4.3) and WARNINGS AND PRECAUTIONS (5.3)]
`
`
`
`a,bGlucose intolerance including impaired glucose tolerance/impaired fasting glucose as well as overt diabetes mellitus
`
`
`[WARNINGS AND PRECAUTIONS (5.5)]
`bIntracranial hypertension [see WARNINGS AND PRECAUTIONS (5.6)]
`
`bSignificant diabetic-retinopathy [see CONTRAINDICATIONS (4.4)]
`
`
`bSlipped capital femoral epiphysis in pediatric patients [see WARNINGS AND PRECAUTIONS (5.9)]
`bProgression of preexisting scoliosis in pediatric patients [see WARNINGS AND PRECAUTIONS (5.10)]
`
`aFluid retention manifested by edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel
`syndrome/paraesthesias [see WARNINGS AND PRECAUTIONS (5.7)]
`aUnmasking of latent central hypothyroidism [see WARNINGS AND PRECAUTIONS (5.8)]
`aInjection site reactions/rashes and lipoatrophy (as well as rare generalized hypersensitivity reactions) [see WARNINGS AND
`
`PRECAUTIONS (5.12)]
`
`•
`
`
`•
`
`
`•
`
`•
`
`•
`
`•
`
`•
`
`
`•
`
`•
`
`
`
`
`Novo Nordisk A/S Ex. 2020, P. 7
`Mylan Institutional v. Novo Nordisk
`IPR2020-00324
`
`

`

`6.2 Clinical Trials Experience
`
`Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials
`performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical
`trials performed with a second somatropin formulation, and may not reflect the adverse reaction rates observed in practice.
`
`
`As with all protein drugs, a small percentage of patients may develop antibodies to the protein. GH antibodies with
`
`binding capacities lower than 2 mg/L have not been associated with growth attenuation. In a very small number of
`patients, when binding capacity was greater than 2 mg/L, interference with the growth response was observed.
`
`Clinical Trials in Pediatric GHD Patients
`The following events were observed during clinical studies with Omnitrope® Cartridge conducted in children with GHD:
`Table 1. Incidence of adverse reactions occurring in ≥ 5% pediatric patients with GHD during treatment with
`
`Omnitrope® Cartridge (N=86)
`
`
`n (%)
`
`12 (14%)
`10 (12%)
`8 (9%)
`
`Adverse Event
`
`Elevated HbA1c
`Eosinophilia
`Hematoma
`N=
`number of patients receiving treatment
`
`n =
`number of patients who reported the event during study period
`
`percentage of patients who reported the event during study period
`% =
`
`
`The following events were observed during clinical studies with Omnitrope® for injection conducted in children with
`GHD:
`Table 2. Incidence of adverse reactions occurring in ≥ 5% pediatric patients with GHD during treatment with
`
`Omnitrope® for injection (N=44)
`
`
`n (%)
`
`7 (16%)
`5 (11%)
`4 (9%)
`4 (9%)
`3 (7%)
`
`
`2 (5%)
`2 (5%)
`
`Adverse Event
`
`Hypothyroidism
`Eosinophilia
`Elevated HbA1c
`Hematoma
`Headache
`Hypertriglyceridemia
`Leg Pain
`
`N=
`number of patients receiving treatment
`
`n =
`number of patients who reported the event during study period
`
`percentage of patients who reported the event during study period
`% =
`
`Clinical Trials in PWS
`In two clinical studies in pediatric patients with Prader-Willi Syndrome carried out with another somatropin product, the
`following drug-related events were reported: edema, aggressiveness, arthralgia, benign intracranial hypertension, hair loss,
`headache, and myalgia.
`
`Clinical Trials in Children with SGA
`In clinical studies of 273 pediatric patients born small for gestational age treated with another somatropin product, the
`following clinically significant events were reported: mild transient hyperglycemia, one patient with benign intracranial
`hypertension, two patients with central precocious puberty, two patients with jaw prominence, and several patients with
`
`aggravation of preexisting scoliosis, injection site reactions, and self-limited progression of pigmented nevi.
`
`
`
`Novo Nordisk A/S Ex. 2020, P. 8
`Mylan Institutional v. Novo Nordisk
`IPR2020-00324
`
`

`

`Clinical Trials in Adults with GHD
`In clinical trials with another somatropin product in 1,145 GHD adults, the majority of the adverse events consisted of
`mild to moderate symptoms of fluid retention, including peripheral swelling, arthralgia, pain and stiffness of the
`extremities, peripheral edema, myalgia, paresthesia, and hypoesthesia. These events were reported early during therapy,
`
`
`and tended to be transient and/or responsive to dosage reduction.
`
`Table 3 displays the adverse events reported by 5% or more of adult GHD patients in clinical trials after various durations
`
`of treatment with another somatropin product Also presented are the corresponding incidence rates of these adverse
`
`events in placebo patients during the 6-month double-blind portion of the clinical trials.
`
`
`Table 3
`Adverse Events Reported by ≥ 5% of 1,145 Adult GHD Patients During Clinical Trials of
`
`
`Another Somatropin Product and Placebo, Grouped by Duration of Treatment
`Double Blind Phase
`Open Label Phase
`
`
`Another Somatropin Product
`
`
`
`
`
`
`6–12 mo.
`12–18 mo.
`18–24 mo.
`(n = 504)
`(n = 63)
`(n = 60)
`% Patients % Patients % Patients
`
`Adverse Event
`
`
`Placebo
`0–6 mo.
`(n = 572)
`% Patients
`
`5.6
`
`6.9
`
`13.1
`6.7
`3.0
`2.2
`6.2
`2.4
`
`
`
`0
`
`1.7
`
`3.3
`
`13.3
`3.3
`
`0
`
`0
`
`0
`
`0
`
`6.3
`
`15.9
`1.6
`
`0
`3.2
`
`0
`1.6
`
`Swelling,
`peripheral
`Arthralgia
`Upper respiratory
`infection
`Pain, extremities