SOMATROPIN: 68,384 Adverse Event Reports & Safety Profile

Somatropin is a human growth hormone produced by recombinant DNA technology in Escherichia coli. The protein is comprised of 191 amino acid residues and has a molecular weight of 22,124 daltons. The amino acid sequence is identical to that of human growth hormone of pituitary origin. GENOTROPIN (somatropin) for injection is a sterile, white, lyophilized powder in a single-patient-use or single-dose, two-chamber cartridge intended for subcutaneous injection after reconstitution. The front chamber contains somatropin and the rear chamber contains diluent. GENOTROPIN 5 mg is a single-patient-use, two-chamber cartridge. GENOTROPIN 5 mg is designed for use with a reusable device (GENOTROPIN PEN 5) for product reconstitution and drug delivery. After reconstitution, each mL contains 5 mg of somatropin, dibasic sodium phosphate (0.27 mg), glycine (2 mg), mannitol (41 mg), metacresol (3 mg) (as a preservative), monobasic sodium phosphate (0.28 mg) and water for injection. The reconstituted concentration is 5 mg/mL with a deliverable volume of 1 mL. GENOTROPIN 12 mg is a single‑patient‑use, two-chamber cartridge. GENOTROPIN 12 mg is designed for use with a reusable device (GENOTROPIN PEN 12) for product reconstitution and drug delivery. After reconstitution, each mL contains 12 mg of somatropin, dibasic sodium phosphate (0.4 mg), glycine (2 mg), mannitol (40 mg), metacresol (3 mg) (as a preservative), monobasic sodium phosphate (0.41 mg) and water for injection. The reconstituted concentration is 12 mg/mL with a deliverable volume of 1 mL. GENOTROPIN MINIQUICK is a single-dose Growth Hormone Delivery Device containing a two-chamber cartridge supplied in the following strengths: 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, or 2 mg. After reconstitution, each 0.25 mL contains 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, or 2 mg of somatropin, dibasic sodium phosphate (0.03 mg), glycine (0.21 mg), mannitol (12.5 mg), monobasic sodium phosphate (0.05 mg) and water for injection. Each cartridge provides a deliverable volume of 0.25 mL. The reconstituted recombinant somatropin solution has an osmolality of approximately 300 mOsm/kg, and a pH of approximately 6.7.

AND USAGE GENOTROPIN 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, Turner syndrome, and Idiopathic Short Stature ( 1.1 )
• Adult: Treatment of adults with either adult onset or childhood onset GHD ( 1.2 )

1.1 Pediatric Patients GENOTROPIN is indicated for the treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone. GENOTROPIN 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 <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . GENOTROPIN is indicated for the treatment of growth failure in pediatric patients born small for gestational age (SGA) who fail to manifest catch-up growth by age 2 years. GENOTROPIN is indicated for the treatment of growth failure associated with Turner syndrome. GENOTROPIN is indicated for the treatment of idiopathic short stature (ISS), also called non-growth hormone-deficient short stature, defined by height standard deviation score (SDS) ≤-2.25, and associated with growth rates unlikely to permit attainment of adult height in the normal range, in pediatric patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other causes associated with short stature that should be observed or treated by other means.

1.2 Adult Patients GENOTROPIN is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who meet either of the following two criteria: Adult Onset (AO): Patients who have growth hormone deficiency, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or Childhood Onset (CO) : Patients who were growth hormone 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. According to current standards, 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.

AND ADMINISTRATION For subcutaneous injection . Therapy with Nutropin AQ should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with short stature associated with growth hormone deficiency (GHD), chronic kidney disease, Turner syndrome, idiopathic short stature, or adult patients with either childhood-onset or adult-onset GHD. Nutropin AQ should be administered subcutaneously ( 2 ). Injection sites should always be rotated to avoid lipoatrophy ( 2.3 ). Pediatric GHD: Up to 0.3 mg/kg/week ( 2.1 )

Pubertal

Patients: Up to 0.7 mg/kg/week ( 2.1 )

Idiopathic Short

Stature: Up to 0.3 mg/kg/week ( 2.1 )

Chronic Kidney

Disease: Up to 0.35 mg/kg/week ( 2.1 )

Turner

Syndrome: Up to 0.375 mg/kg/week ( 2.1 ) Adult GHD: Either a non-weight based or weight-based dosing regimen may be followed, with doses adjusted based on treatment response and IGF-I concentrations ( 2.2 ). Non-weight-based: A starting dose of approximately 0.2 mg/day (range 0.15–0.3 mg/day) increased gradually every 1–2 months by increments of approximately 0.1–0.2 mg/day. Weight-based : Initiate from not more than 0.006 mg/kg/day; the dose may be increased up to a maximum of 0.025 mg/kg/day in patients ≤ 35 years old or 0.0125 mg/kg/day in patients > 35 years old.

2.1 Dosing for Pediatric Patients Nutropin AQ dosage and administration schedule should be individualized for each patient. Response to growth hormone (GH) therapy in pediatric patients tends to decrease with time. However, in pediatric patients failure to increase growth rate, particularly during the first year of therapy, suggests the need for close assessment of compliance and evaluation of other causes of growth failure, such as hypothyroidism, under-nutrition, advanced bone age and antibodies to recombinant human GH (rhGH). Treatment with Nutropin AQ for short stature should be discontinued when the epiphyses are fused.

Pediatric Growth Hormone

Deficiency (GHD ) A weekly dosage of up to 0.3 mg/kg of body weight divided into daily subcutaneous injection is recommended. In pubertal patients, a weekly dosage of up to 0.7 mg/kg divided daily may be used.

Growth Failure

Secondary to Chronic Kidney Disease (CKD) A weekly dosage of up to 0.35 mg/kg of body weight divided into daily subcutaneous injection is recommended. Nutropin AQ therapy may be continued up to the time of renal transplantation. In order to optimize therapy for patients who require dialysis, the following guidelines for injection schedule are recommended: Hemodialysis patients should receive their injection at night just prior to going to sleep or at least 3 to 4 hours after their hemodialysis to prevent hematoma formation due to the heparin.

Chronic Cycling Peritoneal

Dialysis (CCPD) patients should receive their injection in the morning after they have completed dialysis.

Chronic Ambulatory Peritoneal

Dialysis (CAPD) patients should receive their injection in the evening at the time of the overnight exchange.

Idiopathic Short

Stature (ISS) A weekly dosage of up to 0.3 mg/kg of body weight divided into daily subcutaneous injections is recommended.

Short Stature

Associated with Turner Syndrome (TS) A weekly dosage of up to 0.375 mg/kg of body weight divided into equal doses 3 to 7 times per week by subcutaneous injection is recommended.

2.2 Dosing for Adult Patients Adult Growth Hormone Deficiency (GHD) Either of two approaches to Nutropin AQ dosing may be followed: a weight-based regimen or a non-weight-based regimen. Weight based – Based on the dosing regimen used in the original adult GHD registration trials, the recommended dosage at the start of treatment is not more than 0.006 mg/kg daily. The dose may be increased according to individual patient requirements to a maximum of 0.025 mg/kg daily in patients ≤ 35 years and to a maximum of 0.0125 mg/kg daily in patients over 35 years old. Clinical response, side effects, and determination of age- and gender-adjusted serum insulin-like growth factor (IGF-1) concentrations should be used as guidance in dose titration. Non-weight based – Alternatively, taking into account the published literature, a starting dose of approximately 0.2 mg/day (range, 0.15 to 0.30 mg/day) may be used without consideration of body weight. This dose can be increased gradually every 1 to 2 months by increments of approximately 0.1 to 0.2 mg/day, according to individual patient requirements based on the clinical response and serum IGF-1 concentrations. The dose should be decreased as necessary on the basis of adverse events and/or serum IGF-1 concentrations above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to person, and between male and female patients. 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 The solution should be clear immediately after removal from the refrigerator. Occasionally, after refrigeration, you may notice that small colorless particles of protein are present in the solution. This is not unusual for solutions containing proteins. Allow the pen cartridge or NuSpin ® to come to room temperature and gently swirl. If the solution is cloudy, the contents MUST NOT be injected. Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Injection sites, which may be located on the thigh, upper arm, abdomen or buttock, should always be rotated to avoid lipoatrophy. Nutropin AQ Pen Cartridge The Nutropin AQ Pen 10 and 20 mg Cartridges are color-banded to help ensure appropriate use with the Nutropin AQ Pen delivery device. Each cartridge must be used with its corresponding color-coded Nutropin AQ Pen [See Dosage Forms and Strengths (3) ] . Wipe the septum of the Nutropin AQ Pen Cartridge with rubbing alcohol or an antiseptic solution to prevent contamination of the contents by microorganisms that may be introduced by repeated needle insertions. It is recommended that Nutropin AQ be administered using sterile, disposable needles. Follow the directions provided in the Nutropin AQ Pen Instructions for Use.

The

Nutropin AQ Pen 10 allows for administration of a minimum dose of 0.1 mg to a maximum dose of 4.0 mg, in 0.1 mg increments.

The

Nutropin AQ Pen 20 allows for administration of a minimum dose of 0.2 mg to a maximum dose of 8.0 mg, in 0.2 mg increments. Nutropin AQ NuSpin The Nutropin AQ NuSpin 5, 10 and 20 are multi-dose, dial-a-dose injection devices prefilled with Nutropin AQ in a 5 mg/2 mL, 10 mg/2 mL or 20 mg/2 mL cartridge, respectively, for subcutaneous use. It is recommended that Nutropin AQ be administered using sterile, disposable needles. Follow the directions provided in the Nutropin AQ NuSpin 5, 10 or 20 Instructions for Use.

The

Nutropin AQ NuSpin 5 allows for administration of a minimum dose of 0.05 mg to a maximum dose of 1.75 mg, in increments of 0.05 mg.

The

Nutropin AQ NuSpin 10 allows for administration of a minimum dose of 0.1 mg to a maximum dose of 3.5 mg, in increments of 0.1 mg.

The

Nutropin AQ NuSpin 20 allows for administration of a minimum dose of 0.2 mg to a maximum dose of 7.0 mg, in increments of 0.2 mg.

Acute critical illness ( 4 ). Children with Prader-Willi syndrome (PWS) who are severely obese or have severe respiratory impairment – reports of sudden death ( 4 ). Active malignancy ( 4 ). Hypersensitivity to somatropin or excipients ( 4 ). Active proliferative or severe non-proliferative diabetic retinopathy ( 4 ). Children with closed epiphysis ( 4 ).

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 [see Warnings and Precautions (5.1) ]. Prader-Willi Syndrome (PWS) in Children Somatropin is contraindicated in patients with PWS 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. Nutropin AQ is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed PWS [see Warnings and Precautions (5.2) ] .

Active

Malignancy In general, somatropin is contraindicated in the presence of active malignancy. Any pre-existing 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 growth hormone deficiency (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 [see Warnings and Precautions (5.3) ].

Hypersensitivity

Nutropin AQ is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropin products [see Warnings and Precautions (5.6) ].

Diabetic Retinopathy

Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.

Closed Epiphysis

Somatropin should not be used for growth promotion in pediatric patients with closed epiphysis.

REACTIONS The following important adverse reactions are also described elsewhere in the labeling: Increased mortality in patients with acute critical illness [see Warnings and Precautions (5.1) ] Fatalities in pediatric patients with Prader-Willi syndrome [see Warnings and Precautions (5.2) ] Neoplasms [see Warnings and Precautions (5.3) ] Glucose intolerance and diabetes mellitus [see Warnings and Precautions (5.4) ] Intracranial hypertension [see Warnings and Precautions (5.5) ] Severe hypersensitivity [see Warnings and Precautions (5.6) ] Fluid retention [see Warnings and Precautions (5.7) ] Hypoadrenalism [see Warnings and Precautions (5.8) ] Hypothyroidism [see Warnings and Precautions (5.9) ] Slipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.10) ] Progression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.11) ] Pancreatitis [see Warnings and Precautions (5.12) ] Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.13) ] Lipoatrophy [see Warnings and Precautions (5.14) ] Common adverse reactions reported in adult and pediatric patients include: upper respiratory infection, fever, pharyngitis, headache, otitis media, edema, arthralgia, paresthesia, myalgia, carpal tunnel syndrome, peripheral edema, flu syndrome, hypothyroidism, hyperglycemia, and impaired glucose tolerance. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Ferring Pharmaceuticals Inc. at 1-888-337-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 different approved somatropin formulation and may not reflect the adverse reaction rates observed in practice.

Pediatric Patients Growth

Failure due to Inadequate Secretion of Endogenous Growth Hormone ZOMACTON was evaluated in 164 pediatric patients with short stature due to GHD in an open-label study for 24 weeks. The subjects ranged in age from 2.1 to 17.7 years with a mean of 10.8 years. One hundred twenty (73%) of the subjects were male and 44 (27%) were female. Two subjects were Asian, 12 were Black, 130 were Caucasian, and 20 were categorized as 'other'.

Table

1: Adverse Reactions ≥ 5% in Pediatric Patients with Growth Failure Due to GHD Treated with ZOMACTON through 24 Weeks Adverse Reaction 24 Week Exposure to ZOMACTON (n=164) Upper respiratory infection 32% Fever 16% Pharyngitis 12% Headache 11% Otitis Media 10% Increased cough 9% Abdominal pain 7% Anemia 6% Maculopapular rash 6% Diarrhea 5% Pain 5% Rhinitis 5% All pediatric patients were carefully observed for signs or laboratory abnormalities of hypothyroidism. Fifteen patients had T4 values which occasionally fell below the central laboratory's lower limit of normal; T4 levels rose to normal when tested during the next visit for all patients except one who continued to be monitored. Six of the 15 patients received thyroxine therapy before and throughout the study period, and thyroxine dose adjustments were made during the study in 3/6 subjects. In studies with GH deficient pediatric patients, injection site pain was reported in 1.6% of patients. A mild and transient edema, which appeared in 1.6% of patients, was observed early during the course of treatment.

Short Stature

Associated with Turner Syndrome In a randomized, concurrent-controlled, open-label study, there was an increase in the occurrence of otitis media, ear disorders and surgical procedures in patients receiving another somatropin product at a dose of 0.3 mg/kg/week, compared with untreated control patients (Table 2). A similar increase in otitis media was observed in an 18-month placebo-controlled study.

Table

2: Adverse Reactions Occurring in Patients with Turner Syndrome Treated with 0.3 mg/kg/week of Another Somatropin product During a

4.7 Year Randomized Open-Label Study Untreated (n=62) Somatropin (n=74) Surgical procedure 27% 45% Otitis media 26% 43% Ear disorders 5% 18% Idiopathic Short Stature Adverse reactions from a randomized, placebo-controlled study of another somatropin product dosed at 0.22 mg/kg/week are presented in Table 3. Mean fasting serum insulin concentration increased 10% in the group treated with another somatropin product at the end of treatment relative to baseline, but remained within the normal reference range.

Table

3: Adverse Reactions Occurring in Patients with Idiopathic Short Stature Treated with Another Somatropin product during a

4.4 Year Randomized Placebo-Controlled Study Adverse Reactions Placebo (n=31)

Another

Somatropin product (n=37)

Scoliosis

13% 19% Otitis media 7% 16% Hyperlipidemia 3% 8% Gynecomastia 3% 5% Hip pain 0% 3% Arthralgia 3% 11% Arthrosis 7% 11% Myalgia 13% 24% Hypertension 0% 3% In a dose-response study with 239 patients treated for 2 years, mean fasting blood glucose, mean glycosylated hemoglobin, and the incidence of elevated fasting blood glucose concentrations were similar among dose groups. One patient developed glucose intolerance and high serum HbA 1c .

Short

Stature or Growth Failure in SHOX Deficiency Adverse reactions from a 2-year open-label study with another somatropin product compared to no treatment are presented in Table 4. During the study, the proportion of patients who had at least one IGF-1 concentration greater than

2.0 SD above the age- and gender-appropriate mean was 37.0% for the somatropin-treated group vs. 0% patients 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 59% for the somatropin treated group vs. 29% for the untreated group.

Table

4: Adverse Reactions Occurring in Patients with SHOX Deficiency Treated with Another Somatropin product for 2 years Untreated (n=25)

Another

Somatropin product (n=27)

Arthralgia

8% 11% Gynecomastia 0% 8% Excessive number of cutaneous nevi 0% 7% Scoliosis 0% 4% Small for Gestational Age (SGA) with No Catch-up Growth by 2 Years to 4 Years of Age In a 2-year study, 193 pediatric patients were treated with another somatropin product using 2 different treatment regimens: a fixed dose of 0.067 mg/kg/day (FHD group) or an individually adjusted dose regimen (IAD group; starting dose 0.035 mg/kg/day which could be increased as early as Month 3 to 0.067 mg/kg/day based on a validated growth prediction model). Adverse reactions included common childhood infectious diseases, otitis media, headaches, and slipped capital femoral epiphysis (n=1). Six patients (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])) had impaired fasting glucose at Year 2. Two of 6 had impaired fasting glucose during the study, and 1 discontinued treatment at month 15 as a consequence. At study completion, 20-25% of patients had serum IGF-1 SDS values > +2. The following adverse reactions were reported from an observational study of 340 pediatric patients who received another somatropin product with an average dosage of 0.041 mg/kg/day for an average of 3 years: type 2 diabetes mellitus (n=1), carpal tunnel syndrome (n=1) and exacerbation of preexisting scoliosis (n=1).

Adult Patients

Adult-Onset GH Deficiency In the first 6 months of controlled blinded trials during which patients received either another somatropin product or placebo, patients who received this other somatropin product experienced a statistically significant increase in edema (another somatropin product 17% vs. placebo 4%, p=0.043) and peripheral edema (12% vs. 0%, respectively, p=0.017). Edema, muscle pain, joint pain, and joint disorder were reported early in therapy and tended to be transient or responsive to dosage titration. Two of 113 patients developed carpal tunnel syndrome after beginning maintenance therapy without a low dose (0.00625 mg/kg/day) lead-in phase. Symptoms abated in these patients after dosage reduction. All adverse reactions with ≥5% overall occurrence rate during 12 or 18 months of replacement therapy with another somatropin product are shown in Table 5 (adult-onset patients) and in Table 6 (childhood-onset patients). Adult patients treated with another somatropin product who had been diagnosed with GH deficiency in childhood reported adverse reactions less frequently than those with adult-onset GH deficiency.

Table

5: Adverse Reactions Occurring ≥5% in Adult-Onset Growth Hormone-Deficient Patients Treated with Another Somatropin product for 18 Months as Compared with 6-Month Placebo and 12-Month Exposure to Another Somatropin product Abbreviations: GH= another somatropin product; n=number of patients receiving treatment in the period stated 18 Months Exposure Adverse Reaction [Placebo (6 Months)/GH (12 Months)] 18 Months GH Exposure (n=46) (n=52) Edema p=0.04 as compared to placebo (6 months). 15% 21% Arthralgia 15% 17% Paresthesia 13% 17% Myalgia 13% 14% Pain 13% 14% Rhinitis 11% 14% Peripheral edema p=0.02 as compared to placebo (6 months). 17% 12% Back pain 11% 10% Headache 11% 8% Hypertension 4% 8% Acne 0% 6% Joint disorder 2% 6% Surgical procedure 2% 6% Flu syndrome 7% 4% Childhood-Onset GH Deficiency Two double-blind, placebo-controlled trials were conducted in 67 adult patients who had received previous somatropin treatment during childhood. Patients were randomized to receive either placebo injections or another somatropin product (0.00625 mg/kg/day for the first 4 weeks, then 0.0125 mg/kg/day thereafter) for the first 6 months, followed by open-label use of another somatropin product for the next 12 months for all patients. The patients in these studies reported side effects less frequently than those with adult-onset GH deficiency. During the placebo-controlled phase (first 6 months) of the study, elevations of serum glutamic oxaloacetic transferase were reported significantly more often for somatropin-treated (12.5%) than placebo-treated patients (0.0%, p=0.031). No other events were reported significantly more often for somatropin-treated patients during the placebo-controlled phase.

Table

6: Adverse Reactions Occurring ≥5% in Childhood-Onset Growth Hormone-Deficient Patients Treated with Another Somatropin product for 18 Months as Compared with 6-Month Placebo and 12-Month Exposure to Another Somatropin product Abbreviations: GH=another somatropin product; n=number of patients receiving treatment in the period stated; ALT=alanine aminotransferase, formerly SGPT; AST=aspartate aminotransferase, formerly SGOT. 18 Months Exposure 18 Months GH Exposure Adverse Reaction [Placebo (6 Months)/GH (12 Months)] (n=35) (n=32) Flu syndrome 23% 16% AST increased p=0.03 as compared to placebo (6 months). 6% 13% Headache 11% 9% Asthenia 3% 6% Cough increased 0% 6% Edema 9% 6% Hypesthesia 0% 6% Myalgia 6% 6% Pain 9% 6% Rhinitis 6% 6% ALT increased 6% 6% Respiratory disorder 6% 3% Gastritis 6% 0% Pharyngitis 14% 3% In an ongoing post-marketing observational study of treatment with another somatropin product in 3,102 GH-deficient adults, hypertension, dyspnea, and sleep apnea were reported by 1% to less than 10% of patients after various durations of treatment.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of somatropin or ZOMACTON. Because the following adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders — Pancreatitis Immune system disorders — Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema Metabolism and nutrition disorders — New-onset type 2 diabetes mellitus Musculoskeletal and connective tissue disorders – osteonecrosis in pediatric patients Neoplasms benign, malignant and unspecified — Leukemia has been reported in a small number of GH deficient pediatric patients treated with somatropin, somatrem (methionylated rhGH), and GH of pituitary origin Nervous system disorders — Headaches (common in pediatric patients and occasional in adults) Reproductive system and breast disorders — Gynecomastia Skin and subcutaneous tissue disorders — Increase in size or number of cutaneous nevi

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 )
• Hypersensitivity: Serious hypersensitivity reactions may occur. In the event of an allergic reaction, seek prompt medical attention ( 5.6 )
• Fluid Retention (i.e., edema, arthralgia, carpal tunnel syndrome - especially in adults): May occur frequently. Reduce dose as necessary ( 5.7 )
• Hypoadrenalism: Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism ( 5.8 )
• Hypothyroidism: May first become evident or worsen ( 5.9 )
• Slipped Capital Femoral Epiphysis: May develop. Evaluate children with the onset of a limp or hip/knee pain ( 5.10 )
• Progression of Preexisting Scoliosis: May develop ( 5.11 )
• Pancreatitis: Consider pancreatitis in patients with persistent severe abdominal pain (5.15)

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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . 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 (42% vs. 19%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo. 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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

5.3 Neoplasms In childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent GHD and were treated with somatropin, an increased risk of a second neoplasm has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor recurrence <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . Monitor all patients with a history of GHD secondary to an intracranial neoplasm routinely while on somatropin therapy for progression or recurrence of the tumor <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, practitioners should thoroughly consider the risks and benefits of starting somatropin in these patients. If treatment with somatropin is initiated, these patients should be carefully monitored for development of neoplasms. Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes, of preexisting nevi.

5.4 Impaired Glucose Tolerance and Diabetes Mellitus Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a result, previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked, and new onset type 2 diabetes mellitus has been reported in patients taking somatropin. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus, such as obesity, Turner Syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during somatropin therapy. The doses of antihyperglycemic drugs (i.e., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients <span class="opacity-50 text-xs">[see Drug Interactions ( 7.5 )]</span>.

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 somatropins. 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 fundoscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin can be restarted at a lower dose after IH-associated signs and symptoms have resolved. Patients with Turner Syndrome and Prader-Willi Syndrome may be at increased risk for the development of IH.

5.6 Hypersensitivity Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropins. Patients and caregivers should be informed that such reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>.

5.7 Fluid Retention Fluid retention during somatropin replacement therapy in adults may frequently occur. Clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paresthesias) are usually transient and dose dependent.

5.8 Hypoadrenalism Patients receiving somatropin therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span>.

5.9 Hypothyroidism Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response in children. Patients with Turner Syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism and 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.

5.10 Slipped Capital Femoral Epiphysis in Pediatric Patients Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including GHD and Turner Syndrome) or in patients undergoing rapid growth. Slipped capital femoral epiphysis may lead to osteonecrosis. Cases of slipped capital femoral epiphysis with or without osteonecrosis have been reported in pediatric patients with short stature receiving somatropin. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during OMNITROPE therapy should be evaluated for slipped capital femoral epiphysis and osteonecrosis and managed accordingly.

5.11 Progression of Preexisting Scoliosis in Pediatric Patients Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases growth rate, patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis. However, somatropin has not been shown to increase the occurrence of scoliosis. Skeletal abnormalities including scoliosis are commonly seen in untreated Turner Syndrome patients. Scoliosis is also commonly seen in untreated patients with Prader-Willi Syndrome. Physicians should be alert to these abnormalities, which may manifest during somatropin therapy .

5.12 Otitis Media and Cardiovascular Disorders in Turner Syndrome Patients with Turner Syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear and hearing disorders. Somatropin treatment may increase the occurrence of otitis media in patients with Turner Syndrome. In addition, patients with Turner Syndrome should be monitored closely for cardiovascular disorders (e.g., stroke, aortic aneurysm/dissection, hypertension) as these patients are also at risk for these conditions.

5.13 Lipoatrophy 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> .

5.14 Laboratory Tests Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and IGF-1 may increase after somatropin therapy.

5.15 Pancreatitis Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment, with some evidence supporting a greater risk in children compared with adults. Published literature indicates that girls who have Turner Syndrome may be at greater risk than other somatropin-treated children. Pancreatitis should be considered in any somatropin treated patient, especially a child, who develops persistent severe abdominal pain.

5.16 Benzyl Alcohol Benzyl alcohol, a component of OMNITROPE Cartridge 5 mg/1.5 mL and the diluent for OMNITROPE for injection 5.8 mg/vial, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome,” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages &gt;99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

INTERACTIONS Inhibition of 11 β-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 other hypoglycemic agents: May require adjustment ( 7.5 ). 7.1 11 β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-1) The microsomal enzyme 11βHSD-1 is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Growth hormone (GH) and somatropin inhibit 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. As a consequence, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with somatropin. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1.

7.2 Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth-promoting effects of somatropin in children. Therefore, glucocorticoid replacement therapy should be carefully adjusted in children with concomitant GH and glucocorticoid deficiency to avoid both hypoadrenalism and an inhibitory effect on growth. The use of Nutropin AQ in patients with Chronic Kidney Disease (CKD) requiring glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth promoting effect of Nutropin AQ. Therefore, if glucocorticoid replacement is required for CKD, the glucocorticoid dose should be carefully adjusted to avoid an inhibitory effect on growth. In the clinical trials there was no evidence of drug interactions with Nutropin and commonly used drugs used in the management of CKD.

7.3 Cytochrome P450 (CYP450)-Metabolized Drugs Limited published data indicate that somatropin treatment increases CYP450-mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CYP450 liver enzymes. However, formal drug interaction studies have not been conducted.

7.4 Oral Estrogen Because oral estrogens may reduce insulin-like growth factor (IGF-1) response to somatropin treatment, girls and women receiving oral estrogen replacement may require greater somatropin dosages <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> .

7.5 Insulin and/or Oral/Injectable Hypoglycemic Agents In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral/injectable hypoglycemic agents may require adjustment when somatropin therapy is initiated <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> .

Active Ingredients - Equal Amounts Of: Human Growth Hormone 30X, Liver Extract 6X, Pituitary Extract 30X. * Claims based on traditional homeopathic practice, not accepted medical evidence. Not FDA evaluated

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