Genotropin

Genotropin Prescribing Information: Indications & Dosage

Pediatric Patients

GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone.

GENOTROPIN (somatropin [rDNA origin] for 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).

GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment o...

What is Genotropin Prescribing Information?

Genotropin Patient Information: Side Effects

If you have Prader-Willi syndrome, call your doctor promptly if you develop signs of lung or breathing problems such as shortness of breath, coughing, or new or increased snoring. Rare cases of serious breathing problems have occurred in patients with Prader-Willi syndrome who use somatropin.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any of these serious side effects:

• sudden and severe pain or tenderness i...

What is Genotropin Patient Information?

Genotropin Consumer Information: Uses

Various brands of this medication are used for the treatment of one of the following medical conditions: growth failure, growth hormone deficiency, intestinal disorder (short bowel syndrome) or HIV-related weight loss or wasting.

Somatropin is also used to increase height in children with a certain genetic disorder (Noonan syndrome).

HOW TO USE: Read the Patient Information Leaflet that may come with your brand of this medication provided by your pharmacist before you start using somatropin and each time you get a refill. If you have any question...

INDICATIONS

Pediatric Patients

GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone.

GENOTROPIN (somatropin [rDNA origin] for 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).

GENOTROPIN (somatropin [rDNA origin] for 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.

GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of growth failure associated with Turner syndrome.

GENOTROPIN (somatropin [rDNA origin] for injection) 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.

Adult Patients

GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who meet either of the following two criteria:

Adult Onset: 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: Patients who were growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes.

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.

DOSAGE AND ADMINISTRATION

The weekly dose should be divided into 6 or 7 subcutaneous injections. GENOTROPIN (somatropin [rdna origin]) must not be injected intravenously.

Therapy with GENOTROPIN (somatropin [rdna origin]) should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with growth failure associated with growth hormone deficiency (GHD), Prader-Willi syndrome (PWS), Turner syndrome (TS), those who were born small for gestational age (SGA) or Idiopathic Short Stature (ISS), and adult patients with either childhood onset or adult onset GHD.

Dosing of Pediatric Patients

General Pediatric Dosing Information

The GENOTROPIN (somatropin [rdna origin]) 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, undernutrition, advanced bone age and antibodies to recombinant human GH (rhGH).

Treatment with GENOTROPIN (somatropin [rdna origin]) for short stature should be discontinued when the epiphyses are fused.

Pediatric Growth Hormone Deficiency (GHD)

Generally, a dose of 0.16 to 0.24 mg/kg body weight/week is recommended.

Prader-Willi Syndrome

Generally, a dose of 0.24 mg/kg body weight/week is recommended.

Small for Gestational Age

Generally, a dose of 0.48 mg/kg body weight/week is recommended.

Turner Syndrome

Generally, a dose of 0.33 mg/kg body weight/week is recommended.

Idiopathic Short Stature

Generally, a dose up to 0.47 mg/kg of body weight/week is recommended.

Dosing of Adult Patients

Adult Growth Hormone Deficiency (GHD)

Based on the weight-based dosing utilized in the original pivotal studies described herein, 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 a maximum of 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.

Preparation and Administration

The GENOTROPIN (somatropin [rdna origin]) 5 and 12 mg cartridges are color-coded to help ensure proper use with the GENOTROPIN (somatropin [rdna origin]) Pen delivery device. The 5 mg cartridge has a green tip to match the green pen window on the Pen 5, while the 12 mg cartridge has a purple tip to match the purple pen window on the Pen 12.

Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. GENOTROPIN (somatropin [rdna origin]) MUST NOT BE INJECTED if the solution is cloudy or contains particulate matter. Use it only if it is clear and colorless.

GENOTROPIN (somatropin [rdna origin]) may be given in the thigh, buttocks, or abdomen; the site of SC injections should be rotated daily to help prevent lipoatrophy.

HOW SUPPLIED

Dosage Forms And Strengths

GENOTROPIN (somatropin [rdna origin]) lyophilized powder:

• 5 mg two-chamber cartridge (green tip, with preservative)
  concentration of 5 mg/mL (approximately 15 IU/mL)
• 12 mg two-chamber cartridge (purple tip, with preservative)
  concentration of 12 mg/mL (approximately 36 IU/mL)

GENOTROPIN (somatropin [rdna origin]) MINIQUICK Growth Hormone Delivery Device containing a two-chamber cartridge of GENOTROPIN (somatropin [rdna origin]) (without preservative)

• 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, and 2.0 mg

GENOTROPIN (somatropin [rdna origin]) lyophilized powder is available in the following packages:

5 mg two-chamber cartridge (with preservative)

concentration of 5 mg/mL (approximately 15 IU/mL)

For use with the GENOTROPIN (somatropin [rdna origin]) PEN® 5 Growth Hormone Delivery Device and/or the GENOTROPIN (somatropin [rdna origin]) MIXER™ Growth Hormone Reconstitution Device.

Package of 5.........NDC 0013-2626-94
Package of 1.........NDC 0013-2626-81

12 mg two-chamber cartridge (with preservative)

concentration of 12 mg/mL (approximately 36 IU/mL)

For use with the GENOTROPIN (somatropin [rdna origin]) PEN 12 Growth Hormone Delivery Device and/or the GENOTROPIN (somatropin [rdna origin]) MIXER Growth Hormone Reconstitution Device.

Package of 5.........NDC 0013-2646-94
Package of 1.........NDC 0013-2646-81

GENOTROPIN (somatropin [rdna origin]) MINIQUICK Growth Hormone Delivery Device containing a two-chamber cartridge of GENOTROPIN (somatropin [rdna origin]) (without preservative)

After reconstitution, each GENOTROPIN (somatropin [rdna origin]) MINIQUICK delivers 0.25 mL, regardless of strength. Available in the following strengths, each in a package of 7:

Storage and Handling

Except as noted below, store GENOTROPIN (somatropin [rdna origin]) lyophilized powder under refrigeration at 2° to 8°C (36° to 46°F). Do not freeze. Protect from light.

The 5 mg and 12 mg cartridges of GENOTROPIN (somatropin [rdna origin]) contain a diluent with a preservative. Thus, after reconstitution, they may be stored under refrigeration for up to 28 days.

The GENOTROPIN (somatropin [rdna origin]) MINIQUICK Growth Hormone Delivery Device should be refrigerated prior to dispensing, but may be stored at or below 25°C (77°F) for up to three months after dispensing. The diluent has no preservative. After reconstitution, the GENOTROPIN (somatropin [rdna origin]) MINIQUICK may be stored under refrigeration for up to 24 hours before use. The GENOTROPIN (somatropin [rdna origin]) MINIQUICK should be used only once and then discarded.

SIDE EFFECTS

Most Serious and/or Most Frequently Observed Adverse Reactions

This list presents the most serious^b and/or most frequently observed^a adverse reactions during treatment with somatropin:

• ^b Sudden 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 and WARNINGS AND PRECAUTIONS]
• ^b Intracranial tumors, in particular meningiomas, in teenagers/young adults treated with radiation to the head as children for a first neoplasm and somatropin [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
• ^{a, b} Glucose intolerance including impaired glucose tolerance/impaired fasting glucose as well as overt diabetes mellitus [see WARNINGS AND PRECAUTIONS]
• ^b Intracranial hypertension [see WARNINGS AND PRECAUTIONS]
• ^b Significant diabetic retinopathy [see CONTRAINDICATIONS]
• ^b Slipped capital femoral epiphysis in pediatric patients [see WARNINGS AND PRECAUTIONS]
• ^b Progression of preexisting scoliosis in pediatric patients [see WARNINGS AND PRECAUTIONS]
• ^a Fluid retention manifested by edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias [see WARNINGS AND PRECAUTIONS]
• ^a Unmasking of latent central hypothyroidism [see WARNINGS AND PRECAUTIONS]
• ^a Injection site reactions/rashes and lipoatrophy (as well as rare generalized hypersensitivity reactions) [see WARNINGS AND PRECAUTIONS]

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.

Clinical Trials in children with GHD

In clinical studies with GENOTROPIN (somatropin [rdna origin]) in pediatric GHD patients, the following events were reported infrequently: injection site reactions, including pain or burning associated with the injection, fibrosis, nodules, rash, inflammation, pigmentation, or bleeding; lipoatrophy; headache; hematuria; hypothyroidism; and mild hyperglycemia.

Clinical Trials in PWS

In two clinical studies with GENOTROPIN (somatropin [rdna origin]) in pediatric patients with Prader-Willi syndrome, 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 GENOTROPIN (somatropin [rdna origin]) , 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. Anti-hGH antibodies were not detected in any of the patients treated with GENOTROPIN (somatropin [rdna origin]) .

Clinical Trials in children with Turner Syndrome

In two clinical studies with GENOTROPIN (somatropin [rdna origin]) in pediatric patients with Turner syndrome, the most frequently reported adverse events were respiratory illnesses (influenza, tonsillitis, otitis, sinusitis), joint pain, and urinary tract infection. The only treatment-related adverse event that occurred in more than 1 patient was joint pain.

Clinical Trials in children with Idiopathic Short Stature

In two open-label clinical studies with GENOTROPIN (somatropin [rdna origin]) in pediatric patients with ISS, the most commonly encountered adverse events include upper respiratory tract infections, influenza, tonsillitis, nasopharyngitis, gastroenteritis, headaches, increased appetite, pyrexia, fracture, altered mood, and arthralgia. In one of the two studies, during Genotropin (somatropin [rdna origin]) treatment, the mean IGF-1 standard deviation (SD) scores were maintained in the normal range. IGF-1 SD scores above +2 SD were observed as follows: 1 subject (3%), 10 subjects (30%) and 16 subjects (38%) in the untreated control, 0. 23 and the 0.47 mg/kg/week groups, respectively, had at least one measurement; while 0 subjects (0%), 2 subjects (7%) and 6 subjects (14%) had two or more consecutive IGF-1 measurements above +2 SD.

Clinical Trials in adults with GHD

In clinical trials with GENOTROPIN (somatropin [rdna origin]) 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 1 displays the adverse events reported by 5% or more of adult GHD patients in clinical trials after various durations of treatment with GENOTROPIN (somatropin [rdna origin]) . 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 1: Adverse Events Reported by ≥ 5% of 1,145 Adult GHD Patients During Clinical Trials of GENOTROPIN (somatropin [rdna origin]) and Placebo, Grouped by Duration of Treatment

Post-Trial Extension Studies in Adults

In expanded post-trial extension studies, diabetes mellitus developed in 12 of 3,031 patients (0.4%) during treatment with GENOTROPIN (somatropin [rdna origin]) . All 12 patients had predisposing factors, e.g., elevated glycated hemoglobin levels and/or marked obesity, prior to receiving GENOTROPIN (somatropin [rdna origin]) . Of the 3,031 patients receiving GENOTROPIN (somatropin [rdna origin]) , 61 (2%) developed symptoms of carpal tunnel syndrome, which lessened after dosage reduction or treatment interruption (52) or surgery (9). Other adverse events that have been reported include generalized edema and hypoesthesia.

Anti-hGH Antibodies

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.

In 419 pediatric patients evaluated in clinical studies with GENOTROPIN (somatropin [rdna origin]) lyophilized powder, 244 had been treated previously with GENOTROPIN (somatropin [rdna origin]) or other growth hormone preparations and 175 had received no previous growth hormone therapy. Antibodies to growth hormone (anti-hGH antibodies) were present in six previously treated patients at baseline. Three of the six became negative for anti-hGH antibodies during 6 to 12 months of treatment with GENOTROPIN (somatropin [rdna origin]) . Of the remaining 413 patients, eight (1.9%) developed detectable anti-hGH antibodies during treatment with GENOTROPIN (somatropin [rdna origin]) ; none had an antibody binding capacity > 2 mg/L. There was no evidence that the growth response to GENOTROPIN (somatropin [rdna origin]) was affected in these antibody-positive patients.

Periplasmic Escherichia coli Peptides

Preparations of GENOTROPIN (somatropin [rdna origin]) contain a small amount of periplasmic Escherichia coli peptides (PECP). Anti-PECP antibodies are found in a small number of patients treated with GENOTROPIN (somatropin [rdna origin]) , but these appear to be of no clinical significance.

Post-Marketing Surveillance

Because these adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The adverse events reported during post-marketing surveillance do not differ from those listed/discussed above in Sections 6.1 and 6.2 in children and adults.

Leukemia has been reported in a small number of GH deficient children treated with somatropin, somatrem (methionylated rhGH) and GH of pituitary origin. It is uncertain whether these cases of leukemia are related to GH therapy, the pathology of GHD itself, or other associated treatments such as radiation therapy. On the basis of current evidence, experts have not been able to conclude that GH therapy per se was responsible for these cases of leukemia. The risk for children with GHD, if any, remains to be established [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

The following additional adverse reactions have been observed during the appropriate use of somatropin: headaches (children and adults),rare gynecomastia (children), and rare pancreatitis (children).

DRUG INTERACTIONS

Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-1)

Somatropin inhibits 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) in adipose/hepatic tissue and may significantly impact the metabolism of cortisol and cortisone. As a consequence, in patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism may be unmasked requiring glucocorticoid replacement therapy. In addition, patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses; 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 the 11βHSD-1 enzyme.

Glucocorticoid Replacement

Excessive glucocorticoid therapy 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.

Cytochrome P450-Metabolized Drugs

Limited published data indicate that somatropin treatment increases cytochrome P450 (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.

Oral Estrogen

In patients on oral estrogen replacement, a larger dose of somatropin may be required to achieve the defined treatment goal [see DOSAGE AND ADMINISTRATION].

Insulin and/or Oral Hypoglycemic Agents

In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral agent may require adjustment when somatropin therapy is initiated [see WARNINGS AND PRECAUTIONS).

PRECAUTIONS

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]. 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 having acute critical illnesses should be weighed against the potential risk.

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 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].

Neoplasms

Patients with preexisting tumors or growth hormone deficiency secondary to an intracranial lesion should be examined 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 any malignant transformation of skin lesions.

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.

Intracranial Hypertension

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting has been reported in a small number of patients treated with somatropin products. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating treatment with somatropin to exclude preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed by funduscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin can be restarted at a lower dose after IH-associated signs and symptoms have resolved. Patients with Turner syndrome and Prader-Willi syndrome may be at increased risk for the development of IH.

Fluid Retention

Fluid retention during somatropin replacement therapy in adults may occur. Clinical manifestations of fluid retention are usually transient and dose dependent.

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. In patients with growth hormone deficiency, 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.

In patients with hypopituitarism (multiple hormonal deficiencies), standard hormonal replacement therapy should be monitored closely when somatropin therapy is administered.

Slipped Capital Femoral Epiphyses in Pediatric Patients

Slipped capital femoral epiphyses may occur more frequently in patients with endocrine disorders (including GHD and Turner syndrome) or in patients undergoing rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated.

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.

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.

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 before continuing on somatropin therapy at the reduced dose level recommended for GHD adults.

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].

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.

Laboratory Tests

Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and IGF-I may increase during somatropin therapy.

Patient Counseling Information

Patients being treated with GENOTROPIN (somatropin [rdna origin]) (and/or their parents) should be informed about the potential benefits and risks associated with GENOTROPIN treatment [in particular, see ADVERSE REACTIONS for a listing of the most serious and/or most frequently observed adverse reactions associated with somatropin treatment in children and adults]. This information is intended to better educate patients (and caregivers); it is not a disclosure of all possible adverse or intended effects.

Patients and caregivers who will administer GENOTROPIN (somatropin [rdna origin]) should receive appropriate training and instruction on the proper use of GENOTROPIN (somatropin [rdna origin]) from the physician or other suitably qualified health care professional. A puncture-resistant container for the disposal of used syringes and needles should be strongly recommended. Patients and/or parents should be thoroughly instructed in the importance of proper disposal, and cautioned against any reuse of needles and syringes. This information is intended to aid in the safe and effective administration of the medication.

GENOTROPIN (somatropin [rdna origin]) is supplied in a two-chamber cartridge, with the lyophilized powder in the front chamber and a diluent in the rear chamber. A reconstitution device is used to mix the diluent and powder. The two-chamber cartridge contains overfill in order to deliver the stated amount of GENOTROPIN (somatropin [rdna origin])

The GENOTROPIN (somatropin [rdna origin]) 5 mg and 12 mg cartridges are color-coded to help ensure proper use with the GENOTROPIN (somatropin [rdna origin]) Pen delivery device. The 5 mg cartridge has a green tip to match the green pen window on the Pen 5, while the 12 mg cartridge has a purple tip to match the purple pen window on the Pen 12.

Follow the directions for reconstitution provided with each device. Do not shake; shaking may cause denaturation of the active ingredient.

Please see directions for use of the reconstitution and/or delivery device.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with GENOTROPIN (somatropin [rdna origin]) . No potential mutagenicity of GENOTROPIN (somatropin [rdna origin]) was revealed in a battery of tests including induction of gene mutations in bacteria (the Ames test), gene mutations in mammalian cells grown in vitro (mouse L5178Y cells), and chromosomal damage in intact animals (bone marrow cells in rats). See Pregnancy section for effect on fertility.

Use In Specific Populations

Pregnancy

Pregnancy Category B. Reproduction studies carried out with GENOTROPIN (somatropin [rdna origin]) at doses of 0.3, 1, and 3.3 mg/kg/day administered SC in the rat and 0.08, 0.3, and 1.3 mg/kg/day administered intramuscularly in the rabbit (highest doses approximately 24 times and 19 times the recommended human therapeutic levels, respectively, based on body surface area) resulted in decreased maternal body weight gains but were not teratogenic. In rats receiving SC doses during gametogenesis and up to 7 days of pregnancy, 3.3 mg/kg/day (approximately 24 times human dose) produced anestrus or extended estrus cycles in females and fewer and less motile sperm in males. When given to pregnant female rats (days 1 to 7 of gestation) at 3.3 mg/kg/day a very slight increase in fetal deaths was observed. At 1 mg/kg/day (approximately seven times human dose) rats showed slightly extended estrus cycles, whereas at 0.3 mg/kg/day no effects were noted.

In perinatal and postnatal studies in rats, GENOTROPIN (somatropin [rdna origin]) doses of 0.3, 1, and 3.3 mg/kg/day produced growth-promoting effects in the dams but not in the fetuses. Young rats at the highest dose showed increased weight gain during suckling but the effect was not apparent by 10 weeks of age. No adverse effects were observed on gestation, morphogenesis, parturition, lactation, postnatal development, or reproductive capacity of the offsprings due to GENOTROPIN (somatropin [rdna origin]) . There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

There have been no studies conducted with GENOTROPIN (somatropin [rdna origin]) in nursing mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GENOTROPIN (somatropin [rdna origin]) is administered to a nursing woman.

Geriatric Use

The safety and effectiveness of GENOTROPIN (somatropin [rdna origin]) in patients aged 65 and over have not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of GENOTROPIN (somatropin [rdna origin]) , and therefore may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for older patients [see DOSAGE AND ADMINISTRATION].

OVERDOSE

Short-Term

Short-term overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Furthermore, overdose with somatropin is likely to cause fluid retention.

Long-Term

Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess growth hormone [see DOSAGE AND ADMINISTRATION].

CONTRAINDICATIONS

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].

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].

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 growth hormone deficiency may be an early sign of the presence of a pituitary tumor (or, rarely, other brain tumors), the presence of such tumors should be ruled out prior to initiation of treatment. Somatropin should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor.

Diabetic Retinopathy

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

Closed Epiphyses

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

Hypersensitivity

GENOTROPIN (somatropin [rdna origin]) is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. The 5 mg and 12 mg presentations of GENOTROPIN (somatropin [rdna origin]) lyophilized powder contain m-cresol as a preservative. These products should not be used by patients with a known sensitivity to this preservative. The GENOTROPIN (somatropin [rdna origin]) MINIQUICK presentations are preservative-free (see HOW SUPPLIED). Localized reactions are the most common hypersensitivity reactions.

CLINICAL PHARMACOLOGY

Mechanism of Action

In vitro, preclinical, and clinical tests have demonstrated that GENOTROPIN (somatropin [rdna origin]) lyophilized powder is therapeutically equivalent to human growth hormone of pituitary origin and achieves similar pharmacokinetic profiles in normal adults. In pediatric patients who have growth hormone deficiency (GHD), have Prader-Willi syndrome (PWS), were born small for gestational age (SGA), have Turner syndrome (TS), or have Idiopathic short stature (ISS), treatment with GENOTROPIN (somatropin [rdna origin]) stimulates linear growth. In patients with GHD or PWS, treatment with GENOTROPIN (somatropin [rdna origin]) also normalizes concentrations of IGF-I (Insulin-like Growth Factor-I/Somatomedin C). In adults with GHD, treatment with GENOTROPIN (somatropin [rdna origin]) results in reduced fat mass, increased lean body mass, metabolic alterations that include beneficial changes in lipid metabolism, and normalization of IGF-I concentrations.

In addition, the following actions have been demonstrated for GENOTROPIN (somatropin [rdna origin]) and/or somatropin.

Pharmacodynamics

Tissue Growth

1. Skeletal Growth: GENOTROPIN (somatropin [rdna origin]) stimulates skeletal growth in pediatric patients with GHD, PWS, SGA, TS, or ISS. The measurable increase in body length after administration of GENOTROPIN (somatropin [rdna origin]) results from an effect on the epiphyseal plates of long bones. Concentrations of IGF-I, which may play a role in skeletal growth, are generally low in the serum of pediatric patients with GHD, PWS, or SGA, but tend to increase during treatment with GENOTROPIN (somatropin [rdna origin]) . Elevations in mean serum alkaline phosphatase concentration are also seen.
2. 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 with the normal pediatric population. Treatment with somatropin results in an increase in both the number and size of muscle cells.

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 GENOTROPIN (somatropin [rdna origin]) .

Carbohydrate Metabolism

Pediatric patients with hypopituitarism sometimes experience fasting hypoglycemia that is improved by treatment with GENOTROPIN (somatropin [rdna origin]) . Large doses of growth hormone may impair glucose tolerance.

Lipid Metabolism

In GHD patients, administration of somatropin has resulted in lipid mobilization, reduction in body fat stores, and increased plasma fatty acids.

Mineral Metabolism

Somatropin induces retention of sodium, potassium, and phosphorus. Serum concentrations of inorganic phosphate are increased in patients with GHD after therapy with GENOTROPIN (somatropin [rdna origin]) . Serum calcium is not significantly altered by GENOTROPIN (somatropin [rdna origin]) . Growth hormone could increase calciuria.

Body Composition

Adult GHD patients treated with GENOTROPIN at the recommended adult dose (see DOSAGE AND ADMINISTRATION) demonstrate a decrease in fat mass and an increase in lean body mass. When these alterations are coupled with the increase in total body water, the overall effect of GENOTROPIN (somatropin [rdna origin]) is to modify body composition, an effect that is maintained with continued treatment.

Pharmacokinetics

Absorption

Following a 0.03 mg/kg subcutaneous (SC) injection in the thigh of 1.3 mg/mL GENOTROPIN (somatropin [rdna origin]) to adult GHD patients, approximately 80% of the dose was systemically available as compared with that available following intravenous dosing. Results were comparable in both male and female patients. Similar bioavailability has been observed in healthy adult male subjects.

In healthy adult males, following an SC injection in the thigh of 0.03 mg/kg, the extent of absorption (AUC) of a concentration of 5.3 mg/mL GENOTROPIN (somatropin [rdna origin]) was 35% greater than that for 1.3 mg/mL GENOTROPIN (somatropin [rdna origin]) . The mean (± standard deviation) peak (Cmax) serum levels were 23.0 (± 9.4) ng/mL and 17.4 (± 9.2) ng/mL, respectively.

In a similar study involving pediatric GHD patients, 5.3 mg/mL GENOTROPIN (somatropin [rdna origin]) yielded a mean AUC that was 17% greater than that for 1.3 mg/mL GENOTROPIN (somatropin [rdna origin]) . The mean Cmax levels were 21.0 ng/mL and 16.3 ng/mL, respectively.

Adult GHD patients received two single SC doses of 0.03 mg/kg of GENOTROPIN (somatropin [rdna origin]) at a concentration of 1.3 mg/mL, with a one- to four-week washout period between injections. Mean Cmax levels were 12.4 ng/mL (first injection) and 12.2 ng/mL (second injection), achieved at approximately six hours after dosing.

There are no data on the bioequivalence between the 12 mg/mL formulation and either the 1.3 mg/mL or the 5.3 mg/mL formulations.

Distribution

The mean volume of distribution of GENOTROPIN (somatropin [rdna origin]) following administration to GHD adults was estimated to be 1.3 (± 0.8) L/kg.

Metabolism

The metabolic fate of GENOTROPIN (somatropin [rdna origin]) involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products are returned to the systemic circulation. The mean terminal half-life of intravenous GENOTROPIN (somatropin [rdna origin]) in normal adults is 0.4 hours, whereas subcutaneously administered GENOTROPIN (somatropin [rdna origin]) has a half-life of 3.0 hours in GHD adults. The observed difference is due to slow absorption from the subcutaneous injection site.

Excretion

The mean clearance of subcutaneously administered GENOTROPIN (somatropin [rdna origin]) in 16 GHD adult patients was 0.3 (± 0.11) L/hrs/kg.

Special Populations

Pediatric: The pharmacokinetics of GENOTROPIN (somatropin [rdna origin]) are similar in GHD pediatric and adult patients.

Gender: No gender studies have been performed in pediatric patients; however, in GHD adults, the absolute bioavailability of GENOTROPIN (somatropin [rdna origin]) was similar in males and females.

Race: No studies have been conducted with GENOTROPIN (somatropin [rdna origin]) to assess pharmacokinetic differences among races.

Renal or hepatic insufficiency: No studies have been conducted with GENOTROPIN (somatropin [rdna origin]) in these patient populations.

Table 2: Mean SC Pharmacokinetic Parameters in Adult GHD Patients

Clinical Studies

Adult Growth Hormone Deficiency (GHD)

GENOTROPIN (somatropin [rdna origin]) lyophilized powder was compared with placebo in six randomized clinical trials involving a total of 172 adult GHD patients. These trials included a 6-month double-blind treatment period, during which 85 patients received GENOTROPIN (somatropin [rdna origin]) and 87 patients received placebo, followed by an open-label treatment period in which participating patients received GENOTROPIN (somatropin [rdna origin]) for up to a total of 24 months. GENOTROPIN (somatropin [rdna origin]) was administered as a daily SC injection at a dose of 0.04 mg/kg/week for the first month of treatment and 0.08 mg/kg/week for subsequent months.

Beneficial changes in body composition were observed at the end of the 6-month treatment period for the patients receiving GENOTROPIN (somatropin [rdna origin]) as compared with the placebo patients. Lean body mass, total body water, and lean/fat ratio increased while total body fat mass and waist circumference decreased. These effects on body composition were maintained when treatment was continued beyond 6 months. Bone mineral density declined after 6 months of treatment but returned to baseline values after 12 months of treatment.

Prader-Willi Syndrome (PWS)

The safety and efficacy of GENOTROPIN (somatropin [rdna origin]) in the treatment of pediatric patients with Prader-Willi syndrome (PWS) were evaluated in two randomized, open-label, controlled clinical trials. Patients received either GENOTROPIN (somatropin [rdna origin]) or no treatment for the first year of the studies, while all patients received GENOTROPIN (somatropin [rdna origin]) during the second year. GENOTROPIN (somatropin [rdna origin]) was administered as a daily SC injection, and the dose was calculated for each patient every 3 months. In Study 1, the treatment group received GENOTROPIN (somatropin [rdna origin]) at a dose of 0.24 mg/kg/week during the entire study. During the second year, the control group received GENOTROPIN (somatropin [rdna origin]) at a dose of 0.48 mg/kg/week. In Study 2, the treatment group received GENOTROPIN (somatropin [rdna origin]) at a dose of 0.36 mg/kg/week during the entire study. During the second year, the control group received GENOTROPIN (somatropin [rdna origin]) at a dose of 0.36 mg/kg/week.

Patients who received GENOTROPIN (somatropin [rdna origin]) showed significant increases in linear growth during the first year of study, compared with patients who received no treatment (see Table 3). Linear growth continued to increase in the second year, when both groups received treatment with GENOTROPIN (somatropin [rdna origin]) .

Table 3: Efficacy of GENOTROPIN (somatropin [rdna origin]) in Pediatric Patients with Prader-Willi Syndrome (Mean ± SD)

Changes in body composition were also observed in the patients receiving GENOTROPIN (somatropin [rdna origin]) (see Table 4). These changes included a decrease in the amount of fat mass, and increases in the amount of lean body mass and the ratio of lean-to-fat tissue, while changes in body weight were similar to those seen in patients who received no treatment. Treatment with GENOTROPIN (somatropin [rdna origin]) did not accelerate bone age, compared with patients who received no treatment.

Table 4: Effect of GENOTROPIN (somatropin [rdna origin]) on Body Composition in Pediatric Patients with Prader-Willi Syndrome (Mean ± SD)

SGA

Pediatric Patients Born Small for Gestational Age (SGA) Who Fail to Manifest Catch-up Growth by Age 2

The safety and efficacy of GENOTROPIN (somatropin [rdna origin]) in the treatment of children born small for gestational age (SGA) were evaluated in 4 randomized, open-label, controlled clinical trials. Patients (age range of 2 to 8 years) were observed for 12 months before being randomized to receive either GENOTROPIN (somatropin [rdna origin]) (two doses per study, most often 0.24 and 0.48 mg/kg/week) as a daily SC injection or no treatment for the first 24 months of the studies. After 24 months in the studies, all patients received GENOTROPIN (somatropin [rdna origin]) .

Patients who received any dose of GENOTROPIN (somatropin [rdna origin]) showed significant increases in growth during the first 24 months of study, compared with patients who received no treatment (see Table 5). Children receiving 0.48 mg/kg/week demonstrated a significant improvement in height standard deviation score (SDS) compared with children treated with 0.24 mg/kg/week. Both of these doses resulted in a slower but constant increase in growth between months 24 to 72 (data not shown).

Table 5: Efficacy of GENOTROPIN (somatropin [rdna origin]) in Children Born Small for Gestational Age (Mean ± SD)

Turner Syndrome

Two randomized, open-label, clinical trials were conducted that evaluated the efficacy and safety of GENOTROPIN (somatropin [rdna origin]) in Turner syndrome patients with short stature. Turner syndrome patients were treated with GENOTROPIN (somatropin [rdna origin]) alone or GENOTROPIN (somatropin [rdna origin]) plus adjunctive hormonal therapy (ethinylestradiol or oxandrolone). A total of 38 patients were treated with GENOTROPIN (somatropin [rdna origin]) alone in the two studies. In Study 055, 22 patients were treated for 12 months, and in Study 092, 16 patients were treated for 12 months. Patients received GENOTROPIN (somatropin [rdna origin]) at a dose between 0.13 to 0.33 mg/kg/week.

SDS for height velocity and height are expressed using either the Tanner (Study 055) or Sempé (Study 092) standards for age-matched normal children as well as the Ranke standard (both studies) for age-matched, untreated Turner syndrome patients. As seen in Table 5, height velocity SDS and height SDS values were smaller at baseline and after treatment with GENOTROPIN (somatropin [rdna origin]) when the normative standards were utilized as opposed to the Turner syndrome standard.

Both studies demonstrated statistically significant increases from baseline in all of the linear growth variables (i.e., mean height velocity, height velocity SDS, and height SDS) after treatment with GENOTROPIN (somatropin [rdna origin]) (see Table 6). The linear growth response was greater in Study 055 wherein patients were treated with a larger dose of GENOTROPIN (somatropin [rdna origin]) .

Table 6: Growth Parameters (mean ± SD) after 12 Months of Treatment with GENOTROPIN (somatropin [rdna origin]) in Pediatric Patients with Turner Syndrome in Two Open Label Studies

Idiopathic Short Stature

The long-term efficacy and safety of GENOTROPIN (somatropin [rdna origin]) in patients with idiopathic short stature (ISS) were evaluated in one randomized, open-label, clinical trial that enrolled 177 children. Patients were enrolled on the basis of short stature, stimulated GH secretion > 10 ng/mL, and prepubertal status (criteria for idiopathic short stature were retrospectively applied and included 126 patients). All patients were observed for height progression for 12 months and were subsequently randomized to Genotropin (somatropin [rdna origin]) or observation only and followed to final height. Two Genotropin (somatropin [rdna origin]) doses were evaluated in this trial: 0.23 mg/kg/week (0.033 mg/kg/day) and 0.47 mg/kg/week (0.067 mg/kg/day). Baseline patient characteristics for the ISS patients who remained prepubertal at randomization (n= 105) were: mean (± SD): chronological age 11.4 (1.3) years, height SDS -2.4 (0.4), height velocity SDS -1.1 (0.8), and height velocity 4.4 (0.9) cm/yr, IGF-1 SDS -0.8 (1.4). Patients were treated for a median duration of 5.7 years. Results for final height SDS are displayed by treatment arm in Table 7. GENOTROPIN (somatropin [rdna origin]) therapy improved final height in ISS children relative to untreated controls. The observed mean gain in final height was 9.8 cm for females and 5.0 cm for males for both doses combined compared to untreated control subjects. A height gain of 1 SDS was observed in 10 % of untreated subjects, 50% of subjects receiving 0.23 mg/kg/week and 69% of subjects receiving 0.47 mg/kg/week

Table 7. Final height SDS results for pre-pubertal patients with ISS*

PATIENT INFORMATION

Instructions for Use

Important Note

Please read these instructions completely before using the GENOTROPIN (somatropin [rdna origin]) MINIQUICK. If there is anything you do not understand or cannot do, call the toll-free number listed at the end of this leaflet.

If you have any questions about your dose or your treatment with GENOTROPIN (somatropin [rdna origin]) , call your healthcare provider right away.

Use this device only for the person for whom it was prescribed.

GENOTROPIN (somatropin [rdna origin]) MINIQUICK is a device used to mix and administer a single dose of GENOTROPIN (somatropin [rdna origin]) Lyophilized Powder (somatropin [rDNA origin] for injection).

Each GENOTROPIN (somatropin [rdna origin]) MINIQUICK comes preloaded with a two-chamber cartridge of GENOTROPIN (somatropin [rdna origin]) . GENOTROPIN (somatropin [rdna origin]) MINIQUICK is available in ten different dose sizes. Be sure you have the dose your doctor prescribed.

The GENOTROPIN (somatropin [rdna origin]) MINIQUICK is disposable; after you administer the dose, you throw the empty unit away. IMPORTANT - always throw away the GENOTROPIN (somatropin [rdna origin]) MINIQUICK properly, as directed by your healthcare provider.

Components

This system consists of the delivery device, the two-chamber cartridge of GENOTROPIN (somatropin [rdna origin]) packaged inside it, and a separate injection needle. The diagram below identifies the different components.

A needle for injection is provided with each device. If you need additional needles, ask for Becton Dickinson Ultra-Fine pen needles, either 29, 30 or 31 gauge.

The two-chamber cartridge of GENOTROPIN (somatropin [rdna origin]) contains the growth hormone powder in one chamber and a liquid in the other. When you turn the plunger rod clockwise (to the right), the GENOTROPIN (somatropin [rdna origin]) MINIQUICK automatically mixes the growth hormone powder and the liquid.

Storage

Before the drug is reconstituted (the powder mixed with the liquid), you can store the GENOTROPIN (somatropin [rdna origin]) MINIQUICK at room temperature (77° F or less) for up to three months. Keep it in the carton to protect it from light.

You should inject the GENOTROPIN (somatropin [rdna origin]) right after you reconstitute it. If that is not possible, you can keep the GENOTROPIN (somatropin [rdna origin]) MINIQUICK in the refrigerator (in the carton) for up to 24 hours after reconstitution. Do not freeze. If you do not use the GENOTROPIN (somatropin [rdna origin]) MINIQUICK within 24 hours after reconstitution, throw it away.

Single Use

There are no preservatives in the GENOTROPIN (somatropin [rdna origin]) MINIQUICK.

Use each GENOTROPIN (somatropin [rdna origin]) MINIQUICK only once and then throw it away.

To help prevent infection, always wash your hands well with soap and water before using the GENOTROPIN (somatropin [rdna origin]) MINIQUICK.

1. Wipe the rubber stopper on the GENOTROPIN (somatropin [rdna origin]) MINIQUICK with a pad or swab moistened with rubbing alcohol.

2. Peel the paper covering from the back of the injection needle. Leave both protective caps (inner and outer) on the needle.

Screw the needle onto the GENOTROPIN (somatropin [rdna origin]) MINIQUICK, turning it until it stops.

3. Hold the GENOTROPIN (somatropin [rdna origin]) MINIQUICK with the needle pointing up. To mix the growth hormone powder with the liquid, turn the plunger rod clockwise (to the right) until it will go no further.

4. Do not shake the GENOTROPIN (somatropin [rdna origin]) MINIQUICK. Shaking may inactivate the growth hormone so it will not work.

Check to make sure the solution is clear, indicating that the growth hormone powder is completely dissolved. If you see particles, or if the solution is discolored, do not inject it. Instead, call the toll-free number listed at the end of this leaflet.

If using the optional, reusable Needle Guard to hide the needle, go to step 5. If the Needle Guard is not used, go to step 6.

5. To attach the optional reusable Needle Guard, remove the outer protective cap from the needle, place the Needle Guard on to the GENOTROPIN (somatropin [rdna origin]) MINIQUICK, and press gently until the Needle Guard snaps into place.

6. Select and disinfect an appropriate injection site, as instructed by your healthcare provider.

If the optional Needle Guard is not used, remove the outer and inner protective caps from the needle. If the Needle Guard is used, remove the inner protective cap from the needle.

7. Pinch a fold of skin at the injection site firmly, and push the needle straight into the skinfold at a 90-degree angle. When using the Needle Guard, the retractable plastic needle shield will push in as the GENOTROPIN (somatropin [rdna origin]) MINIQUICK is pushed against the skin.

8. Push the plunger rod as far as it will go, to inject all the medicine in the GENOTROPIN (somatropin [rdna origin]) MINIQUICK.

Wait a few seconds to be sure that all the growth hormone has been injected. Then, pull out the needle.

9. After injection, carefully replace the outer protective cap on the needle if you are not using the optional Needle Guard. If you are using the Needle Guard, carefully replace the inner protective cap on the needle while the Needle Guard is on the unit. Then remove the Needle Guard and save it for future use. Throw away the GENOTROPIN (somatropin [rdna origin]) MINIQUICK in a suitable container.

Always throw away the GENOTROPIN (somatropin [rdna origin]) MINIQUICK properly, as instructed by your healthcare provider.

The reusable Needle Guard may be cleaned by wiping with a damp cloth or alcohol swab. If it cannot be cleaned satisfactorily, or does not function properly, throw it away and contact Pharmacia & Upjohn for a replacement.

Genotropin Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

SOMATROPIN - INJECTION

(so-mah-TROW-pin)

COMMON BRAND NAME(S): Genotropin, Humatrope, Norditropin, Nutropin, Serostim, Zorbtive

USES: Various brands of this medication are used for the treatment of one of the following medical conditions: growth failure, growth hormone deficiency, intestinal disorder (short bowel syndrome) or HIV-related weight loss or wasting.

Somatropin is also used to increase height in children with a certain genetic disorder (Noonan syndrome).

HOW TO USE: Read the Patient Information Leaflet that may come with your brand of this medication provided by your pharmacist before you start using somatropin and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Some brands of this medication are given by injection into a muscle or under the skin. Some brands may only be injected under the skin. The way you inject this medicine will depend on the brand that you are using. Check with your pharmacist to ensure that the way you are injecting your medicine is correct. It is important to change the location of the injection site to avoid problem areas under the skin. For best results, this medication must be used exactly as prescribed by your doctor. It is important to understand your therapy and to follow your doctor's instructions closely.

If you are giving this medication to yourself at home, learn all preparation and usage instructions from your health care professional. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. Learn how to store and discard medical supplies safely.

If this medicine is used for short bowel syndrome, consult your doctor if a special diet (high carbohydrate/lowfat) or the use of nutritional supplements may be helpful.

If this medicine is used for weight loss/muscle wasting, it may take up to 2 weeks to notice the effects of the drug. Do not use more of this medication than prescribed or use it more often since the risk of side effects will be increased.

Genotropin Consumer (continued)

SIDE EFFECTS: Headache, nausea, vomiting, fatigue, muscle pain, or weakness may occur. If these symptoms continue or become bothersome, inform your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if you have any serious side effects, including: development of a limp, persistent fatigue, unusual/unexplained weight gain, persistent cold intolerance, persistent slow heartbeat, fast heartbeat, ear pain/itching, hearing problems, joint/hip/knee pain, numbness/tingling, unusual increase in thirst or urination, swelling hands/ankles/feet, change in the appearance or size of any mole, severe headache, persistent nausea/vomiting, severe stomach/abdominal pain, vision problems or changes, seizure.

Rare (possibly fatal) lung/breathing problems may be caused by this medication in children with Prader-Willi syndrome. Those at higher risk include males, severely overweight children, or those with serious lung/breathing problems ( e.g., sleep apnea, lung infections, lung disease). Children should be checked for certain breathing problems (upper airway obstruction) before and during treatment. Heavy snoring or irregular breathing during sleep (sleep apnea) are signs of airway obstruction. Tell the doctor immediately if these signs occur. Also report any signs of lung infection, such as fever, persistent cough, or trouble breathing.

A serious allergic reaction to this drug is unlikely, but get medical help right away if it occurs. Symptoms of a serious allergic reaction include: rash, itching/severe swelling (especially of the face/tongue/throat), dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at             1-800-FDA-1088      .

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at             1-866-234-2345      .

PRECAUTIONS: Before using somatropin, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients (such as benzyl alcohol found in some brands), which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: eye problems (e.g., diabetic retinopathy), major surgery or trauma, severe breathing problems (acute respiratory failure), undergoing therapy for tumors (cancer), Prader-Willi syndrome (see Side Effects section above), normal growth has stopped (closed epiphyses).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: adrenal gland problems, diabetes or family history of diabetes, obesity, kidney disease, tumors (cancer), thyroid problems, back problems (scoliosis), a certain genetic condition (Turner syndrome).

When this medication is given to newborns, mix with sterile water for injection that does not contain a preservative. A preservative (benzyl alcohol) which may be found in the liquid used to mix this product can infrequently cause serious problems (sometimes death), if given by injection to an infant during the first months of life. The risk is greater with lower birth weight infants and is greater with increased amounts of benzyl alcohol. Symptoms include sudden gasping, low blood pressure, or a very slow heartbeat. Report these symptoms to the doctor immediately should they occur.

Caution is advised when using in the elderly because elderly patients may be more sensitive to its effects.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known if this drug passes into breast milk. Consult your doctor before breast-feeding.

Genotropin Consumer (continued)

DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: drugs to treat diabetes (e.g., insulin, sulfonylureas such as glyburide), estrogen hormone replacement, glucocorticoids (e.g., prednisone, hydrocortisone).

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at             1-800-222-1222      . Canadian residents should call their local poison control center directly. Symptoms of overdose may include severe headache, nausea, or vomiting; sudden onset of sweating, fatigue, shakiness, confusion (hypoglycemia); or persistent swelling of hands and feet.

NOTES: Laboratory and/or medical tests (e.g., eye exams, thyroid function tests, glucose levels, growth hormone antibody levels) will be done routinely to monitor your response to the medication or check for side effects. Keep all medical appointments and laboratory visits so your therapy can be monitored closely. Consult your doctor for more details.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor or pharmacist immediately to establish a new dosing schedule.

STORAGE: Consult the product instructions and your pharmacist for storage details. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

Information last revised December 2010 Copyright(c) 2010 First DataBank, Inc.

Genotropin Patient Information Including Side Effects

Brand Names: Genotropin, Genotropin Miniquick, Humatrope, Norditropin, Norditropin Cartridge, Norditropin Nordiflex Pen, Nutropin, Nutropin AQ, Omnitrope, Saizen, Serostim, Tev-tropin, Zorbtive

Generic Name: somatropin (Pronunciation: soe ma TROE pin)

• What is somatropin (Genotropin)?
• What are the possible side effects of somatropin?
• What is the most important information I should know about somatropin?
• What should I discuss with my healthcare provider before using somatropin?
• How should I use somatropin?
• What happens if I miss a dose?
• What happens if I overdose?
• What should I avoid while using somatropin?
• What other drugs will affect somatropin?
• Where can I get more information?

What is somatropin (Genotropin)?

Somatropin is a form of human growth hormone. Human growth hormone is important in the body for the growth of bones and muscles.

Somatropin is used to treat growth failure in children and adults who lack natural growth hormone, and in those with chronic kidney failure, Noonan syndrome, Turner syndrome, short stature at birth with no catch-up growth, and other causes. Somatropin is also used to prevent severe weight loss in people with AIDS, or to treat short bowel syndrome.

Somatropin may also be used for other purposes not listed in this medication guide.

What are the possible side effects of somatropin?

If you have Prader-Willi syndrome, call your doctor promptly if you develop signs of lung or breathing problems such as shortness of breath, coughing, or new or increased snoring. Rare cases of serious breathing problems have occurred in patients with Prader-Willi syndrome who use somatropin.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any of these serious side effects:

• sudden and severe pain or tenderness in your upper stomach;
• nausea, vomiting, sweating, fever, fast heartbeat, yellowing of the skin or eyes;
• increased thirst and urination;
• sudden and severe pain behind your eyes, vision changes;
• swelling in your head, face, hands, or feet; or
• numbness or tingling in your wrist, hand, or fingers.

Less serious side effects may include:

• headache;
• redness, soreness, swelling, skin rash, itching, pain, or bruising where the medicine was injected;
• breast swelling;
• joint pain, swelling, or stiffness; or
• mild nausea, stomach pain, gas.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at             1-800-FDA-1088      .

What is the most important information I should know about somatropin?

Before you receive somatropin, tell your doctor about all your past and present medical conditions, especially allergies, trauma, surgery, diabetes, cancer, breathing problems, liver or kidney disease, scoliosis, high blood pressure, pancreas disorder, underactive thyroid, or a brain tumor.

Also tell your doctor about all other medications you use, especially steroids or diabetes medications. Your dosages of these medicines may need to be changed when you start using somatropin. Do not stop using a steroid suddenly or change any of your medication doses without your doctor's advice.

If you have Prader-Willi syndrome and are using somatropin, call your doctor promptly if you develop signs of lung or breathing problems such as shortness of breath, coughing, or new or increased snoring.

Call your doctor at once if you have sudden and severe pain or tenderness in your upper stomach, with nausea, vomiting, sweating, fever, fast heartbeat, and yellowing of the skin or eyes. You should also call your doctor promptly if you have vision changes and sudden, severe pain behind your eyes.

Genotropin Patient Information including How Should I Take

What should I discuss with my healthcare provider before using somatropin?

Before you receive somatropin, tell your doctor if you have ever had an allergic reaction to a growth hormone medicine, or to drug preservatives such as benzyl alcohol, metacresol or glycerin.

You should not use this medication if you are allergic to somatropin, or if you have:

• diabetic retinopathy (a serious eye condition caused by diabetes);
• cancer; or
• Prader-Willi syndrome and are also overweight or have sleep apnea or severe respiratory (lung) problems.

You should also not use somatropin if you have a serious medical condition after having:

• open heart surgery or stomach surgery;
• trauma or other medical emergency; or
• breathing problems (such as lung failure).

If you have certain conditions, you may need a dose adjustment or special tests to safely use this medication. Before using somatropin, tell your doctor if you have:

• liver disease;
• kidney disease (or if you are on dialysis);
• diabetes;
• scoliosis;
• high blood pressure (hypertension);
• a pancreas disorder;
• a history of cancer;
• carpal tunnel syndrome;
• underactive thyroid; or
• a brain tumor or lesion.

FDA pregnancy category C. It is not known whether somatropin is harmful to an unborn baby. Before using this medication, tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether somatropin passes into breast milk or if it could harm a nursing baby. Do not use somatropin without telling your doctor if you are breast-feeding a baby.

How should I use somatropin?

Use this medication exactly as it was prescribed for you. Do not use the medication in larger amounts, or use it for longer than recommended by your doctor.

Your dose and brand of somatropin, and how often you give it will depend on what you are being treated for. Follow the directions on your prescription label.

Somatropin is given as an injection under the skin or into a muscle. Your doctor, nurse, or other healthcare provider will give you this injection. You may be given instructions on how to inject your medicine at home. Do not use this medicine at home if you do not fully understand how to give the injection and properly dispose of needles and syringes used in giving the medicine.

Your doctor or nurse will show you several areas on your body where you can inject somatropin. Use a different injection place each time you give yourself the shot. Do not inject this medicine into skin or muscle that is red, sore, infected, or injured.

Do not shake the medication vial (bottle). Vigorous shaking can ruin the medicine. When mixing somatropin with a diluent (liquid), use a gentle swirling motion. Do not use the medication if it has changed colors or is cloudy. Call your doctor for a new prescription.

Use each disposable needle only one time. Throw away used needles in a puncture-proof container (ask your pharmacist where you can get one and how to dispose of it). Keep this container out of the reach of children and pets.

To be sure this medication is helping your condition and not causing harm, your blood and growth progress will need to be tested on a regular basis. Your eyes may also need to be checked. Do not miss any scheduled visits to your doctor.

If you are being treated for short bowel syndrome, follow the diet plan created for you by your doctor or nutrition counselor to help control your condition. Somatropin is not a cure for short bowel syndrome.

If you use a form of somatropin that comes in a cartridge for use with an injection pen, use only the pen injection system provided with the somatropin brand you use.

How you store this medicine will depend on what brand you are using and what diluent you are mixing somatropin with. After mixing somatropin, you may need to use it right away or you may be able to store it for later use. Read and carefully follow the instructions provided with your medicine about proper storage of somatropin before and after it has been mixed. Ask your pharmacist if you have any questions about proper storage of your medication.

Throw away any somatropin left over after the expiration date on the label has passed.

Genotropin Patient Information including If I Miss a Dose

What happens if I miss a dose?

Use the medication as soon as you remember. If it is almost time for the next dose, skip the missed dose and use the medicine at the next regularly scheduled time. Do not use extra medicine to make up the missed dose.

Call your doctor if you miss more than 3 doses in a row.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose can cause tremors or shaking, cold sweats, increased hunger, headache, drowsiness, weakness, dizziness, fast heartbeat, and nausea. Long-term overdose may cause excessive growth.

What should I avoid while using somatropin?

If you use Zorbtive to treat short bowel syndrome, avoid drinking fruit juices or soda beverages. Follow the instructions of your doctor or nutrition counselor about what types of liquids you should drink while using Zorbtive.

Avoid drinking alcohol if you have short bowel syndrome. Alcohol can irritate your stomach and could make your condition worse.

What other drugs will affect somatropin?

Before using somatropin, tell your doctor if you use insulin or take oral (by mouth) medicine to treat diabetes. Somatropin may affect blood sugar levels and you may need to adjust your dose of the diabetes medication. Do not change the dose of your diabetes medication without your doctor's advice.

Tell your doctor if you use any type of steroid medicine such as cortisone, dexamethasone, methylprednisolone, prednisone, and others. Steroids can make somatropin less effective and your doses may need to be adjusted. Do not stop using a steroid suddenly. Follow your doctor's instructions.

Tell your doctor about all other medications you use, especially cyclosporine (Gengraf, Neoral, Sandimmune), seizure medication, birth control pills, anabolic steroids, or hormone replacement medications for men or women.

This list is not complete and there may be other drugs that can interact with somatropin. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about somatropin.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2010 Cerner Multum, Inc. Version: 8.01. Revision date: 04/29/2009.