GENOTROPIN Drug Interactions

SUMMARY PRODUCT INFORMATION

GENOTROPIN (somatropin for injection) is a polypeptide hormone of recombinant DNA origin. It has 191 amino acid residues, a molecular weight of 22,124 daltons, and an isoelectric point (pH) of 5.0. The amino acid sequence of the product is identical to that of human growth hormone of pituitary origin (somatropin). GENOTROPIN is synthesized in a strain of Escherichia coli that has been modified by the addition of the gene for human growth hormone.

GENOTROPIN (somatropin for injection) is indicated for:

Children

The long‑term treatment of children who have growth failure due to an inadequate secretion of endogenous growth hormone (growth hormone deficiency (GHD)). Other causes of short stature should be excluded.

SGA Indication

GENOTROPIN is indicated for the treatment of growth failure (current height standard deviation score [SDS] < - 2) in short children born SGA (birth weight and/or length below -2 SD) and who fail to achieve catch-up growth (height velocity SDS < 0 during the last year) by 2 to 4 years or later.

TS Indication

The treatment of short stature associated with Turner syndrome in patients whose epiphyses are not closed.

ISS Indication

The long-term 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 for whom diagnostic evaluation excludes other causes associated with short stature that should be observed or treated by other means. Genotropin treatment for ISS should be prescribed only for those patients whose epiphyses are not closed.

PWS Indication

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. GENOTROPIN is also indicated for improvement of body composition in children with Prader-Willi syndrome.

Adults

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 (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.

Geriatrics

The safety and effectiveness of GENOTROPIN in patients aged 65 and over have not been evaluated in clinical studies. (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics).

GENOTROPIN (somatropin for injection) should not be used when there is any evidence of neoplastic activity. Intracranial lesions must be inactive and antitumour therapy complete prior to the institution of therapy. GENOTROPIN should be discontinued if there is evidence of tumour growth.

Growth hormone should not be used for growth promotion in children with fused epiphyses.

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

GENOTROPIN is contraindicated in patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma, or acute respiratory failure. (see WARNINGS AND PRECAUTIONS).

GENOTROPIN is contraindicated in patients with a history of hypersensitivity to any of its components.

GENOTROPIN is contraindicated in patients with Prader-Willi syndrome who have uncontrolled diabetes, or active psychosis, or have active cancer.

GENOTROPIN 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 SERIOUS WARNINGS AND PRECAUTIONS).

Certain formulations of growth hormones contain metacresol as a preservative. These formulations should not be used by patients with a known sensitivity to these preservatives (see WARNINGS AND PRECAUTIONS, General).

General

Patients and caregivers who administer GENOTROPIN should receive appropriate training and instruction on the proper use of GENOTROPIN from the physician or suitably qualified health professional.

The 5 mg, 5.3 mg and 12 mg presentations of GENOTROPIN GoQuick 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 MiniQuick presentations are preservative-free.

Myositis is a very rare adverse event that may be related to the preservative m-cresol. If myalgia or disproportionate pain at injection site develops, myositis should be considered and, if confirmed, a presentation of somatropin without m-cresol should be used.

The site of SC injections of GENOTROPIN should be rotated daily between the thigh, buttocks and abdomen in order to avoid lipoatrophy.

It is recommended that insulin-like growth factor‑I (IGF‑I) concentrations be monitored regularly and maintained within the normal range for age and sex.

To avoid transmission of disease, GENOTROPIN cartridges must not be used by more than one person.

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.

The effects of GENOTROPIN on recovery were studied in two placebo controlled trials involving 522 critically ill adult patients suffering complications following open heart surgery, abdominal surgery, multiple accidental trauma or acute respiratory failure. Mortality was higher in patients treated with daily doses of 5.3 or 8 mg GENOTROPIN compared to patients receiving placebo, 42% vs. 19%. Based on this information, these types of patients should not be treated with GENOTROPIN.

Carcinogenesis and Mutagenesis

Carcinogenesis studies have not been conducted with rhGH. rhGH is not expected to be carcinogenic in human as the rhGH molecule is identical to the native hormone and the treatment is substitution therapy. No potential mutagenicity of rhGH was revealed in a battery of tests including the Ames test, a test designed to demonstrate chromosome damaging potential, induction of gene mutations in mammalian cells (L5178Y) in vitro and in intact bone marrow cells (rats).

Leukemia has been reported in a small number of growth hormone-deficient patients, treated with growth hormone, including growth hormone of pituitary origin as well as of recombinant DNA origin (somatrem and somatropin). Based on the current evidence, experts cannot conclude that growth hormone therapy is responsible for these occurrences.

Patients treated with growth hormone may have an increased risk of developing neoplasm.

Neoplasms

Patients with pre-existing tumours or with GHD secondary to an intracranial lesion should be examined frequently 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) tumour recurrence or new extracranial tumours. 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 tumours, in particular meningiomas were the most common of these second neoplasms especially in patients treated with radiation to the head. In adults, it is unknown whether there is any relationship between somatropin replacement therapy and CNS tumour recurrence. Patients should be monitored carefully for any malignant transformation of skin lesions.

Closed Epiphyses

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

Treatment of pediatric growth disorders with growth hormones should be discontinued when the patient has reached satisfactory adult height, or when the epiphyses are closed.

Congenital Disorders

There have been reports of fatalities associated with the use of growth hormone in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of respiratory impairment or sleep apnea, or unidentified respiratory infection. Another possible risk factor may be male gender. (see CONTRAINDICATIONS).

Prader Willi Syndrome:

Patients with Prader Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin.

If a somatropin treated patient shows signs of upper airway obstruction (including onset of or increased snoring) and /or new onset of sleep apnea, somatropin treatment should be interrupted and the patient should be treated for upper airway obstruction and/or sleep apnea.

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).

Progression of scoliosis can occur in patients who experience rapid growth. Because growth hormone increases growth rate, physicians should be alert to this abnormality, which may manifest during growth hormone therapy. Scoliosis is commonly seen in patients with Prader-Willi syndrome.

Turner’s syndrome:

Patients with Turner syndrome may be at increased risk for development of intracranial hypertension. Therefore, these patients should be evaluated for signs and symptoms of intracranial hypertension and, if present, this condition should be treated before initiation of treatment with somatropin.

Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders before and during treatment with somatropin because these patients have an increased risk of ear and hearing disorders (see ADVERSE REACTIONS).

Patients with Turner syndrome are at risk for cardiovascular disorders (e.g. hypertension, stroke, and aortic dilatation, aneurysm and dissection) and these patients should be monitored closely for development or worsening of these conditions before and during treatment with somatropin.

Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease. Therefore, these patients should have periodic thyroid function tests performed and be treated appropriately (see Endocrine and Metabolism).

Note: Skeletal abnormalities including scoliosis are commonly seen in untreated patients with Turner syndrome.

Dependence/Liability

GENOTROPIN is not considered to be a drug that has potential to produce drug dependency. GENOTROPIN does not have stimulant, depressant or hallucinogenic effects on the central nervous system that could be expected to lead to psychological or physical dependency.

Potential for Misuse: Inappropriate use of somatropin by individuals who do not have indications for which somatropin is approved, may result in clinically significant negative health consequences.

Endocrine and Metabolism

Patients with diabetes mellitus or glucose intolerance should be monitored closely during therapy with somatropin, as an adjustment of their antidiabetic therapy may be required.

Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in patients with risk factors for diabetes mellitus, such as obesity, Turner syndrome, or a family history of diabetes mellitus, those receiving high dose corticosteroid therapy, and patients with impaired glucose tolerance or pre‑existing diabetes mellitus. As a result, previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked during somatropin treatment. Therefore, patients who receive somatropin should be monitored for evidence of abnormal glucose metabolism and/or diabetes mellitus. New‑onset type 2 diabetes mellitus has been reported in children and adults receiving somatropin.

In patients with hypopituitarism standard hormonal replacement therapy should be monitored closely when somatropin therapy is administered.

Somatropin can increase the extrathyroidal conversion of thyroxine (T4) to triiodothyronine (T3) and may unmask incipient hypothyroidism. Because inadequate treatment of hypothyroidism may prevent optimal response to somatropin, thyroid function should be evaluated before starting somatropin therapy and should be monitored regularly during treatment, not less frequently than annually.

Notes Regarding Potential Effects of Somatropin on Glucocorticoid Metabolism: The microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol in hepatic and adipose tissue. Endogenous growth hormone and exogenous somatropin inhibit the activity of 11βHSD-1. Therefore growth hormone deficiency is associated with a relative increase in 11βHSD-1 activity, which in turn results in a relative increase in serum cortisol. Somatropin treatment may inhibit 11βHSD-1, resulting in relative reduction of serum cortisol concentrations.

In addition, somatropin may enhance the activity of CYP3A4, a cytochrome P450 enzyme involved in glucocorticoid catabolism. Therefore, by increasing the activity of CYP3A4, somatropin could potentially decrease serum cortisol concentration. Because somatropin may both inhibit 11βHSD-1 (an enzyme required for production of cortisol) and induce activity of CYP3A4 (an enzyme involved in cortisol breakdown), careful monitoring of serum cortisol concentrations is required for all patients receiving concomitant glucocorticoid and somatropin therapy.

As a consequence of its actions on enzymes involved in cortisol metabolism, somatropin treatment may unmask previously undiagnosed central (secondary) hypoadrenalism, and glucocorticoid replacement may be required. In addition, patients treated with glucocorticoids for previously diagnosed hypoadrenalism (primary or secondary) may require adjustments of their maintenance or stress doses following initiation of somatropin treatment; this may be especially true for patients treated with cortisone acetate and prednisone, because conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1 (see Monitoring and Laboratory Tests).

Fluid Retention

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

Immune

Local allergic reactions:

Patients receiving somatropin treatment may experience redness, swelling, pain, inflammation, or itching at the site of injection (see ADVERSE REACTIONS).

Most of these minor reactions usually resolve in a few days to a few weeks. Such reactions may occur if the injection is given incorrectly (irritants in the skin cleansing agent or poor injection technique), or if the patient is allergic to somatropin or any non-medicinal ingredient (see CONTRAINDICATIONS).

Rarely, subcutaneous administration of somatropin can result in lipoatrophy or lipohypertrophy. Regular rotation of the injection site may help reduce or prevent these reactions.

Patients should be advised to consult their doctor if they notice any of the conditions described above.

On rare occasions, injection site reactions may require discontinuation of somatropin therapy.

Systemic allergic reactions:

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.

These reactions may be characterized by a generalized rash (with pruritus), shortness of breath, wheezing, angioneurotic edema and drop in blood pressure (see ADVERSE REACTIONS).

Severe cases of generalized allergy including anaphylactic reaction may be life threatening (see CONTRAINDICATIONS).

If any serious hypersensitivity or allergic reaction occurs, somatropin therapy should be discontinued immediately and appropriate therapy initiated.

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with post-marketing use of somatropin products. Patients and caregivers should be informed that such reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs (see CONTRAINDICATIONS).

Antibody production:

A small percentage of patients treated with somatropin may develop antibodies during treatment that could potentially reduce treatment response (see ADVERSE REACTIONS).

Patients who have demonstrated an allergic reaction to other somatropin products may demonstrate an allergic reaction to GENOTROPIN.

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 growth hormone products. Symptoms usually occurred within the first eight weeks of initiation of growth hormone therapy. In all reported cases, IH-associated signs and symptoms resolved after termination of therapy or a reduction of growth hormone dose. Fundoscopic examination of patients is recommended at the initiation, and periodically during the course of, growth hormone therapy. If papilledema is observed by funduscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin can be restarted at a lower dose after IH associated signs and symptoms have resolved. Patients with Turner syndrome may be at increased risk for the development of IH.

Musculoskeletal

Musculoskeletal discomfort (pain, swelling and/or stiffness) may occur during treatment with somatropin (see ADVERSE REACTIONS). These symptoms may resolve spontaneously, with analgesic therapy, or after reducing the dosage (see DOSAGE AND ADMINISTRATION).

Swelling of the hands and feet may occur during treatment with somatropin and may lead to carpal tunnel syndrome, which may be improved by decreasing the dosage of somatropin.

Somatropin has not been shown to increase the occurrence of scoliosis. However, progression of pre existing scoliosis can occur in pediatric patients who experience rapid growth. Therefore, because somatropin increases growth rate, patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis.

Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including pediatric growth hormone deficiency, Turner syndrome and hypothyroidism) or in patients undergoing rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated (see Monitoring and Laboratory Tests).

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. Pancreatitis should be considered in any somatropin treated patients, especially a child, who develops persistent severe abdominal pain.

Renal/Hepatic/Biliary/Pancreatic Impairments

Somatropin doses may need to be adjusted in patients with renal and/or hepatic and/or biliary and/or pancreatic impairments.

Reproduction Studies

No adequate and well-controlled clinical studies with GENOTROPIN on reproductive function have been performed (see Special Populations, Pregnant Women)

Animal reproductive studies in rats and rabbits treated during the period of organogenesis have not given evidence of any harmful effects on the fetus. There are however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Information for Patients

Patients and/or their caregivers should be informed about potential advantages and disadvantages of GENOTROPIN therapy including the possible side effects. It should be noted that although serious adverse events may be rare, their occurrence needs to be outweighed by the benefits.

If home use is determined to be desirable by the physician, patients should also be offered instruction for use of injection devices, storage, travelling and other pertinent information. (see CONSUMER INFORMATION, INSTRUCTION FOR USE).

Special Populations

Pregnant Women:
There are no adequate and well controlled studies of GENOTROPIN treatment in pregnant women. Therefore, the safety of GENOTROPIN has not been established in this subpopulation. It is not known whether GENOTROPIN can cause fetal harm when administered to a pregnant woman. GENOTROPIN should be given to a pregnant woman only if the benefits clearly outweigh the risks and only under medical supervision.

Female patients should be advised to inform their doctor if they are, or become pregnant, or are contemplating pregnancy.

Nursing Women:
There is no experimental data available that suggests whether peptide hormones, such as growth hormone, pass over into the breast milk but absorption in the gastrointestinal tract of the infant of intact protein is extremely unlikely.

Obese patients:
Obese individuals are more likely to manifest adverse effects when treated with a weight-based regimen (see DOSAGE AND ADMINISTRATION).

Pediatric Patients: (see INDICATIONS AND CLINICAL USE)

Children who have endocrine disorders, including growth hormone deficiency, may develop slipped capital femoral epiphyses more frequently than children in the general population. Any pediatric patient with onset of a limp during somatropin therapy should be evaluated.

Note: Some of the height gain obtained with somatropin treatment may be lost if treatment is stopped before final height is reached.

Turner Syndrome: see Congenital Disorders.

Idiopathic Short Stature: Other medical reasons or treatments that could explain growth disturbance should be ruled out before starting GENOTROPIN treatment for children with idiopathic short stature. GENOTROPIN treatment for idiopathic short stature should be prescribed only for those patients whose epiphyses are not closed and should be managed by physicians who have sufficient knowledge of idiopathic short stature and the efficacy/safety profile of GENOTROPIN.

Small for Gestational Age: In short children born small for gestational age (SGA) other medical reasons or treatments that could explain growth disturbance should be ruled out before starting treatment with somatropin (GENOTROPIN). Experience with SGA patients with Silver-Russell syndrome is limited, as is experience in initiating treatment in SGA patients near onset of puberty.

In short children born SGA, it is recommended that IGF-I concentration should be measured before initiation of treatment and monitored every 6 months thereafter. If on repeated measurements IGF-I concentrations exceed +2 SD compared to references for age and pubertal status, the IGF-I/IGFBP-3 ratio could be taken into account to consider dose adjustment.

Adult Patients:
Patients with ephiphyseal closure who were treated with somatropin therapy in childhood should be re‑evaluated according to the criteria provided in INDICATIONS AND CLINICAL USE before continuation of somatropin therapy at the reduced dose level required for growth hormone‑deficient adults.

Experience with prolonged treatment in adults is limited. Adverse events such as peripheral edema, myalgia, arthralgia, and paresthesiae have been reported during post‑marketing studies (see ADVERSE REACTIONS).

Growth hormone deficiency in the adult is a lifelong condition and should be treated accordingly. Experience with patients over sixty years of age is limited.

Note: Based on assessment of clinical trial data, post‑marketing data, and spontaneous reports carpal tunnel syndrome appears to occur more frequently in patients over 40 years of age than in younger patients. In almost half of the reported cases the recommended maximum somatropin dose had been exceeded. In the majority of cases, the condition resolved spontaneously or with a decrease in dosage, interruption of treatment, or discontinuation of treatment. The maximum recommended dosage should not be exceeded.

Geriatrics:
The safety and effectiveness of GENOTROPIN in patients aged 65 and over have not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of GENOTROPIN, and therefore may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for older patients.

Monitoring and Laboratory Tests

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

Adults: Adult patients, during GH treatment, should be monitored at 1- to 2-month intervals during dose titration and every 6 months thereafter with clinical assessment, evaluation for adverse effects, IGF-I levels, and other parameters of GH response. Other laboratory testing should include a lipid profile and a fasting glucose. These should be assessed annually.

Patients with an intra- or extra-cranial neoplasm in remission who are receiving treatment with somatropin should be examined carefully and at regular intervals by the physician. In case of persistent edema or severe paraesthesia the dosage should be decreased in order to avoid the development of carpal tunnel syndrome (see ADVERSE REACTIONS).

Children:
Children, during GH treatment, should be monitored every 3 to 6 months with measurement of IGF-1/IGFBP-3 levels and clinical assessment expressed as increase in height (SD per year) and change in height velocity.

Bone age should be monitored periodically during somatropin administration.

Patients with an intra- or extra-cranial neoplasm in remission who are receiving treatment with somatropin should be examined carefully and at regular intervals by the physician.

In short children born SGA, it is recommended that IGF I concentration be measured before initiation of treatment and monitored every 6 months thereafter. If on repeated measurements IGF-I concentrations exceed +2 SD compared to references for age and pubertal status, the IGF-I/IGFBP-3 ratio could be taken into account to consider dose adjustment.

Adverse Drug Reaction Overview

Patients with growth hormone deficiency are characterized by extracellular volume deficit. When treatment with somatropin is started this deficit is rapidly corrected. In adult patients adverse effects related to fluid retention, such as peripheral edema, face edema, stiffness in the extremities, arthralgia, myalgia and paraesthesia are common. In general these adverse effects are mild to moderate, arise within the first months of treatment and subside spontaneously or with dose-reduction. Severe hypersensitivity has been reported in post-marketing use of somatropin products.

The incidence of these adverse effects is related to the administered dose, the age of patients, and possibly inversely related to the age of patients at the onset of growth hormone deficiency. In children such adverse effects are uncommon.

Somatropin has been reported to reduce serum cortisol levels, possibly by affecting carrier proteins or by increased hepatic clearance. The clinical relevance of these findings may be limited. Nevertheless, corticosteroid replacement therapy should be optimised before initiation of GENOTROPIN (somatropin for injection) therapy (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Children

Anti-hGH Antibodies

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to GENOTROPIN with the incidence of antibodies to other products may be misleading. In the case of growth hormone, antibodies with binding capacities lower than 2 mg/mL have not been associated with growth attenuation. In a very small number of patients treated with somatropin, when binding capacity was greater than 2 mg/mL, interference with the growth response was observed.

In 419 pediatric patients evaluated in clinical studies with GENOTROPIN lyophilized powder, 244 had been treated previously with GENOTROPIN 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. Of the remaining 413 patients, eight (1.9%) developed detectable anti-hGH antibodies during treatment with GENOTROPIN; none had an antibody binding capacity > 2 mg/L. There was no evidence that the growth response to GENOTROPIN was affected in these antibody-positive patients.

Clinical Trials in children with GHD
In clinical studies with GENOTROPIN in children, the following events were reported infrequently: injection site reactions, e.g. pain or burning associated with the injection, fibrosis, nodules, rash, inflammation, pigmentation; bleeding; lipoatrophy; headache; hematuria; hypothyroidism; mild hyperglycemia.

Clinical Trials in children with SGA
In clinical studies of 273 pediatric patients born small for gestational age treated with GENOTROPIN, 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. IGF-I levels ranged from <20ng/ml to 593 ng/ml.

Anti-GH antibodies were assessed at baseline, 12 and 24 months in Genotropin-treated SGA children enrolled in study 89-041. At 12 months, the study included 27 untreated SGA children, 59 SGA children treated with Genotropin at a dose of 33 µg/kg body weight/day and 51 short SGA children treated with Genotropin at a dose of 67µg/kg body weight/day. At 24 months, the study included 10 untreated SGA children, 62 short SGA children treated with Genotropin at a dose of 33 µg/kg body weight/day (including 9 children who received no treatment during the first 12 months of the study) and 56 SGA children treated with Genotropin at a dose of 67 µg/kg body weight/day (including 8 children who received no treatment during the first 12 months of the study). None of these patients were determined to be positive for anti-GH antibodies at baseline or at any time during the course of the 24 months of the study.

Less Common Clinical Trial Adverse Drug Reactions (Baseline to Month 12)

Clinical trial adverse drug reactions with a frequency of less than 1% are presented in the following listing:
Skin & Appendage disorders: eczema
Musculoskeletal disorders: bone development abnormal, spine malformation
Central and Peripheral nervous system disorders: ataxia
Psychiatric disorders: aggressive reaction, concentration impaired
Gastrointestinal disorders: abdominal pain, malabsorption
Endocrine disorders: gynaecomastia, puberty precocious
Respiratory disorders: sinusitis
Urinary disorders: dysuria
General disorders: hepatomegaly

Less Common Clinical Trial Adverse Drug Reactions (12 to 24 Month)

Clinical trial adverse drug reactions with a frequency of less than 1% are presented in the following listing:
Skin & Appendage disorders: acne, nail disorder, pruritus, skin dry, sweating increased, urticaria
Musculoskeletal disorders: arthralgia, fracture, spine malformation
Central and Peripheral nervous system disorders: absences, headaches
Vision: conjunctivitis
Hearing and Vestibular system disorders: earache
Gastrointestinal disorders: abdominal pain, anorexia, enteritis
Metabolism and nutritional system disorders: hypoglycemia
Endocrine disorders: puberty precocious
Extra cardiac: vein distended
Respiratory disorders: thyroid adenoma
Red blood cell: anemia
White blood cell: lymphadenopathy
Platelet/bleed disorder: purpura, thrombocytopenia
Urinary disorders: cystitis, urinary tract infection, urogenital malformation
Neoplasm disorder: neoplasm nos
General disorders: accident

Adverse Events Leading to Termination of Treatment

Clinical trial adverse drug reactions that lead to treatment termination are listed below by dose group:
0.033 mg/kg/day: Thrombocytopenic purpura
0.067 mg/kg/day: Aggressive reaction, Ataxia, Retinal dystrophy (2 patients)
Discontinuous therapy: Diabetes mellitus, Surgical intervention, Muscle malformation.

Respiratory Adverse Events in children with SGA
In the open- label SGA studies, the percentage of respiratory adverse events for the 3 active treatment groups (16.2% in 0.033 mg/kg/day, 20.5% in 0.067 mg/kg/day and 26.3% in 0.1 mg/kg/day) were higher than in the untreated group (10.5%) between 0 - 12 months. Between 12 - 24 months, the incidence of respiratory events was also higher in the 3 active treatment groups (18.9% in 0.033 mg/kg/day; 13.6% in 0.067 mg/kg/day; 21.1% in 0.1 mg/kg/day) compared to 7.5% in the untreated control group. Respiratory adverse events included mostly upper respiratory tract infections. Adverse events classified as 'resistance mechanism' which included viral infection, otitis media, and pharyngitis occurred at a higher rate in 2 of the active treatment groups (21.9% in 0.033 mg/kg/day; 19.7% in 0.067 mg/kg/day; 0% in 0.1 mg/kg/day) compared to the untreated control group (15.8%) between 0 - 12 months. Between 12 - 24 months, the incidence of resistance mechanism adverse events was higher in all 3 active treatment groups (25.5% in 0.033 mg/kg/day; 16.1% in 0.067 mg/kg/day; 31.6% in 0.1 mg/kg/day) compared to 13.2% in the untreated control group. However, none of the differences among the four study groups were evaluated for statistical significance.

The adverse events most frequently reported for the study periods were: viral infections, otitis media, pharyngitis, upper respiratory tract infections, and rhinitis. Overall, these events were consistent with the pattern of normal childhood illnesses in this age group. No evidence of a dose-related pattern was apparent. There were a higher number of patients in 2 of the somatropin-treated groups (0.033 mg/kg/day, n=105; 0.067 mg/kg/day, n=117) than in the untreated group (n=76); however the highest dose group (0.1 mg/kg/day) had only 19 patients. While, the investigators did not consider these events to be treatment-related, this cannot be ruled out.

IGF-I levels:

Table 4 summarizes the frequencies of subjects with IGF-I levels below/above or within normal range, organized for all treatment groups side-by-side and across all visits from CTN 89-041 (France). Subject groups Untreated/0.033 mg/kg/wk and Untreated/0.067 mg/kg/wk include subjects who served as untreated controls for 12 months or longer, and were subsequently treated with Genotropin 0.033 mg/kg/wk or 0.067 mg/kg/wk, respectively. In figure 1, the solid reference lines were created by averaging individual upper and lower limits of normal ranges across all subjects with observed IGF-I levels at a given time-point. As such, the reference lines are for overall inference, as they represent an approximation of the exact normative values. As can be seen in the various graphs, IGF-1 levels generally ranged from <20ng/ml to 593 ng/ml.

Clinical Trials in children with Turner Syndrome
In two clinical studies with GENOTROPIN 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. In one study in children with TS, none of the 42 patients discontinued from the study early while in the second study, none of the patients discontinued before 18 months.

Clinical Trials in children with Turner’s syndrome
In one study with patients with TS, respiratory infections (otitis, tonsillitis, sinusitis, influenza, bronchitis) represented the majority of adverse events in children with TS with eight patients in the Genotropin group and 11 patients in the Genotropin and oxandrolone groups. The instances of the respiratory infections were assessed as unrelated to study drug. No patient discontinued treatment due to a treatment related adverse event. Younger patients, including patients with TS, treated or untreated, are known to have generally greater incidence of otitis media and ear problems.

In a second study, one patient experienced sinusitis, orbital cellulitis and grand mal seizure. These events were considered to be unlikely related to the study drug as per the investigator and they were also low in frequency.

Clinical Trials in children with Idiopathic Short Stature
In two open-label clinical studies with GENOTROPIN 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 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.

Study 88-080: Adverse Events Leading to Termination of Treatment

Clinical trial adverse drug reactions that lead to treatment termination are listed below:
Dissociative identity disorder, pituitary cyst, mood swings and irritability.