Committed to patients with short stature associated with Noonan syndrome

Norditropin^® is the first and only growth hormone therapy FDA-approved for the treatment of children with short stature associated with Noonan syndrome¹

Height velocity during first two years of treatment and mean HSDS over time

^a The mean HSDS of participants was compared with the national reference.
^b Dose was adjusted after two years to either 0.066 mg/kg/d or 0.033 mg/kg/d based on growth response.
^c Final height was considered attained when the height velocity of a participant was less than 1 cm/y in the previous year.³

A prospective, open-label, randomized, parallel-group trial with 21 children was conducted for two years to evaluate the efficacy and safety of Norditropin^® treatment for short stature in children with Noonan syndrome. An additional six children were not randomized, but did follow the treatment protocol. This trial was followed by a retrospective data collection from 18 of the 21 subjects treated with Norditropin^® until adult height who were originally enrolled in the trial, and from the six children who had followed the protocol without randomization. Historical reference materials of height velocity and adult height analyses of patients with Noonan syndrome served as controls.¹

Not all patients with Noonan syndrome have short stature. Some patients will achieve a normal adult height without treatment. Prior to initiating treatment with Norditropin^®, establish that the patient does have short stature.

Norditropin^® increased height velocity during the first two years.²
Dosages of 0.033 mg/kg/d and 0.066 mg/kg/d proved effective.¹
A clinically relevant mean height gain of +1.5 SDS (-3 at baseline, -1.5 at adult height) was observed.¹
Norditropin^® has been shown to be an effective therapy for short stature associated with Noonan syndrome
A greater initial change was seen when treatment began at a younger age.¹ A correlation between age at treatment start and adult height was not observed.

Growth hormone therapy for the treatment of children with short stature associated with Noonan syndrome

Up to 83% of children diagnosed with Noonan syndrome are affected by short stature.^3,4 Patients with Noonan syndrome at birth are usually within the normal ranges for weight, length, and growth hormone serum levels, however puberty and its associated growth spurt may be absent or delayed. Bone age may also be delayed.⁴ Short stature may be due to insufficient growth hormone in patients with Noonan syndrome, in which case growth hormone therapy may provide a treatment option.

Long-term growth hormone treatment with Norditropin^® has been shown to improve final height in patients with Noonan syndrome.¹ A prospective, open label, randomized, parallel group trial with 21 children was conducted for 2 years to evaluate the efficacy and safety of Norditropin^® treatment for short stature in children with Noonan syndrome. Patients obtained a final height (FH) gain from baseline of 1.5 and 1.6 SDS estimated according to the national and the Noonan reference, respectively.¹

Norditropin^® is the first and only growth hormone therapy indicated for the treatment of children with short stature associated with Noonan syndrome.

References

Norditropin^® cartridges [prescribing information]. Princeton, NJ: Novo Nordisk Inc; 2010.
Data on file. Trial ID: GHNOO-1658. Individual Efficacy Response Data. Princeton, NJ: Novo Nordisk Inc; 2006.
Osio D, Dahlgren J, Wikland KA, Westphal O. Improved final height with long-term growth hormone treatment in Noonan syndrome. Acta Paediatr. 2005:94:1232-1237.
van der Burgt I. Noonan syndrome [review]. Orphanet J Rare Dis. 2007;2(4):1-6.

Indications and Usage:

Norditropin® (somatropin [rDNA origin] injection) is indicated for the treatment of pediatric patients with growth failure due to inadequate secretion of endogenous growth hormone, the treatment of pediatric patients with short stature associated with Noonan syndrome or Turner syndrome, the treatment of pediatric patients with short stature born small for gestational age (SGA) with no catch-up growth by age 2 to 4 years, and for the replacement of endogenous growth hormone in adults with growth hormone deficiency (GHD) who meet either of the following two criteria: 1. Adult Onset: Patients who have GHD, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or 2. Childhood Onset: Patients who were growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes.

Important Safety Information:

Somatropin should not be used to treat patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or acute respiratory failure as increased mortality may occur.

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. Norditropin® is not indicated for the treatment of patients who have growth failure due to genetically confirmed Prader-Willi syndrome.

Somatropin should not be used or should be discontinued with any evidence 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. Patients with preexisting tumors or GHD secondary to an intracranial lesion should be monitored routinely for progression or recurrence. In childhood cancer survivors, an increased risk of a second neoplasm, particularly meningiomas in patients treated with radiation to the head for their first neoplasm, has been reported in patients treated with somatropin.

Somatropin should not be used in patients with active proliferative or severe non-proliferative diabetic retinopathy, for growth promotion in pediatric patients with closed epiphyses, or in patients with known hypersensitivity to somatropin or any of its excipients.

Somatropin may decrease insulin sensitivity particularly at higher doses in susceptible patients. Glucose levels should be monitored periodically, including close monitoring of patients with preexisting diabetes or glucose intolerance. New onset of Type 2 Diabetes Mellitus has been reported. Doses of anti-hyperglycemic drugs (insulin, oral, or injectable agents) may require adjustment for patients with diabetes on somatropin therapy.

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting, usually occurring within the first eight (8) weeks after initiation of somatropin therapy, has been reported in a small number of patients. In all reported cases, rapid resolution has occurred after therapy cessation or a reduction of dose. Funduscopic examination should be performed routinely before and during somatropin therapy. If papilledema is observed, somatropin treatment should be discontinued.

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

In patients with GHD, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Periodic thyroid function tests are recommended and thyroid hormone replacement therapy should be initiated or adjusted as needed.

Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including GHD and Turner syndrome) or with rapid growth. Onset of a limp or complaints of hip or knee pain in somatropin patients should be carefully evaluated. Rapid growth may also result in progression of preexisting scoliosis. Patients with a history of scoliosis or skeletal abnormalities, which may be present in untreated Noonan, Turner or Prader-Willi syndrome, should be monitored.

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. Somatropin may also increase the risk of IH in Turner patients. 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.

Congenital heart disease is an inherent component of Noonan syndrome. Though a clinical study in Noonan syndrome reported no evidence of somatropin-induced ventricular hypertrophy or exacerbation of preexisting ventricular hypertrophy (as judged by echocardiography), the safety of Norditropin® in children with Noonan syndrome and significant cardiac disease is not known.

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. Girls who have Turner syndrome may be at greater risk than other somatropin-treated children. Pancreatitis should be considered in any somatropin-treated patient, especially a child, who develops persistent severe abdominal pain.

Other somatropin-related adverse reactions include injection site reactions/rashes, lipoatrophy and headaches. Subcutaneous injection of somatropin at the same site repeatedly may result in tissue atrophy and can be avoided by rotating the injection site.

Somatropin inhibits 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD-1) in adipose/hepatic tissue, and may significantly impact the metabolism of cortisol and cortisone. 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, especially with cortisone acetate and prednisone, for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses.

Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine) as limited published data suggest somatropin may alter clearance of these compounds.

Because oral estrogen may reduce IGF-1 response to somatropin treatment, girls and women on oral estrogen replacement may require greater doses of somatropin.

The safety and effectiveness of Norditropin® in patients age 65 years and older has not been evaluated in clinical studies. Elderly patients may be more sensitive to the actions of somatropin and may be more prone to develop adverse reactions.

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Noonan syndrome clinical data

Committed to patients with short stature associated with Noonan syndrome

Norditropin® is the first and only growth hormone therapy FDA-approved for the treatment of children with short stature associated with Noonan syndrome1

Growth hormone therapy for the treatment of children with short stature associated with Noonan syndrome

Indications and Usage:

Important Safety Information:

EDUCATIONAL CONTENT

Norditropin^® is the first and only growth hormone therapy FDA-approved for the treatment of children with short stature associated with Noonan syndrome¹