Professional Viewpoints
Growth Failure Related to Chronic Kidney Disease*
with Dr. John D. Mahan and Dr. Bradley A. Warady
These videos (requires Macromedia Flash Player 7) provide education around the need for growth hormone therapy in CRI patients with growth failure. Doctors John Mahan and Bradley Warady have been working with children with CKD for more than 25 years and have devoted much of their energy toward developing guidelines on how to assess, treat and monitor those patients.
*Growth hormone indicated for CRI patients only, i.e. patients with GFR <75 mL/min/1.73m2
Please See Indications and Important Safety Information
INDICATIONS
Pediatric Patients
Nutropin AQ and Nutropin are indicated for the long-term treatment of growth failure due to a lack of adequate endogenous GH secretion.
Nutropin AQ and Nutropin are also indicated for the treatment of growth failure associated with chronic renal insufficiency up to the time of renal transplantation. Nutropin AQ and Nutropin therapy should be used in conjunction with optimal management of chronic renal insufficiency.
Nutropin AQ and Nutropin are also indicated for the long-term treatment of short stature associated with Turner syndrome.
Nutropin AQ and Nutropin are also indicated for the long-term treatment of idiopathic short stature, also called non-growth hormone-deficient short stature, defined by height 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
Nutropin AQ and Nutropin are 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.
In general, confirmation of the diagnosis of adult growth hormone deficiency in both groups usually requires an appropriate growth hormone stimulation test. However, confirmatory growth hormone stimulation testing may not be required in patients with congenital/genetic growth hormone deficiency or multiple pituitary hormone deficiencies due to organic disease.
Important Safety Information
Contraindications
Growth hormone (GH) should not be used for growth promotion in pediatric patients with closed epiphyses.
GH should not be used in patients with active proliferative or severe non-proliferative diabetic retinopathy.
In general, GH should not be used in patients with active malignancy. Any pre-existing malignancy should be inactive and its treatment complete prior to instituting therapy with growth hormone. GH therapy should be discontinued if there is evidence of recurring activity. GH should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor.
GH should not be used to treat patients with acute critical illness due to complications following open heart surgery, abdominal surgery, or multiple accidental trauma, or those with acute respiratory failure.
GH is contraindicated in patients with Prader-Willi syndrome who are severely obese or have severe respiratory impairment (see WARNINGS in full prescribing information). Unless patients with Prader-Willi syndrome also have a diagnosis of GH deficiency, Nutropin AQ and Nutropin are not indicated for the long-term treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.
Nutropin, when reconstituted with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved), should not be used in patients with a known sensitivity to benzyl alcohol.
Warnings
Benzyl alcohol as a preservative in Bacteriostatic Water for Injection, USP, has been associated with toxicity in newborns. When administering Nutropin to newborns, reconstitute with Sterile Water for Injection, USP. USE ONLY ONE DOSE PER NUTROPIN VIAL AND DISCARD THE UNUSED PORTION.
Precautions
General
Nutropin AQ and Nutropin should be prescribed by physicians experienced in the diagnosis and management of patients with pediatric GH deficiency, adult GH deficiency, Turner syndrome, or chronic renal insufficiency.
Because treatment with GH may reduce insulin sensitivity, patients should be monitored for signs of glucose intolerance. For patient with diabetes mellitus or impaired glucose tolerance, antihyperglycemic drug (i.e. insulin or oral agents) dosage may require adjustment when somatropin therapy is instituted.
Patients with a history of an intracranial lesion should be examined frequently for progression or recurrence of the lesion. In childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients treated with GH after the 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.
Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a smaller number of patients treated with GH products. Symptoms usually occurred within the first weeks of the initiation of GH therapy. In all reported cases, IH-associated signs and symptoms resolved after termination of therapy or a reduction of the GH dose. Funduscopic examination of patients is recommended at the initiation and periodically during the course of GH therapy. If papilledema is observed by funduscopy during GH treatment, treatment should be stopped. If GH -induced IH is diagnosed, treatment with GH can be restarted at a lower dose after IH-associated signs and symptoms have resolved. Patients with Turner syndrome and CRI patients may be at increased risk for development of IH.
In patients with hypopituitarism (multiple hormone deficiencies), standard hormonal replacement therapy should be monitored closely when GH therapy is administered. Special attention should be paid to the evaluation of the integrity of the hypothalamic-pituitary-adrenal axis.
Undiagnosed, untreated hypothyroidism may prevent an optimal response to GH . Patients with Turner syndrome have an inherently increased risk for developing autoimmune thyroid disease and primary hypothyroidism. In patients with growth hormone deficiency, central (secondary) hypothyroidism may first become evident or worsen during growth hormone treatment. Therefore, patients treated with GH should have periodic thyroid function tests and thyroid replacement therapy should be initiated or appropriately adjusted when indicated.
Patients should be monitored carefully for any malignant transformation of skin lesions.
When GH 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.
As with any protein, local or systemic allergic reactions may occur. Prompt medical attention should be sought if allergic reactions occur.
Pediatric Patients
Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders or in patients undergoing rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during GH therapy should be carefully evaluated
Children with growth failure secondary to CRI should be examined periodically for evidence of progression of renal osteodystrophy. Slipped capital femoral epiphysis or avascular necrosis of the femoral head may be seen in children with advanced renal osteodystrophy, and it is uncertain whether these problems are affected by GH therapy. X-rays of the hip should be obtained prior to initiating GH therapy for CRI patients.
Progression of scoliosis can occur in patients who experience rapid growth. Because GH increases growth rate, patients with a history of scoliosis who are treated with GH should be monitored for progression of scoliosis. GH has not been shown to increase the incidence 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 GH therapy.
Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear or hearing disorders.
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.
Adult Patients
Fluid retention during GH replacement therapy in adults may occur. Clinical manifestations of fluid retention are usually transient and dose dependent.
Experience with prolonged rhGH treatment in adults is limited.
Drug Interactions
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 GH , 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.
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.
The use of Nutropin AQ and Nutropin in patients with CRI receiving glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit growth-promoting effect of Nutropin AQ or Nutropin.
Limited published data indicate that somatropin treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. Careful monitoring is advisable when GH is given in any combination with agents metabolized by CP450 liver enzymes.
In adult women on oral estrogen replacement, a larger dose of somatropin may be required to achieve the defined treatment goal.
Carcinogenicity, mutagenicity, and reproduction studies have not been conducted with Nutropin AQ or Nutropin.
*Consideration for transition pieces to be reviewed on a case-by-case basis.
GH should be given to a pregnant woman only if clearly needed, and caution should be exercised when administered to a nursing mother.
Additional Safety Information
In a clinical trial of pubertal patients who were treated with Nutropin over a mean duration of 2.7 years, patients in the 0.7 mg/kg/wk group were more likely to have IGF-I values above the normal range than patients in the 0.3 mg/kg/wk group (27.7% vs. 9.0% of IGF-I measurements for individual patients). The clinical significance of elevated IGF-I levels is unknown.
Thirty-five percent of childhood-onset adult AGHD subjects treated with GH [0.025 mg/kg/d] for two years had supraphysiological levels of insulin-like growth factor-I (IGF-I) at some time during the study, which may carry unknown risks. During therapy, dosage should be decreased if required by the occurrence of side effects or excessive IGF-I levels.
Other adverse drug reactions that have been reported in GH-treated patients include the following:
1) Metabolic: mild, transient peripheral edema. In GHD adults, edema or peripheral edema was reported in 41% of GH-treated patients and 25% of placebo-treated patients; 2) Musculoskeletal: arthralgias; carpal tunnel syndrome. In GHD adults, arthralgias and other joint disorders were reported in 27% of GH-treated patients and 15% of placebo-treated patients; 3) Skin: rare increased growth of pre-existing nevi; patients should be monitored for malignant transformation; and 4) Endocrine: gynecomastia. Rare pancreatitis.
