Nutropin

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Clinical studies and safety

GHD in pubertal patients
One open-label, multicenter, randomized clinical trial of 2 dosages of Nutropin was performed in pubertal patients with GH deficiency.1 Ninety-seven patients (83 male, 14 female, mean age 13.9 years) currently being treated with approximately 0.3 mg/kg/wk of GH were randomized to 0.3 mg/kg/wk or 0.7 mg/kg/wk Nutropin doses. All patients were already in puberty (Tanner stage >2) and had bone ages <14 years in males or <12 years in females. Mean baseline height standard deviation (SD) score was –1.3.

The mean last measured height in all 97 patients after a mean duration of 2.7 ± 1.2 years, by analysis of covariance (ANCOVA) adjusting for baseline height, is shown below.

The mean height SD score at last measured height (n = 97) was –0.7 ± 1.0 in the 0.3 mg/kg/wk group and –0.1 ± 1.2 in the 0.7 mg/kg/wk group. For patients completing 3.5 or more years (mean 4.1 years) of Nutropin treatment (15/49 patients in the 0.3 mg/kg/wk group and 16/48 patients in the 0.7 mg/kg/wk group), the mean last measured height was 166.1 ± 8.0 cm in the 0.3 mg/kg/wk group and 171.8 ± 7.1 cm in the 0.7 mg/kg/wk group, adjusting for baseline height and sex.

The mean change in bone age was approximately one year for each year in the study in both dose groups. Patients with baseline height SD scores above –1.0 were able to attain normal adult heights with the 0.3 mg/kg/wk dose of Nutropin (mean height SD score at near-adult height = –0.1, n = 15).

Thirty-one patients had bone mineral density (BMD) determined by dual energy X-ray absorptiometry (DEXA) scans at study conclusion. The 2 dose groups did not differ significantly in mean SD score for total body BMD (–0.9 ± 1.9 in the 0.3 mg/kg/wk group vs –0.8 ± 1.2 in the 0.7 mg/kg/wk group, n = 20) or lumbar spine BMD (–1.0 ± 1.0 in the 0.3 mg/kg/wk group vs –0.2 ± 1.7 in the 0.7 mg/kg/wk group, n = 21).

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 values is unknown.

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Idiopathic short stature
In a long-term open-label study, children with ISS treated with Nutropin therapy (2-10 years) showed an increase in adult height above pretreatment predictions.

Of the 118 subjects who were treated with Nutropin therapy in this study, 70% (n=83) reached near-adult height. Adult height was greater than pretreatment predicted adult height in 49 of 60 males (82%) and 19 of 23 females (83%).

The mean difference between predicted and achieved adult height for children treated with Nutropin therapy was 5.2 cm (2.0 inches) for males, 6.0 cm (2.4 inches) for females (p<0.0001 for both).

This resulted in a mean adult height SD score of –1.5±0.8 for males and –1.6±0.7 for females.

Mean fasting and postprandial insulin levels increased, while mean fasting and postprandial glucose levels were unchanged. Mean hemoglobin A_1c levels rose slightly from baseline as expected during adolescence. Sporadic values outside normal limits occurred transiently.

In a post-marketing surveillance study, the National Cooperative Growth Study, the pattern of adverse events in over 8000 patients with idiopathic short stature was consistent with the known safety profile of GH, and no new safety signals attributable to GH were identified. The frequency of protocol-defined targeted adverse events is described in the table here.

Chronic renal insufficiency
Two multicenter, randomized, controlled clinical trials were conducted to determine whether treatment with Nutropin prior to renal transplantation in children with chronic renal insufficiency could improve their growth rates and height deficits. One study was a double-blind, placebo-controlled trial, and the other was an open-label, randomized trial. The dose of Nutropin in both controlled studies was 0.05 mg/kg/d (0.35 mg/kg/wk) administered daily by subcutaneous injection. Combining the data from those patients completing 2 years in the two controlled studies results in 62 children treated with Nutropin and 28 children in the control groups (either placebo-treated or untreated). The mean first-year growth rate was 10.8 cm/yr for the Nutropin-treated patients, compared with a mean growth rate of 6.5 cm/yr for placebo/untreated controls (p<0.00005). The mean second-year growth rate was 7.8 cm/yr for the Nutropin-treated group, compared with 5.5 cm/yr for controls (p<0.00005). There was a significant increase in mean height standard deviation score in the Nutropin group (–2.9 at baseline to –1.5 at Month 24, n = 62), but no significant change in the controls (–2.8 at baseline to –2.9 at Month 24, n = 28). The mean third-year growth rate of 7.6 cm/yr in the patients treated with Nutropin (n = 27) suggests that Nutropin stimulates growth beyond 2 years; however, there are no control data for the third year because control patients crossed over to GH treatment after 2 years of participation. The gains in height were accompanied by appropriate advancement of skeletal age—one year for each year in the study.1

Five years of treatment with Nutropin in 20 children with growth failure due to chronic renal insufficiency produced a significant (p<0.00005) improvement in standardized height (from –2.6 at baseline to –0.7 following 5 years of treatment).2 Although predicted final height was improved during Nutropin therapy, the effect of Nutropin on final adult height remains to be determined.1

These data demonstrate that Nutropin therapy improves growth rate and helps correct the acquired height deficit associated with chronic renal insufficiency.

Precautions
Patients with growth failure secondary to chronic renal insufficiency 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. Physicians and parents should be alert to the development of a limp or complaints of hip or knee pain in patients treated with Nutropin.

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with GH products. Symptoms usually occurred within the first 8 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. Patients with chronic renal insufficiency and Turner syndrome may be at increased risk for development of IH.1

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Turner syndrome1
To evaluate the efficacy of GH for the treatment of girls with short stature due to Turner syndrome, the following studies were conducted:

• One long-term, randomized, open-label, multicenter, concurrently controlled study
• Two long-term, open-label, multicenter, historically controlled studies
• One long-term, randomized dose-response study

In the randomized study GDCT, which compared GH-treated patients with a concurrent control group who received no GH, the GH-treated patients who received a dose of 0.3 mg/kg/wk given 6 times per week from a mean age of 11.7 years for a mean duration of 4.7 years attained a mean near-final height of 146.0 cm (n = 27), while the control group attained a near-final height of 142.1 cm (n = 19). By analysis of covariance, the effect of GH therapy was a mean height increase of 5.4 cm (p = 0.001).

In 2 of the studies (85-023 and 85-044), the effect of long-term GH treatment (0.375 mg/kg/wk given either 3 times per week or daily) on adult height was determined by comparing adult heights in the treated patients with those of age-matched historical controls with Turner syndrome who never received any growth-promoting therapy. In Study 85-023, estrogen treatment was delayed until patients were at least age 14 years. GH therapy resulted in a mean adult height gain of 7.4 cm (mean duration of GH therapy of 7.6 years) vs matched historical controls by analysis of covariance.

In Study 85-044, patients treated early with GH therapy were randomized to receive estrogen-replacement therapy (conjugated estrogens, 0.3 mg escalating to 0.625 mg daily) at either age 12 or 15 years. Compared with matched historical controls, early GH therapy (mean duration of GH therapy 5.6 years) combined with estrogen replacement at age 12 years resulted in an adult height gain of 5.9 cm (n = 26), whereas girls who initiated estrogen at age 15 years (mean duration of GH therapy 6.1 years) had a mean adult height gain of 8.3 cm (n = 29). Patients who initiated GH therapy after age 11 (mean age 12.7 years; mean duration of GH therapy 3.8 years) had a mean adult height gain of 5.0 cm (n = 51).

Thus, in both studies 85-023 and 85-044, the greatest improvement in adult height was observed in patients who received early GH treatment and estrogen after age 14 years.

In the randomized, blinded dose-response study GDCI, patients were treated from a mean age of 11.1 years for a mean duration of 5.3 years with a weekly GH dose of either 0.27 mg/kg or 0.36 mg/kg administered 3 or 6 times weekly. The mean near-final height of patients receiving GH was 148.7 cm (n = 31). This represents a mean gain in adult height of approximately 5 cm compared with previous observations of untreated Turner syndrome girls.

In these studies, Turner syndrome patients (n = 181) treated to final adult height achieved statistically significant gains in average estimated adult height gains ranging from 5.0 to 8.3 cm.

Skeletal abnormalities including scoliosis are commonly seen in untreated Turner syndrome patients. Physicians should be alert to these abnormalities, which may manifest during GH therapy.

Precautions
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. In a randomized, controlled trial, there was a statistically significant increase, as compared with untreated controls, in otitis media (43% vs 26%) and ear disorders (18% vs 5%) in patients receiving GH. In addition, patients with Turner syndrome should be monitored closely for cardiovascular disorders (eg, stroke, aortic aneurysm, hypertension), as these patients are also at risk for these conditions.

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. Physicians should be alert to these abnormalities which may manifest during GH therapy.

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with GH products. Symptoms usually occurred within the first 8 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. Patients with chronic renal insufficiency and Turner syndrome may be at increased risk for development of IH.

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Adult GH deficiency
Body composition and lipid profile data
Two multicenter, double-blind, placebo-controlled trials were performed to assess the effects of Nutropin therapy on body composition and lipids in adults with GH deficiency (AGHD).

One study was conducted in patients with adult-onset AGHD at doses of 0.0125 or 0.00625 mg/kg/d. The 0.025 mg/kg/d dose was not tolerated by the adult-onset AGHD patients. A second study examined patients with childhood-onset AGHD who had previously been treated with GH during childhood and received doses of either 0.0125 mg/kg/d or 0.025 mg/kg/d.

Body composition results

Lipid profile results
In the adult-onset AGHD study, significant decreases from baseline to Month 12 in mean LDL cholesterol and LDL:HDL ratio were seen in the Nutropin group compared with the placebo group (p<0.02). There were no statistically significant between-group differences in change from baseline to Month 12 in mean total cholesterol, HDL cholesterol, or triglycerides.1

In the childhood-onset AGHD study, significant decreases from baseline to Month 12 in mean total cholesterol, LDL cholesterol, and LDL:HDL ratio were seen in the high-dose Nutropin group only, compared with the placebo group (p<0.05). There were no statistically significant between-group differences in mean HDL cholesterol or triglycerides from baseline to Month 12.1

Bone mineral density (BMD) data
An additional objective of the AGHD studies was to determine the effects of prolonged Nutropin treatment on BMD in childhood-onset AGHD and adult-onset AGHD.

The childhood-onset AGHD study was a multicenter, randomized, placebo-controlled, double-blind trial in young adults with GH deficiency who had previously received GH but who had not received treatment for at least one year prior to enrollment. A total of 64 patients were enrolled and were randomized to one of the following 3 treatment groups and maintained on the assigned regimen for 24 months: 0.025 mg/kg/d of Nutropin by subcutaneous injection; 0.0125 mg/kg/d of Nutropin by subcutaneous injection; or placebo by subcutaneous injection.

Childhood-onset AGHD patients treated for one year with the higher dose of Nutropin (0.025 mg/kg/d) showed significant improvement in spine BMD percent change from baseline compared with placebo at 24 months (4.6 % vs 1.07%) and no significant improvement in total body BMD compared with those receiving placebo.1

Adult-onset AGHD patients who were treated for one year with the lower dose of Nutropin (0.0125 mg/kg/d) for one year showed no significant improvement in BMD parameters measured compared with those receiving placebo.1 The 0.025 mg/kg/d dose was not tolerated by these patients.

Precautions/adverse events
Nutropin therapy in adults with GHD of adult onset was associated with an increase of median fasting insulin in the Nutropin 0.0125 mg/kg/day group from 9.0 μU/mL at baseline to 13.0 μU/mL at Month 12 with a return to the baseline median after a 3-week post-washout period off GH therapy. In the placebo group there was no change from 8.0 μU/mL at baseline to Month 12, and after the post-washout the median was 9.0 μU/mL. The between-treatment-groups difference in change from baseline to Month 12 was significant, p<0.0001. In childhood-onset subjects, there was a change of median fasting insulin in the Nutropin 0.025 mg/kg/day group from 11.0 μU/mL at baseline to 20.0 μU/mL at Month 12, in the Nutropin 0.0125 mg/kg/day group from 8.5 μU/mL to 11.0 μU/mL, and in the placebo group from 7.0 μU/mL to 8.0 μU/mL. The between-treatment-groups difference for these changes was significant, p=0.0007.

In subjects with adult-onset GHD, there was no between-treatment-group difference in changes from baseline to Month 12 in mean HbAIc, p=0.08. In childhood-onset, mean HbAIc increased in the Nutropin 0.025 mg/kg/day group from 5.2% at baseline to 5.5% at Month 12, and did not change in the Nutropin 0.0125 mg/kg/day group from 5.1% at baseline or in the placebo group from 5.3% at baseline. The between-treatment-groups difference was significant, p=0.009.

Patients with a history of an intracranial lesion should be examined frequently for progression or recurrence of the lesion. In pediatric patients, clinical literature has demonstrated no relationship between GH-replacement therapy and CNS tumor recurrence or new extracranial tumors. In adults, it is unknown whether there is any relationship between GH-replacement therapy and CNS tumor recurrence.

Experience with prolonged GH treatment in adults is limited.

Nutropin should be given to a pregnant woman only if clearly needed, and caution should be exercised when administered to a nursing mother.

Adverse events frequently reported in adult patients were edema (41%) and arthralgias and other joint disorders (27%). Thirty-five percent of childhood-onset adult GH-deficient subjects treated with GH 0.025 mg/kg/day for 2 years had supraphysiologic 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.

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Adult GH deficiency

• It is recommended that treatment be initiated at not more than 0.006 mg/kg/d subcutaneously injected, and may be increased to meet individual patient requirements up to a maximum of 0.025 mg/kg/d in patients under 35 years, and a maximum of 0.0125 mg/kg/d in patients over 35 years
• Dosage can be increased gradually to the recommended maximum based on clinical and biochemical response
• Sensitivity to GH treatment varies considerably among individuals
• Adults require considerably less GH than children
• Lower doses may be necessary to minimize the occurrence of adverse events in older or overweight patients
• During therapy, dosage should be decreased if required by the occurrence of side effects or excessive IGF-I levels

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References

1. Nutropin prescribing information [package insert]. South San Francisco, Calif: Genentech Inc; Jan 2004.
    
2. Fine RN, Kohaut E, Brown D, Kuntze J, Attie KM. Long-term treatment of growth retarded children with chronic renal insufficiency, with recombinant human growth hormone. Kidney Int. 1996;49:781-785.
    
3. Amato G, Carella C, Fazio S, et al. Body composition, bone metabolism, and heart structure and function in growth hormone (GH)-deficient adults before and after GH replacement therapy at low doses. J Clin Endocrinol Metab. 1993;77:1671-1676.
    
4. Rosen T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet. 1990;336:285-288.
    
5. Rosen T, Eden S, Larson G, Wilhelmsen L, Bengtsson BA. Cardiovascular risk factors in adult patients with growth hormone deficiency. Acta Endocrinol. 1993;129:195-200.
    
6. Bates AS, Van't Hoff W, Jones PJ, Clayton RN. The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab. 1996;81:1169-1172.
    
7. Underwood LE, Attie KM, Baptista J, Genentech Collaborative Study Group. Growth hormone (GH) dose-response in young adults with childhood-onset GH deficiency: A two-year, multicenter, multiple-dose, placebo-controlled study. J Clin Endocrinol Metab. 2003;88: 5273–5280.