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Valtropin

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Valtropin

CLINICAL PHARMACOLOGY

General

In vitro, pre-clinical and clinical testing have demonstrated that somatropin is therapeutically equivalent to pituitary-derived human growth hormone (pit-hGH). Clinical studies in normal adults also demonstrate equivalent pharmacokinetics.

a. Tissue Growth

The primary and most intensively studied action of somatropin is the stimulation of linear growth. This effect is demonstrated in children with somatropin deficiency.

  1. Skeletal growth - the measurable increase in bone length after administration of somatropin results from its effect on the cartilaginous growth areas of long bones. Studies in vitro have shown that the incorporation of sulfate into proteoglycans is not due to a direct effect of somatropin, but rather is mediated by the somatomedins or insulin-like growth factors (IGF). The somatomedins, among them IGF-1, are polypeptide hormones which are synthesized in the liver, kidney, and various other tissues. IGF-1 levels are low in the serum of growth hormone deficient children with short stature and hypophysectomized humans or animals, but its presence can be demonstrated after treatment with somatropin.
  2. Cell growth - it has been shown that the total number of skeletal muscle cells is markedly decreased in children with short stature lacking endogenous growth hormone compared with normal children, and that treatment with somatropin results in an increase in both the number and size of muscle cells.
  3. Organ growth - somatropin influences the size of internal organs, and it also increases red cell mass.
b. Protein Metabolism

Linear growth is facilitated in part by increased cellular protein synthesis. This synthesis and growth are reflected by nitrogen retention, which can be quantitated by observing the decline in urinary nitrogen excretion and blood urea nitrogen following the initiation of somatropin therapy.

c. Carbohydrate Metabolism

Hypopituitary children sometimes experience fasting hypoglycemia that may be improved by treatment with somatropin. In healthy subjects, large doses of somatropin may impair glucose tolerance. Although the precise mechanism of the diabetogenic effect of somatropin is not known, it is attributed to blocking the action of insulin rather than blocking insulin secretion. Insulin levels in serum actually increase as somatropin levels increase. Administration of somatropin to normal adults and patients with growth hormone deficiency (GHD) results in increases in mean serum fasting and postprandial insulin levels, although mean values remain in the normal range. In addition, mean fasting and postprandial glucose and hemoglobin A1C levels remain in the normal range.

d. Lipid Metabolism

Somatropin stimulates intracellular lipolysis, and administration of somatropin leads to an increase in plasma free fatty acids and triglycerides. Untreated GHD is associated with increased body fat stores, including increased subcutaneous and visceral adipose tissue in the abdomen. Treatment of growth hormone deficient patients with somatropin results in a general reduction of fat stores, in particular in subcutaneous and visceral abdominal tissue and decreased serum levels of low-density lipoprotein (LDL) cholesterol.

e. Mineral Metabolism

Administration of somatropin results in the retention of total body potassium and phosphorus, and to a lesser extent sodium. This retention is thought to be the result of cell growth. Serum levels of phosphate increase in patients with GHD after somatropin therapy due to metabolic activity associated with bone growth. Serum calcium levels are not altered. Although calcium excretion in the urine is increased, there is a simultaneous increase in calcium absorption from the intestine. Negative calcium balance, however, may occasionally occur during somatropin treatment.

f. Connective Tissue Metabolism

Somatropin stimulates the synthesis of chondroitin sulfate and collagen as well as the urinary excretion of hydroxyproline.

Pharmacokinetics

In a single dose study in 24 healthy volunteers, subcutaneous administration of 0.073 mg/kg of body weight of Valtropin (somatropin injection) ® resulted in a mean maximum serum concentration (Cmax) of 43.97 ng/mL and an area under the curve (AUC0-24h) of 369.90 ng·hr/mL. Cmax was reached at 4.00 hr and terminal elimination half-life was 3.03 hr.

The metabolic fate of somatropin involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products is returned to the systemic circulation.

Special Populations

Pediatric - The pharmacokinetics of somatropin is similar in children and adults.

Geriatric - The pharmacokinetic properties of somatropin have not been studied in patients greater than 60 years of age.

Gender - No gender studies have been performed.

Race - No race studies have been performed.

Renal Insufficiency - No studies have been performed in patients with renal insufficiency.

Hepatic Insufficiency - No studies have been performed in patients with hepatic insufficiency.

Clinical Trials

Pediatric Patients With Growth Hormone Deficiency (GHD)

A one-year, multicenter, multinational, randomized, double-blind, parallel-group, active- controlled study was conducted in treatment-naive children with GHD and short stature comparing the linear growth effect of Valtropin (somatropin injection) ® with another approved formulation of somatropin. All patients were treated with somatropin 0.033 mg/kg/day administered subcutaneously (SC). One hundred and forty nine children were randomized in a 2:1 ratio to receive Valtropin (somatropin injection) ® (n=99) or the active control (n=50). Combining both treatment groups, mean age was 8.2, 60-70% of patients were male, ~95% were Caucasian, baseline height standard deviation score for chronological age (height SDSCA) was -3.43, and pre-treatment height velocity (HV) was 3.34 cm/yr. These demographic and baseline characteristics were similar in the two treatment groups.

Greater than 90% of patients completed the study. The results presented below were obtained from the intent-to-treat (ITT) population (which excluded patients whose height had not been measured with the appropriate stadiometer, who discontinued before 6 months on treatment or whose pre-treatment HV was incomplete) with last observation carried forward (LOCF); and consisted of 88 patients in the Valtropin (somatropin injection) ® group and 41 patients in the active control group.

As seen in Table 1, the adjusted mean HV ± SE at 12 months was 11.21 ± 0.23 cm/year in the Valtropin (somatropin injection) ® group versus 11.00 ± 0.32 cm/year in the active control group, and the mean treatment difference was 0.21. Therefore, Valtropin (somatropin injection) ® was non-inferior to the active control.

Table 1
Difference Between Groups in Height Velocity (Cm/Yr) at Month 12
in a Double Blind Study in Pediatric Patients with GHD


ITT population with LOCF Valtropin® Comparator
Raw Mean SD (n) at Baseline 3.50 1.45 (88) 3.39 1.02 (41)
Raw Mean SD (n) at Month 12 11.36 2.92 (88) 10.54 2.61 (41)
Adjusted Mean SE* (n) at Month 12 11.21 0.23 (88) 11.00 0.32 (41)
Treatment Difference (Adjusted Mean)*
(95% CI)**
0.21 (-0.48, 0.90)
*Adjusted least-squares means were obtained using an ANCOVA model, where treatment and country were the fixed factors and baseline HV, CA, and log maximum GH level after stimulation were the covariates. **Confidence Intervals

The within-group changes from baseline to Month 12 for the Valtropin (somatropin injection) ® group only for HV, HV SDSCA, height SDSCA, and predicted adult height (PAH) by the Bayley-Pinneau (B-P) method expressed both in cm and as a SDS are displayed in Table 2. All within-group changes were significant. The 1.21 unit change in height SDSCA and the 8.05 unit change in HV SDSCA are robust and indicate substantial catch-up growth. The results observed in the active control group were similar.

Table 2
Valtropin (somatropin injection) ® Group Only
Within-Group Change from Baseline to Month 12
in Height Velocity and Other Auxological Secondary Efficacy Endpoints


ITT with LOCF
Efficacy Variable
Valtropin®: Mean SD (n) Mean Change from Baseline (95% CI)
Baseline Month 12
HV (cm/year) 3.50 1.45 (88) 11.36 2.92 (88) 7.87 (7.18, 8.55)
HV SDSCA -2.34 1.78 (88) 5.71 3.44 (88) 8.05 (7.16, 8.94)
Height SDSCA -3.54 1.24 (88) -2.33 1.01 (88) 1.21 (1.08, 1.34)
PAH (B-P) (cm) 162.27 9.7 (32) 165.77 10.0 (32) 3.51 (1.57, 5.44)
PAH SDS (B-P) -1.71 1.10 (32) -1.22 1.08 (32) 0.49 (0.22, 0.76)

Bone maturation expressed as the ratio of change from baseline to Month 12 in bone age (BA) to change from baseline to Month 12 in CA was 1.5 ± 0.9 in the Valtropin (somatropin injection) ® group and 1.5 ± 0.7 in the active control group, and not accelerated.

Furthermore, as expected after somatropin replacement therapy in children with GHD, mean serum insulin-like growth factor 1 (IGF-1) levels in both groups were significantly increased after 12 months of treatment compared to baseline levels.

During the 12-month, open-label extension phase, 82 children continued Valtropin (somatropin injection) ® treatment providing 24-month data for Valtropin (somatropin injection) ®, and 40 patients were switched from the active control to Valtropin (somatropin injection) ®. Growth continued at expected levels for patients on continuous Valtropin (somatropin injection) ® treatment and patients on active control/Valtropin (somatropin injection) treatment.

Pediatric Patients With Turner Syndrome (TS)

Two open-label, single-arm, uncontrolled clinical trials were conducted that evaluated the efficacy and safety of Valtropin (somatropin injection) ® and EutropinTM INJ (a 4 IU formulation qualitatively identical to the 15 IU formulation, Valtropin (somatropin injection) ®) in TS patients with short stature. During Study 1 (conducted at a single center in Russia), 30 Caucasian girls (mean age = 6.9 yr) were treated with Valtropin (somatropin injection) ® 0.053 mg/kg/day SC for 12 months. During Study 2 (conducted at four centers in Korea), 60 Asian girls (mean age = 10.8 yr) were treated with Eutropin™ INJ 0.048 mg/kg/day SC (or 0.056 mg/kg SC 6 days per week) for 12 months. In Studies 1 and 2, pre-treatment HV were 3.75 cm/yr and 3.48 cm/yr, respectively, and baseline height SDSCA were -2.42 and -3.02, respectively. All of the results presented below were obtained from the ITT population.

As seen in Table 3, mean change in HV from baseline to Month 12 (the primary efficacy variable for both studies) was 5.98 cm/yr (mean HV at Month 12 = 9.73 cm/yr) and 3.49 cm/yr (mean HV at Month 12 = 6.97 cm/yr) in Studies 1 and 2, respectively.

The results obtained with respect to other auxological secondary efficacy parameters are also presented for both studies in Table 3. A significant increase in height SDSCA was observed in both studies (0.88 and 0.35 in Studies 1 and 2, respectively), and a substantial increase in HV SDSCA was seen in Study 1 (6.22). B-P PAH increased significantly as well (~4 cm) in Study 1.

Bone maturation (calculated as the ratio of change in BA to change in CA) was not accelerated (1.02 ± 0.35) in Study 1. In Study 2, height age (HA)/BA ratio increased from 0.85 at baseline to 0.88 at Month 12, indicating that HA advanced more rapidly than BA (Table 3).

As expected after somatropin treatment, mean serum IGF-1 levels in both studies were significantly increased after 12 months of treatment compared to baseline levels.

Table 3
Change from Baseline to Month 12 in Height Velocity and Other Auxological Secondary Efficacy Endpoints
After Treatment with Somatropin in Girls with
Short Stature Associated with Turner Syndrome in 2 Open Label Studies


Efficacy Variable Study Mean SD (n) Mean Change from Baseline (95% CI)
Month 0 Month 12
HV (cm/yr)* Study 1 3.75 1.76 (30) 9.73 1.55 (30) 5.98 (5.20, 6.76)
Study 2 3.48 1.40 (58) 6.97 1.84 (58) 3.49 (2.94, 4.03)
HV SDSCA Study 1 -2.39 1.90 (30) 3.82 1.95 (30) 6.22 (5.22, 7.21)
Study 2 NA NA NA NA
Height SDSCA Study 1 -2.42 0.91 (30) -1.54 0.94 (30) 0.88 (0.78, 0.98)
Study 2 -3.02 0.96 (58) -2.67 0.99 (58) 0.35 (0.23, 0.46)
PAH (B-P) (cm) Study 1 152.0 5.23 (14) 156.0 4.21 (14) 4.04 (2.89, 5.19)
Study 2 NA NA NA NA
HA/BA Study 1 NA NA NA NA
Study 2 0.85 0.15 (58) 0.88 0.12 (58) 0.03 (0.00, 0.05)
*Change in HV was the primary efficacy endpoint in both studies and the results are therefore boldened and italicized.
NA=Not available.

Adult Patients With Growth Hormone Deficiency (GHD)

A 6-month, multicenter, randomized, double-blind, placebo-controlled, 3-arm (with 2 arms having a crossover design) clinical trial was conducted in 92 adults (mean age 45-55) with either adult onset (AO) (93.5% of the ITT population) or childhood onset (CO) GHD comparing the effects of Eutropin™ INJ (a 4 IU formulation qualitatively identical to the 15 IU formulation, Valtropin (somatropin injection) ®) and placebo. During treatment period 1 (baseline through the end of Month 3), patients in the active treatment arms (groups A and B) were treated with Eutropin™ INJ at an initial dose of 0.33 mg/day administered SC (6 days per week) for 1 month. During the next 2 months, the dose was up-titrated as necessary in small increments to a maximum of 0.66 mg/day (6 days per week) if serum IGF-1 levels were less than optimal or down-titrated in the presence of significant adverse events or inappropriately elevated serum IGF-1 levels. Patients in group C received placebo for the entire 3 month period. During treatment period 2 (Month 4 through the end of Month 6), patients in group A continued to receive Eutropin™ INJ, patients in group B were crossed over to placebo, and patients in group C were crossed over to Eutropin™ INJ.

Change in fat mass (FM) was the primary efficacy variable and change in lean body mass (LBM) was the most consequential secondary efficacy variable.

The results obtained for changes (decreases) in FM are presented in Tables 4, 5 and 6. As seen in Table 4, after 3 months of treatment with EutropinTM INJ vs. placebo, there was a significant (p=0.003) between-group treatment difference for the change in FM (-1.35 kg). Table 5 depicts the significant (p<0.0001) within-group change in FM (-1.3 kg) after 3 months of treatment with EutropinTM INJ for groups A+B combined (for group A alone, the significant within-group change in FM after 3 months of treatment was -1.7 kg [see Table 6]; during treatment period 2, when patients in group C were crossed over to EutropinTM INJ from placebo, a similar significant within-group change in FM was observed [-1.2 kg; data not shown in a table]). Table 6 also reflects the significant (p<0.0001) within-group change in FM (-2.3 kg) after 6 months of treatment with EutropinTM INJ for group A alone. Furthermore, as seen in Table 6, the within-group change in FM between Month 4 and the end of Month 6 for group A alone was -0.6 kg; this change was not statistically significant suggesting that most of the decrease in FM after treatment with EutropinTM INJ occurred by the end of Month 3.

Table 4
Between-Group Change in Fat Mass After 3 Months of Treatment
with EutropinTM INJ (Groups A+B) vs. Placebo (Group C)


ITT Population with LOCF Groups A and B Combined (n=58)
EutropinTM INJ
Group C
(n=31)
Placebo
Baseline (Mean SD) 23.0 7.7 19.9 3.7
Change from Baseline to Month 3 (Mean SD) -1.25 2.18 +0.16 1.50
Change from Baseline to Month 3 (Adjusted Mean SE)* -1.17 0.25 +0.18 0.35
Treatment Difference (Adjusted Mean)*
(95% CI)
p-value
-1.35
(-0.48, -2.22)
p = 0.003
*Adjusted least-squares means were obtained using an ANCOVA model, where baseline FM and age were the covariates.

Table 5
Within-Group Changes in Fat Mass After 3 Months of Treatment
With EutropinTM INJ (Groups A+B) vs. Placebo (Group C)


  Groups A+B Combined EutropinTM INJ Group C Placebo
ITT Population n   n  
Baseline (Mean SD) 58 23.0 7.7 31 19.9 3.7
Month 3 (Mean SD) 58 21.7 7.7 31 20.2 3.5
Paired t-test p-value   <0.0001*   0.5471

Table 6
Within-Group Changes in Fat Mass After 3 and 6 Months of Treatment with EutropinTM INJ (Group A)


Fat Mass
(mean SD)
Group A
Eutropin™ INJ
(n=31)
Baseline 21.9 6.0 kg
Month 3 20.2 6.3 kg*
Month 6 19.6 5.7 kg*
*Statistically significant within-group change from baseline (p<0.05).

In concert with the significant decreases in FM described above, there were comcomitant significant increases in LBM (tables not provided): a) between-group treatment difference (0.88 kg) after 3 months of treatment with EutropinTM INJ (groups A+B combined) vs. placebo (group C); b) within-group increase from baseline (0.9 kg) after treatment with EutropinTM INJ (groups A+B combined) for 3 months; c) within-group increase from baseline (1.0 kg) after treatment with EutropinTM INJ (group A alone) for 3 months; and d) within-group increase from baseline (2.1 kg) after treatment with EutropinTM INJ (group A alone) for 6 months.

As expected after somatropin replacement therapy in adults with GHD, mean serum IGF-1 levels were significantly increased in group A after 3 and 6 months of EutropinTM INJ treatment compared to baseline levels.

Last reviewed on RxList: 4/30/2007
This monograph has been modified to include the generic and brand name in many instances.

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