Norditropin 5mg/1.5ml (nordiket)
Product Description
Humatropin (Somatropin, rDNA Origin, for Injection) is a polypeptide hormone of recombinant DNA origin. Humatropin has 191 amino acid residues and a molecular weight of about 22,125 daltons. The amino acid sequence of the product is identical to that of human growth hormone of pituitary origin. Humatropin is synthesized in a strain of Escherichia coli that has been modified by the addition of the gene for human growth hormone.
Humatropin is a sterile, white, lyophilized powder intended for subcutaneous or intramuscular administration after reconstitution. Humatropin is a highly purified preparation. Phosphoric acid and/or sodium hydroxide may have been added to adjust the pH. Reconstituted solutions have a pH of approximately 7.5. This product is oxygen sensitive.
VIAL--Each vial of Humatropin contains 5 mg somatropin (15 IU or 225 nanomoles); 25 mg mannitol; 5 mg glycine; and 1.13 mg dibasic sodium phosphate. Each vial is supplied in a combination package with an accompanying 5-mL vial of diluting solution. The diluent contains water for injection with 0.3% Metacresol as a preservative and glycerin.
CARTRIDGE--The cartridges of somatropin contain either 6 mg (18 IU), 12 mg (36 IU), or 24 mg (72 IU) of somatropin. The 6 mg, 12 mg and 24 mg cartridges contain respectively: mannitol 18 mg, 36 mg, and 72 mg; glycine 6 mg, 12 mg, and 24 mg; dibasic sodium phosphate 1.36 mg, 2.72 mg, and 5.43 mg. Each cartridge is supplied in a combination package with an accompanying syringe containing approximately 3 mL of diluting solution. The diluent contains Water for Injection; 0.3% Metacresol as a preservative; and 1.7%, 0.29%, and 0.29% gylcerin in the 6 mg, 12 mg, and 24 mg cartridges respectively.
CLINICAL PHARMACOLOGY:
General: Linear Growth --Humatropin stimulates linear growth in pediatric patients who lack adequate normal endogenous growth hormone. In vitro, preclinical, and clinical testing have demonstrated that Humatropin is therapeutically equivalent to human growth hormone of pituitary origin and achieves equivalent pharmacokinetic profiles in normal adults. Treatment of growth hormone-deficient pediatric patients and patients with Turner syndrome with Humatropin produces increased growth rate and IGF-I(Insulin-like Growth Factor-I/Somatomedin-C) concentrations similar to those seen after therapy with human growth hormone of pituitary origin.
In addition, the following actions have been demonstrated for Humatropin and/or human growth hormone of pituitary origin.
Tissue Growth --
1. Skeletal Growth: Humatropin stimulates skeletal growth in pediatric patients with growth hormone deficiency. The measurable increase in body length after administration of either Humatropin or human growth hormone of pituitary origin results from an effect on the growth plates of long bones. Concentrations of IGF-I, which may play a role in skeletal growth, are low in the serum of growth hormone-deficient pediatric patients but increase during treatment with Humatropin. Elevations in mean serum alkaline phosphatase concentrations are also seen.
2. Cell Growth: It has been shown that there are fewer skeletal muscle cells in short-statured pediatric patients who lack endogenous growth hormone as compared with normal pediatric populations. Treatment with human growth hormone of pituitary origin results in an increase in both the number and size of muscle cells.
Protein Metabolism --Linear growth is facilitated in part by increased cellular protein synthesis. Nitrogen retention, as demonstrated by decreased urinary nitrogen excretion and serum urea nitrogen, follows the initiation of therapy with human growth hormone of pituitary origin. Treatment with Humatropin results in a similar decrease in serum urea nitrogen.
Carbohydrate Metabolism --Pediatric patients with hypopituitarism sometimes experience fasting hypoglycemia that is improved by treatment with Humatropin. Large doses of human growth hormone may impair glucose tolerance. Untreated patients with Turner syndrome have an increased incidence of glucose intolerance. Administration of human growth hormone to normal adults or patients with Turner syndrome resulted in increases in mean serum fasting and postprandial insulin levels although mean values remained in the normal range. In addition, mean fasting and postprandial glucose and hemoglobin A 1C levels remained in the normal range.
Lipid Metabolism --In growth hormone-deficient patients, administration of human growth hormone of pituitary origin has resulted in lipid mobilization, reduction in body fat stores, and increased plasma fatty acids.
Mineral Metabolism --Retention of sodium, potassium, and phosphorus is induced by human growth hormone of pituitary origin. Serum concentrations of inorganic phosphate increased in patients with growth hormone deficiency after therapy with Humatropin or human growth hormone of pituitary origin. Serum calcium is not significantly altered in patients treated with either human growth hormone of pituitary origin or Humatropin.
PHARMACOKINETICS Absorption --Humatropin has been studied following intramuscular, subcutaneous, and intravenous administration in adult volunteers. The absolute bioavailability of somatropin is 75% and 63% after subcutaneous and intramuscular administration, respectively.
Distribution --The volume of distribution of somatropin after intravenous injection is about 0.07 L/kg.
Metabolism --Extensive metabolism studies have not been conducted. 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 of growth hormone is returned to the systemic circulation. In normal volunteers, mean clearance is 0.14 L/hr/kg. The mean half-life of intravenous somatropin is 0.36 hours, whereas subcutaneously and intramuscularly administered somatropin have mean half-lives of 3.8 and 4.9 hours, respectively. The longer half-life observed after subcutaneous or intramuscular administration is due to slow absorption from the injection site.
Excretion --Urinary excretion of intact Humatropin has not been measured. Small amounts of somatropin have been detected in the urine of pediatric patients following replacement therapy.
Special Populations
Geriatric --The pharmacokinetics of Humatropin has not been studied in patients greater than 60 years of age.
Pediatric --The pharmacokinetics of Humatropin in pediatric patients is similar to adults.
Gender --No studies have been performed with Humatropin. The available literature indicates that the pharmacokinetics of growth hormone is similar in both men and women.
Race --No data are available.
Renal, Hepatic insufficiency --No studies have been performed with Humatropin.
Effects of Humatropin treatment in adults with growth hormone deficiency
Two multicenter trials in adult onset growth hormone deficiency (n=98) and two studies in childhood onset growth hormone deficiency (n=67) were designed to assess the effects of replacement therapy with Humatropin. The primary efficacy measures were body composition (lean body mass and fat mass), lipid parameters, and the Nottingham Health Profile. The Nottingham Health Profile is a general health-related quality of life questionnaire. These four studies each included a 6-month randomized, blinded, placebo-controlled phase followed by 12 months of open-label therapy for all patients. The Humatropin dosages for all studies were identical: one month of therapy at 0.00625 mg/kg/day followed by the proposed maintenance dose of 0.0125 mg/kg/day. Adult onset patients and childhood onset patients differed by diagnosis (organic versus idiopathic pituitary disease), body size (normal versus small for mean height and weight), and age (mean = 44 versus 29 years). Lean body mass was determined by bioelectrical impedance analysis (BIA), validated with potassium 40. Body fat was assessed by BIA and sum of skinfold thickness. Lipid subfractions were analyzed by standard assay methods in a central laboratory.
Humatropin-treated adult onset patients, as compared to placebo, experienced an increase in lean body mass (2.59 versus -0.22 kg, p<0.001) and a decrease in body fat (-3.27 versus 0.56 kg, p<0.001). Similar changes were seen in childhood onset growth hormone deficient patients. These significant changes in lean body mass persisted throughout the 18 month period as compared to baseline for both groups, and for fat mass in the childhood onset group. Total cholesterol decreased short term (first 3 months) although the changes did not persist. However, the low HDL cholesterol levels observed at baseline (mean = 30.1 mg/mL and 33.9 mg/mL in adult onset and childhood onset patients) normalized by the end of 18 months of therapy (a change of 13.7 and 11.1 mg/dL for the adult onset and childhood onset groups, p<0.001). Adult onset patients reported significant improvements as compared to placebo in the following 2 of 6 possible health related domains: physical mobility and social isolation (Table 2). Patients with childhood onset disease failed to demonstrate improvements in Nottingham Health Profile outcomes.
Two additional studies on the effect of Humatropin on exercise capacity were also conducted. Improved physical function was documented by increased exercise capacity (VO 2 max, p<0.005) and work performance.
Effects of growth hormone treatment in patients with Turner syndrome
One long-term, randomized, open-label multicenter concurrently controlled study, two long-term, open-label multicenter, historically controlled studies and one long-term, randomized, dose-response study were conducted to evaluate the efficacy of growth hormone for the treatment of patients with short stature due to Turner syndrome.
In two of the studies , the effect of long-term growth hormone treatment (0.375 mg/kg/week 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 growthpromoting therapy. The greatest improvement in adult height was observed in patients who received early growth hormone treatment and estrogen after age 14 years. In Study 85-023, this 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 with early growth hormone 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 patients 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).
In a 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 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 growth hormone was 148.7 ±6.5 cm (n=31). When compared to historical control data, the mean gain in adult height was approximately 5 cm.
INDICATIONS AND USAGE:
Pediatric Patients --Humatropin is indicated for the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of normal endogenous growth hormone.
Humatropin is indicated for the treatment of short stature associated with Turner syndrome in patients whose epiphyses are not closed.
Adult Patients --Humatropin is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who meet both of the following two criteria:
Adult Onset: Patients who have growth hormone deficiency either alone or 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 who have growth hormone deficiency confirmed as an adult before replacement therapy with Humatropin is started.
and
Biochemical diagnosis of growth hormone deficiency, by means of a negative response to a standard growth hormone stimulation test [maximum peak < 5 ng/mL when measured by RIA (polyclonal antibody) or < 2.5 ng/mL when measured by IRMA (monoclonal antibody)].
CONTRAINDICATIONS:
Humatropin should not be used for growth promotion in pediatric patients with closed epiphyses.
Humatropin should not be used or should be discontinued when there is any evidence of active malignancy. Anti-malignancy treatment must be complete with evidence of remission prior to the institution of therapy.
Humatropin should not be reconstituted with the supplied Diluent for Humatropin for use by patients with a known sensitivity to either Melacresol or glycerin.
Growth hormone should not be initiated to treat patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or to patients having acute respiratory failure. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin treated patients (doses 5.3-8 mg/day) compared to those receiving placebo (see WARNINGS ).
Product Description
Humatropin (Somatropin, rDNA Origin, for Injection) is a polypeptide hormone of recombinant DNA origin. Humatropin has 191 amino acid residues and a molecular weight of about 22,125 daltons. The amino acid sequence of the product is identical to that of human growth hormone of pituitary origin. Humatropin is synthesized in a strain of Escherichia coli that has been modified by the addition of the gene for human growth hormone.
Humatropin is a sterile, white, lyophilized powder intended for subcutaneous or intramuscular administration after reconstitution. Humatropin is a highly purified preparation. Phosphoric acid and/or sodium hydroxide may have been added to adjust the pH. Reconstituted solutions have a pH of approximately 7.5. This product is oxygen sensitive.
VIAL--Each vial of Humatropin contains 5 mg somatropin (15 IU or 225 nanomoles); 25 mg mannitol; 5 mg glycine; and 1.13 mg dibasic sodium phosphate. Each vial is supplied in a combination package with an accompanying 5-mL vial of diluting solution. The diluent contains water for injection with 0.3% Metacresol as a preservative and glycerin.
CARTRIDGE--The cartridges of somatropin contain either 6 mg (18 IU), 12 mg (36 IU), or 24 mg (72 IU) of somatropin. The 6 mg, 12 mg and 24 mg cartridges contain respectively: mannitol 18 mg, 36 mg, and 72 mg; glycine 6 mg, 12 mg, and 24 mg; dibasic sodium phosphate 1.36 mg, 2.72 mg, and 5.43 mg. Each cartridge is supplied in a combination package with an accompanying syringe containing approximately 3 mL of diluting solution. The diluent contains Water for Injection; 0.3% Metacresol as a preservative; and 1.7%, 0.29%, and 0.29% gylcerin in the 6 mg, 12 mg, and 24 mg cartridges respectively.
CLINICAL PHARMACOLOGY:
General: Linear Growth --Humatropin stimulates linear growth in pediatric patients who lack adequate normal endogenous growth hormone. In vitro, preclinical, and clinical testing have demonstrated that Humatropin is therapeutically equivalent to human growth hormone of pituitary origin and achieves equivalent pharmacokinetic profiles in normal adults. Treatment of growth hormone-deficient pediatric patients and patients with Turner syndrome with Humatropin produces increased growth rate and IGF-I(Insulin-like Growth Factor-I/Somatomedin-C) concentrations similar to those seen after therapy with human growth hormone of pituitary origin.
In addition, the following actions have been demonstrated for Humatropin and/or human growth hormone of pituitary origin.
Tissue Growth --
1. Skeletal Growth: Humatropin stimulates skeletal growth in pediatric patients with growth hormone deficiency. The measurable increase in body length after administration of either Humatropin or human growth hormone of pituitary origin results from an effect on the growth plates of long bones. Concentrations of IGF-I, which may play a role in skeletal growth, are low in the serum of growth hormone-deficient pediatric patients but increase during treatment with Humatropin. Elevations in mean serum alkaline phosphatase concentrations are also seen.
2. Cell Growth: It has been shown that there are fewer skeletal muscle cells in short-statured pediatric patients who lack endogenous growth hormone as compared with normal pediatric populations. Treatment with human growth hormone of pituitary origin results in an increase in both the number and size of muscle cells.
Protein Metabolism --Linear growth is facilitated in part by increased cellular protein synthesis. Nitrogen retention, as demonstrated by decreased urinary nitrogen excretion and serum urea nitrogen, follows the initiation of therapy with human growth hormone of pituitary origin. Treatment with Humatropin results in a similar decrease in serum urea nitrogen.
Carbohydrate Metabolism --Pediatric patients with hypopituitarism sometimes experience fasting hypoglycemia that is improved by treatment with Humatropin. Large doses of human growth hormone may impair glucose tolerance. Untreated patients with Turner syndrome have an increased incidence of glucose intolerance. Administration of human growth hormone to normal adults or patients with Turner syndrome resulted in increases in mean serum fasting and postprandial insulin levels although mean values remained in the normal range. In addition, mean fasting and postprandial glucose and hemoglobin A 1C levels remained in the normal range.
Lipid Metabolism --In growth hormone-deficient patients, administration of human growth hormone of pituitary origin has resulted in lipid mobilization, reduction in body fat stores, and increased plasma fatty acids.
Mineral Metabolism --Retention of sodium, potassium, and phosphorus is induced by human growth hormone of pituitary origin. Serum concentrations of inorganic phosphate increased in patients with growth hormone deficiency after therapy with Humatropin or human growth hormone of pituitary origin. Serum calcium is not significantly altered in patients treated with either human growth hormone of pituitary origin or Humatropin.
PHARMACOKINETICS Absorption --Humatropin has been studied following intramuscular, subcutaneous, and intravenous administration in adult volunteers. The absolute bioavailability of somatropin is 75% and 63% after subcutaneous and intramuscular administration, respectively.
Distribution --The volume of distribution of somatropin after intravenous injection is about 0.07 L/kg.
Metabolism --Extensive metabolism studies have not been conducted. 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 of growth hormone is returned to the systemic circulation. In normal volunteers, mean clearance is 0.14 L/hr/kg. The mean half-life of intravenous somatropin is 0.36 hours, whereas subcutaneously and intramuscularly administered somatropin have mean half-lives of 3.8 and 4.9 hours, respectively. The longer half-life observed after subcutaneous or intramuscular administration is due to slow absorption from the injection site.
Excretion --Urinary excretion of intact Humatropin has not been measured. Small amounts of somatropin have been detected in the urine of pediatric patients following replacement therapy.
Special Populations
Geriatric --The pharmacokinetics of Humatropin has not been studied in patients greater than 60 years of age.
Pediatric --The pharmacokinetics of Humatropin in pediatric patients is similar to adults.
Gender --No studies have been performed with Humatropin. The available literature indicates that the pharmacokinetics of growth hormone is similar in both men and women.
Race --No data are available.
Renal, Hepatic insufficiency --No studies have been performed with Humatropin.
Effects of Humatropin treatment in adults with growth hormone deficiency
Two multicenter trials in adult onset growth hormone deficiency (n=98) and two studies in childhood onset growth hormone deficiency (n=67) were designed to assess the effects of replacement therapy with Humatropin. The primary efficacy measures were body composition (lean body mass and fat mass), lipid parameters, and the Nottingham Health Profile. The Nottingham Health Profile is a general health-related quality of life questionnaire. These four studies each included a 6-month randomized, blinded, placebo-controlled phase followed by 12 months of open-label therapy for all patients. The Humatropin dosages for all studies were identical: one month of therapy at 0.00625 mg/kg/day followed by the proposed maintenance dose of 0.0125 mg/kg/day. Adult onset patients and childhood onset patients differed by diagnosis (organic versus idiopathic pituitary disease), body size (normal versus small for mean height and weight), and age (mean = 44 versus 29 years). Lean body mass was determined by bioelectrical impedance analysis (BIA), validated with potassium 40. Body fat was assessed by BIA and sum of skinfold thickness. Lipid subfractions were analyzed by standard assay methods in a central laboratory.
Humatropin-treated adult onset patients, as compared to placebo, experienced an increase in lean body mass (2.59 versus -0.22 kg, p<0.001) and a decrease in body fat (-3.27 versus 0.56 kg, p<0.001). Similar changes were seen in childhood onset growth hormone deficient patients. These significant changes in lean body mass persisted throughout the 18 month period as compared to baseline for both groups, and for fat mass in the childhood onset group. Total cholesterol decreased short term (first 3 months) although the changes did not persist. However, the low HDL cholesterol levels observed at baseline (mean = 30.1 mg/mL and 33.9 mg/mL in adult onset and childhood onset patients) normalized by the end of 18 months of therapy (a change of 13.7 and 11.1 mg/dL for the adult onset and childhood onset groups, p<0.001). Adult onset patients reported significant improvements as compared to placebo in the following 2 of 6 possible health related domains: physical mobility and social isolation (Table 2). Patients with childhood onset disease failed to demonstrate improvements in Nottingham Health Profile outcomes.
Two additional studies on the effect of Humatropin on exercise capacity were also conducted. Improved physical function was documented by increased exercise capacity (VO 2 max, p<0.005) and work performance.
Effects of growth hormone treatment in patients with Turner syndrome
One long-term, randomized, open-label multicenter concurrently controlled study, two long-term, open-label multicenter, historically controlled studies and one long-term, randomized, dose-response study were conducted to evaluate the efficacy of growth hormone for the treatment of patients with short stature due to Turner syndrome.
In two of the studies , the effect of long-term growth hormone treatment (0.375 mg/kg/week 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 growthpromoting therapy. The greatest improvement in adult height was observed in patients who received early growth hormone treatment and estrogen after age 14 years. In Study 85-023, this 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 with early growth hormone 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 patients 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).
In a 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 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 growth hormone was 148.7 ±6.5 cm (n=31). When compared to historical control data, the mean gain in adult height was approximately 5 cm.
INDICATIONS AND USAGE:
Pediatric Patients --Humatropin is indicated for the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of normal endogenous growth hormone.
Humatropin is indicated for the treatment of short stature associated with Turner syndrome in patients whose epiphyses are not closed.
Adult Patients --Humatropin is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who meet both of the following two criteria:
Adult Onset: Patients who have growth hormone deficiency either alone or 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 who have growth hormone deficiency confirmed as an adult before replacement therapy with Humatropin is started.
and
Biochemical diagnosis of growth hormone deficiency, by means of a negative response to a standard growth hormone stimulation test [maximum peak < 5 ng/mL when measured by RIA (polyclonal antibody) or < 2.5 ng/mL when measured by IRMA (monoclonal antibody)].
CONTRAINDICATIONS:
Humatropin should not be used for growth promotion in pediatric patients with closed epiphyses.
Humatropin should not be used or should be discontinued when there is any evidence of active malignancy. Anti-malignancy treatment must be complete with evidence of remission prior to the institution of therapy.
Humatropin should not be reconstituted with the supplied Diluent for Humatropin for use by patients with a known sensitivity to either Melacresol or glycerin.
Growth hormone should not be initiated to treat patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or to patients having acute respiratory failure. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin treated patients (doses 5.3-8 mg/day) compared to those receiving placebo (see WARNINGS ).
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