Humatrope® (Somatropin, rDNA Origin, for Injection) is a polypeptide hormone of recombinant DNA origin.
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Humatrope HGH DESCRIPTION:
Humatrope is a polypeptide hormone of rDNA origin.
Humatrope has 191 amino acid residues, with an amino acid sequence that is biologically identical to that of naturally-occurring human growth hormone. Humatrope is produced through synthesis in a strain of E. coli modified with the addition of a gene for HGH.
Humatrope is a sterile lyophilized (freeze-dried) powder made for use in subcutaneous or intramuscular administration after it is reconstituted. Humatrope 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 about 7.5. This product is oxygen sensitive.
Humatropin VIAL–Each vial of Humatrope 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 1.7% glycerin.
SOMATROPIN 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.
HUMATROPIN CLINICAL PHARMACOLOGY
Humatrope stimulates linear growth in pediatric patients who lack adequate normal endogenous growth hormone. Clinical, pre-clinical and in vitro testing have shown that Humatrope is equivalent to HGH of pituitary origin with equivalent pharmacokinetic profiles in typical adults. Treatment of growth hormone deficient (GHD) pediatric patients and those with Turner syndrome with Humatrope produces increased growth rate and Insulin-like Growth Factor-I (IGF-I) concentrations similar to those after therapy with HGH of pituitary origin.
The following actions are been shown for Humatrope and HGH of pituitary origin.
Humatrope prompts skeletal growth in child patients with GHD, producing a measurable improvement in body length by effecting the growth plates of long bones. IGF-I is believed to impact skeletal growth. Concentrations of IGF-I in pediatric GHD patients is typically low and increases with Humatrope treatment. Humatrope also produces elevated mean serum alkaline phosphate concentrations.
Humatrope has been found to increase the size and number of muscle cells. Short-statured pediatric patients lacking natural growth hormone typically have fewer skeletal muscle cells.
Linear growth is assisted by improved cellular protein synthesis. Humatrope treatment improves nitrogen retention and decreases serum urea nitrogen.
Metabolism of Carbohydrates
Children with hypopituitarism occassionally develop fasting hypoglycemia (low blood sugar), which is improved with Humatrope. Large doses may impact glucose tolerance, however. Patients with Turner syndrome who are not treated have higher rates of glucose intolerance. HGH treatment to Turner syndrom patients generally increases mean serum fasting and postprandial insulin levels, with mean values staying in the normal range.
Metabolism of Lipids
GHD patients treated with HGH of pituitary origins has been found to improve lipid mobilization, reduce body fat stores and increase plasma fatty acids.
HGH has been shown to induce retention of potassium, phosphorus and sodium. GHD patients treated with Humatrope experienced increased serum concentrations of inorganic phosphate, while serum calcium did not change significantly.
Absorption –Humatrope 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.
HGH Distribution –The volume of distribution of somatropin after intravenous injection is about 0.07 L/kg.
HGH Metabolism – Extensive studies have not been conducted on HGH metabolism. The metabolic fate of somatropin involves classical protein catabolism in both the liver and kidneys. In renal cells, some breakdown products of growth hormone is returned to 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 caused by slower absorption.
Excretion –Urinary excretion of intact Humatrope has not been measured. Small amounts of somatropin have been detected in the urine of pediatric patients following replacement therapy.
Geriatric –The pharmacokinetics of Humatrope has not been studied in patients greater than 60 years of age.
Pediatric –The pharmacokinetics of Humatrope in pediatric patients is similar to adults.
Gender –No studies have been performed with Humatrope. 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 Humatrope.
Humatropin HGH Table 1
Summary of Somatropin Parameters in the Normal Population C max t ½ AUC 0-(infinity) Cls V(beta)
(ng/mL) (hr) (ng·hr/mL) (L/kg·hr) (L/kg)
0.02 mg (0.05 IU * )/kg
0.1 mg (0.27 IU * )/kg
0.1 mg (0.27 IU * )/kg
Abbreviations: C max = maximum concentration: t ½ = half-life; AUC 0-(infinity) = area under the curve; CIs = systemic clearance; V(beta) = volume distribution; iv = intravenous; SD = standard deviation; IM = intramuscular; SC = subcutaneous.
*Based on previous International Standard of 2.7 IU = 1 mg
Effects of Humatrope 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 Humatrope. 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 Humatrope 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.
Humatrope-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 Humatrope on exercise capacity were also conducted. Improved physical function was documented by increased exercise capacity (VO 2 max, p<0.005) and work performance (Watts, p<0.01) (J Clin Endocrinol Metab 1995; 80:552-557).
Humatropin HGH Table 2
Changes a in Nottingham Health Profile Scores b in Adult Onset Growth Hormone Deficient Patients Outcome
(6 Months) Humatrope
(6 Months) Significance
Level -11.4 -15.5 NS
Mobility -3.1 -10.5 p <0.01
Isolation 0.5 -4.7 p <0.01
Reactions -4.5 -5.4 NS
Sleep -6.4 -3.7 NS
Pain -2.8 -2.9 NS
a =An improvement in score is indicated by a more negative change in the score.
b =To account for multiple analyses, appropriate statistical methods were applied and the required level of significance is 0.01.
NS = not significant
Effects of growth hormone treatment in patients with Turner syndrome
A long-term, open-label multicenter concurrently controlled study, two long-term historically controlled studies and one long-term randomized dose-response study have been conducted evaluating the efficacy of GH in treatment Turner Syndrome patients for short stature.
The randomized study, GDCT, compared GH-treated patients to a concurrent control group who did not receive GH. Patients treated with growth hormone received a dose of 0.3mg/kg/week administered six times per week from a mean age of 11.7 years for a mean duration of 4.7 years and achieved a final mean near final height of 146 ± 6.2 cm, compared to the control group, which achieved a mean height of 142.1 ± 4.8 cm. The growth hormone treatment produced a mean height increase of 5.4 centimeters after adjusting for baseline height relative to age and mid-parental height.
Two studies analyzed the effect of long-term growth hormone therapy on adult height, determined by comparing the heights of treated patients with those of age-matched historical controls with Turner syndrome who did not receive treatment. The greatest improvement in adult height was observed in patients who received early growth hormone treatment and estrogen after age 14 years. With Study 85-023, treatment resulted in a mean adult height increase of 7.4 cm (after a mean duration of growth hormone therapy of 7.6 years) compared to matched historical controls.
With HGH Study 85-044, patients treated early with GH therapy were randomized to receive estrogen replacement therapy at either 12 years old or 15 years old. Compared with historical controls, early growth hormone therapy (with a mean duration of 5.6 years) along with estrogen replacement therapy at 12 years of age resulted in an adult height gain of 5.9 centimeters. Patients who began estrogen replacement at 15 years of age (with a mean duration of 6.1 years) had a mean adult height gain of 8.3 centimeters. Patients who received treatment after the age of 11 had a mean adult height gain of 5.0 cm.
A randomized blindd dose-response study had patients treated from a mean age of 11.1 for a mean duration of 5.3 years with weekly doses of either 0.27 mg/kg or 0.36 mg/kg given three or six times per week. The mean near final height of patients who received GH was 148.7 ± 6.5 cm. Compared to historical control data, adults had a mean gain of 5 cm.
In some studies, patients with Turner syndrome treated to final adult height were able to achieve statistically significant average gains ranging from 5 to 8.3 centimeters.
Humatropin HGH Table 3
Summary Table of Efficacy Results Study
Design a N at
Age (yr) Estrogen
Age (yr) GH
(yr) Adult Height
Gain (cm) b
GDCT RCT 27 11.7 13 4.7 5.4
85-023 MHT 17 9.1 15.2 7.6 7.4
85-044: A *
C * MHT 29
RDT 31 11.1 8-13.5 5.3 ~5 c
a RCT: randomized controlled trial; MHT: matched historical controlled trial; RDT: randomized dose-response trial.
b Analysis of covariance vs controls
c Compared with historical data
* A: GH age <11 yr, estrogen age 15 yr
B: GH age <11 yr, estrogen age 12 yr
C: GH age >11 yr, estrogen at month 12
HUMATROPE HGH INDICATIONS AND USAGE
Pediatric Patients – Humatrope is indicated for long-term treatment of children with growth failure caused by insufficient secretion of normal growth hormone.
Humatrope is indicated for the treatment of short stature associated with Turner syndrome in patients whose epiphyses are not closed.
Adult Patients –Humatrope is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who meet both of the following criteria:
Adult Onset: Patients who have GHD due alone or with several hormone deficiencies as a result of pituitary disease, surgery, radiation therapy, trauma or hypothalamic disease;
Childhood Onset: Patients who were growth hormone-deficient during childhood who have growth hormone deficiency confirmed as an adult before Humatrope is administered.
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)].
HUMATROPE HGH CONTRAINDICATIONS
Humatrope should not be used for growth promotion in pediatric patients with closed epiphyses.
Humatrope 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.
Humatrope should not be reconstituted with the supplied Diluent for Humatrope for use by patients with a known sensitivity to either Melacresol or glycerin.
GH should not be started with patients who have acute critical illness caused by complications from abdominal or open heart surgery or multiple trauma or patients with acute respiratory failure. Two clinical trials in non-GHD adults with these conditions found an increased mortality rate (41.9% versus 19.3%) among those treated with somatropin compared to those receiving a placebo.
If sensitivity to the diluent should occur the vials may be reconstituted with Bacteriostatic Water for Injection, USP or, Sterile Water for Injection, USP. When Humatrope is used with Bacteriostatic Water (Benzyl Alcohol preserved), the solution should be kept refrigerated at 2° to 8°C (36° to 46°F) and used within 14 days. Benzyl alcohol as a preservative in Bacteriostatic Water for Injection, USP has been associated with toxicity in newborns. When administering Humatrope to newborns, use the Humatrope diluent provided or if the patient is sensitive to the diluent, use Sterile Water for Injection, USP. When Humatrope is reconstituted with Sterile Water for Injection, USP in this manner, use only one dose per Humatrope vial and discard the unused portion. If the solution is not used immediately, it must be refrigerated (2° to 8°C [36° to 46°F]) and used within 24 hours.
Cartridges should be reconstituted only with the supplied diluent. Cartridges should not be reconstituted with the Diluent for Humatrope provided with Humatrope Vials, or with any other solution. Cartridges should not be used if the patient is allergic to Metacresol or glycerin.
See CONTRAINDICATIONS for information on increased mortality in patients with acute critical illnesses in intensive care units due to complications following open heart or abdominal surgery, multiple accidental trauma or with acute respiratory failure. The safety of continuing growth hormone treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with growth hormone in patients having acute critical illnesses should be weighed against the potential risk.
General – Humatrope should be administered under the direction of a physician who is experienced with diagnosing and managing patients with GHD, Turner Syndrome, and/or patients with childhood onset or adult onset GHD.
Patients with preexisting tumors or GHD that is secondary to an intracranial lesion should be routinely examined for progression or recurrence of the disease. In pediatric patients, clinical literature has demonstrated no relationship between somatropin replacement therapy and CNS tumor recurrence. In adults, it is unknown whether there is any link between somatropin and CNS tumor recurrence.
Patients should be monitored for malignant changes of any skin lesions.
For patients with diabetes mellitus, the insulin dose may require adjustment when somatropin therapy is instituted. Because human growth hormone may induce a state of insulin resistance, patients should be observed for evidence of glucose intolerance. Patients with diabetes or glucose intolerance should be monitored closely during somatropin therapy.
In patients with hypopituitarism, hormone replacement therapy should be monitored when somatropin therapy is administered. Hypothyroidism may develop, and insufficient treatment may reduce the response to somatropin.
Pediatric Patients ( see General Precautions) –Pediatric patients with endocrine disorders, including growth hormone deficiency, may develop slipped capital epiphyses more frequently. Any pediatric patient with the onset of a limp during growth hormone therapy should be evaluated.
Growth hormone has not been shown to increase the incidence of scoliosis. Progression of scoliosis can occur in children who experience rapid growth. Because growth hormone increases growth rate, patients with a history of scoliosis who are treated with growth hormone should be monitored for progression of scoliosis. Skeletal abnormalities including scoliosis are commonly seen in untreated Turner syndrome patients.
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 (see Adverse Reactions). Patients with Turner syndrome are at risk for cardiovascular disorders (e.g. stroke, aortic aneurysm, hypertension) and these conditions should be monitored closely.
Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease. Therefore, patients should have periodic thyroid function tests and be treated as indicated ( see General Precautions ).
Intracranial hypertension with visual changes, swelling, headaches, vomiting and nausea have been reported in a few pediatric patients treated with GH. Symptoms typically develop within the initial eight weeks and, in all reported cases, symptoms were alieved by reducing the dose or ending treatment. Patients should be examined at the beginning of treatment and periodically. Turner syndrome patients may be at a higher risk of deveoping IH.
Adult Patients (see General Precautions )–Patients with epiphyseal closure who were treated with growth hormone replacement therapy in childhood should be re-evaluated according to the criteria in INDICATIONS AND USAGE before continuation of somatropin therapy at the reduced dose level recommended for growth hormone-deficient adults.
Experience in patients above 60 years is lacking.
Experience with prolonged treatment in adults is limited.
Drug Interactions –Excessive glucocorticoid therapy may prevent optimal response to somatropin. If glucocorticoid replacement therapy is required, the glucocorticoid dosage and compliance should be monitored carefully to avoid either adrenal insufficiency or inhibition of growth promoting effects.
Limited published data indicate that growth hormone (GH) treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that GH administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporin). Careful monitoring is advisable when GH is administered in combination with other drugs known to be metabolized by CP450 liver enzymes.
Carcinogenesis, Mutagenesis, Impairment of Fertility –Long-term animal studies for carcinogenicity and impairment of fertility with this human growth hormone (Humatrope) have not been performed. There has been no evidence to date of Humatrope-induced mutagenicity.
Pregnancy–Pregnancy Category C –Animal reproduction studies have not been conducted with Humatrope. It is not known whether Humatrope can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Humatrope should be given to a pregnant woman only if clearly needed.
Nursing Mothers –There have been no studies conducted with Humatrope in nursing mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Humatrope is administered to a nursing woman.
Information for Patients –Patients being treated with growth hormone and/or their parents should be informed of the potential risks and benefits associated with treatment. Instructions on appropriate use should be given, including a review of the contents of the patient information insert. This information is intended to aid in the safe and effective administration of the medication. It is not a disclosure of all possible adverse or intended effects.
Patients and/or parents should be thoroughly instructed in the importance of proper needle disposal. A puncture resistant container should be used for the disposal of used needles and/or syringes (consistent with applicable state requirements). Needles and syringes must not be reused ( see Information for Patient insert).
Growth-Hormone Deficient Pediatric Patients– – As with all protein pharmaceuticals, a small percentage of patients may develop antibodies to the protein. During the first six months of Humatrope therapy in 314 naive patients, only 1.6% developed specific antibodies to Humatrope (binding capacity >/= 0.02 mg/L). None had antibody concentrations which exceeded 2 mg/L. Throughout 8 years of this same study, 2 patients (0.6%) had binding capacity >2 mg/L. Neither patient demonstrated a decrease in growth velocity at or near the time of increased antibody production. It has been reported that growth attenuation from pituitary-derived growth hormone may occur when antibody concentrations are >1.5 mg/L.
In addition to an evaluation of compliance with the treatment program and of thyroid status, testing for antibodies to human growth hormone should be carried out in any patient who fails to respond to therapy.
In studies with growth hormone-deficient pediatric patients, injection site pain was reported infrequently. A mild and transient edema, which appeared in 2.5% of patients, was observed early during the course of treatment.
Leukemia has been reported in a small number of pediatric patients who have been treated with growth hormone, including growth hormone of pituitary origin as well as of recombinant DNA origin (somatrem and somatropin). The relationship, if any, between leukemia and growth hormone therapy is uncertain.
Turner Syndrome Patients — In a randomized, concurrent controlled trial, there was a statistically significant increase, in the occurrence of otitis media (43% vs 26%), ear disorders (18% vs 5%) and surgical procedures (45% vs 27%) in patients receiving Humatrope compared with untreated control patients (Table 4). Other adverse events of special interest to Turner syndrome patients were not significantly different between treatment groups (Table 4). A similar increase in otitis media was observed in an 18 month placebo-controlled trial.
HUMATROPE HGH Table 4
Treatment-Emergent Events of Special Interest by Treatment Group in Turner Syndrome
Adverse Event Overall hGH 1 Untreated 2 Significance
Total Number of Patients 136 74 62
Surgical Procedure 50 (36.8%) 33 (44.6%) 17 (27.4%) p Otitis Media 48 (35.3%) 32 (43.2%) 16 (25.8%) p Ear Disorders 16 (11.8%) 13 (17.6%) 3 (4.8%) p Bone Disorder 13 (9.6%) 6 (8.1%) 7 (11.3%) NS
Hyperglycemia 0 0 0 NS
Hypothyroidism 15 (11.0%) 10 (13.5%) 5 (8.1%) NS
Increased Nevi 3 10 (7.4%) 8 (10.8%) 2 (3.2%) NS
Lymphedema 0 0 0 NS
1 Dose = 0.3 mg/kg/week
2 Open label study
3 Includes any nevi coded to the following preferred terms:
melanosis, skin hypertrophy, or skin benign neoplasm.
NS = not significant
Adult Patients –In clinical studies in which high doses of Humatrope were administered to healthy adult volunteers, the following events occurred infrequently: headache, localized muscle pain, weakness, mild hyperglycemia, and glucosuria.
In the first 6 months of controlled blinded trial during which patients received either Humatrope or placebo, adult onset growth hormone-deficient adults who received Humatrope experienced a statistically significant increase in edema (Humatrope 17.3% vs. placebo 4.4%, p=0.043) and peripheral edema (11.5% vs. 0% respectively, p=0.017). In patients with adult onset growth hormone deficiency, edema, muscle pain, joint pain, and joint disorder were reported early in therapy and tended to be transient or responsive to dosage titration.
Two out of 113 adult onset patients developed carpal tunnel syndrome after beginning maintenance therapy without a low dose (0.00625 mg/kg/day) lead-in phase. Symptoms abated in these patients after dosage reduction.
All treatment-emergent adverse events with >/=5% overall incidence during 12 or 18 months of replacement therapy with Humatrope are shown in Table 5 (adult onset patients) and in Table 6 (childhood onset patients).
Adult patients treated with Humatrope who had been diagnosed with growth hormone deficiency in childhood reported side effects less frequently than those with adult onset growth hormone deficiency.
HUMATROPE HGH Table 5
Treatment-Emergent Adverse Events with >/=5% Overall Incidence in Adult Onset Growth Hormone Deficient Patients Treated with Humatrope for 18 Months as Compared with 6 Month Placebo and 12 Month Humatrope Exposure 18 Months Exposure
[Placebo (6 Months)/hGH
(N=46) 18 Months hGH Exposure
Adverse Event n % n %
Edema a 7 15.2 11 21.2
Arthralgia 7 15.2 9 17.3
Paresthesia 6 13.0 9 17.3
Myalgia 6 13.0 7 13.5
Pain 6 13.0 7 13.5
Rhinitis 5 10.9 7 13.5
Peripheral Edema b 8 17.4 6 11.5
Back Pain 5 10.9 5 9.6
Headache 5 10.9 4 7.7
Hypertension 2 4.3 4 7.7
Acne 0 0 3 5.8
Joint Disorder 1 2.2 3 5.8
Surgical Procedure 1 2.2 3 5.8
Flu Syndrome 3 6.5 2 3.9
Abbreviations: hGH = Humatrope; N = number of patients receiving treatment in the period stated; n = number of patients reporting each treatment-emergent adverse event.
a p = 0.04 as compared to placebo (6 months)
b p = 0.02 as compared to placebo (6 months)
Treatment-Emergent Adverse Events with >/=5% Overall Incidence in Childhood Onset
Growth Hormone Deficient Patients Treated with Humatrope for 18 Months as Compared
with 6 Month Placebo and 12 Month Humatrope Exposure 18 Months Exposure
[Placebo (6 Months)/hGH
(N=35) 18 Months hGH Exposure
Adverse Event n % n %
Flu Syndrome 8 22.9 5 15.6
AST Increased a 2 5.7 4 12.5
Headache 4 11.4 3 9.4
Asthenia 1 2.9 2 6.3
Cough Increased 0 0 2 6.3
Edema 3 8.6 2 6.3
Hypesthesia 0 0 2 6.3
Myalgia 2 5.7 2 6.3
Pain 3 8.6 2 6.3
Rhinitis 2 5.7 2 6.3
ALT Increased 2 5.7 2 6.3
Respiratory Disorder 2 5.7 1 3.1
Gastritis 2 5.7 0 0
Pharyngitis 5 14.3 1 3.1
Abbreviations: hGH = Humatrope; N = number of patients receiving treatment in the period stated; n = number of patients reporting each treatment-emergent adverse event; ALT = alanine amino transferase, formerly SGPT; AST = aspartate amino transferase, formerly SGOT.
a p = 0.03 as compared to placebo (6 months)
Other adverse drug events that have been reported in growth hormone-treated patients include the following:
1) Metabolic: Infrequent, mild and transient peripheral or generalize 2) Musculoskeletal: Rare carpal tunnel syndrome. 3) Skin: Rare increased growth of pre-existing nevi. Patients should be monitored carefully for malignant transformation. 4) Endocrine: Rare gynecomastia. Rare pancreatitis.
Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Long-term overdosage could result in signs and symptoms of gigantism/acromegaly consistent with the known effects of excess human growth hormone. (See recommended and maximal dosage instructions given below.)
DOSAGE AND ADMINISTRATION
Pediatric Patients – The Humatrope dosage and administration schedule should be individualized for each patient. Therapy should not be continued if epiphyseal fusion has occurred. Response to growth hormone therapy tends to decrease with time. However, failure to increase growth rate, particularly during the first year of therapy, should prompt close assessment of compliance and evaluation of other causes of growth failure such as hypothyroidism, under-nutrition and advanced bone age.
Growth hormone-deficient pediatric patients –The recommended weekly dosage is 0.18 mg/kg (0.54 IU/kg) of body weight. The maximal replacement weekly dosage is 0.3 mg/kg (0.90 IU/kg) of body weight. It should be divided into equal doses given either on 3 alternate days, 6 times per week or daily. The subcutaneous route of administration is preferable; intramuscular injection is also acceptable. The dosage and administration schedule for Humatrope should be individualized for each patient.
Turner Syndrome —A weekly dosage of up to 0.375 mg/kg (1.125 IU/kg) of body weight administered by subcutaneous injection is recommended. It should be divided into equal doses given either daily or on 3 alternate days.
Adminstration of Humatropin Therapy in Adult Patients–
During therapy, dosage should be titrated if required by the occurrence of side effects or to maintain the IGF-I response below the upper limit of normal IGF-I levels, matched for age and sex. To minimize the occurrence of adverse events in patients with increasing age or excessive body weight, dose reductions may be necessary.
Reconstitution: Vial–Each 5-mg vial of Humatrope should be reconstituted with 1.5 to 5 mL of Diluent for Humatrope. The diluent should be injected into the vial of Humatrope by aiming the stream of liquid against the glass wall. Following reconstitution, the vial should be swirled with a GENTLE rotary motion until the contents are completely dissolved. DO NOT SHAKE. The resulting solution should be inspected for clarity. It should be clear. If the solution is cloudy or contains particulate matter, the contents MUST NOT be injected.
Before and after injection, the septum of the vial should be wiped with rubbing alcohol or an alcoholic antiseptic solution to prevent contamination of the contents by repeated needle insertions. Sterile disposable syringes and needles should be used for administration of Humatrope. The volume of the syringe should be small enough so that the prescribed dose can be withdrawn from the vial with reasonable accuracy.
Cartridge: Each cartridge of Humatrope should only be reconstituted using the diluent syringe and the diluent connector which accompany the cartridge and should not be reconstituted with the Diluent for Humatrope provided with Humatrope vials. (See WARNINGS section). See the HumatroPen”! User Guide for comprehensive directions on Humatrope cartridge reconstitution.
The reconstituted solution should be inspected for clarity. It should be clear. If the solution is cloudy or contains particulate matter, the contents MUST NOT be injected.
The HumatroPen”! allows the sumatropin dosage volume to be dialed in increments of 0.048 mL per click of dosage knob, and the maximum dosage volume that can be injected is 0.576 mL (based on a 12 click maximum). (See Table 7 for additional information).
HUMATROPE HGH Table 7
Concentration of Reconstituted Humatrope Solutions, Incremental
Dosage and Maximum Injectable Dose for Each Cartridge Cartridge Somatropin
Concentration Dose per click of
dosage knob Maximum
6 mg 2.08 mg/mL 0.1 mg 1.2 mg
12 mg 4.17 mg/mL 0.2 mg 2.4 mg
24 mg 8.33 mg/mL 0.4 mg 4.8 mg
This cartridge has been designed for use only with the HumatroPen. A sterile disposable needle should be used for each administration of Humatrope.
STABILITY AND STORAGE of HUMATROPIN HGH
Humatrope Vials: Before Reconstitution –Vials of Humatrope and Diluent for Humatrope are stable when refrigerated (2° to 8°C [36° to 46°F]). Avoid freezing Diluent for Humatrope. Expiration dates are stated on the labels.
After Reconstitution — Vials of Humatrope are stable for up to 14 days when reconstituted with Diluent for Humatrope or Bacteriostatic Water for Injection, USP and stored in a refrigerator at 2° to 8°C (36° to 46°F). Avoid freezing the reconstituted vial of Humatrope.
After Reconstitution with Sterile Water, USP- -Use only one dose per Humatrope vial and discard the unused portion. If the solution is not used immediately, it must be refrigerated (2° to 8°C [36° to 46°F]) and used within 24 hours.
Humatrope Cartridges: Before Reconstitution– Cartridges of Humatrope and Diluent for Humatrope are stable when refrigerated (2° to 8°C [36° to 46°F]). Avoid freezing Diluent for Humatrope. Expiration dates are stated on the labels.
After Reconstitution– Cartridges of Humatrope are stable for up to 28 days when reconstituted with Diluent for Humatrope and stored in a refrigerator at (2° to 8°C [36° to 46°F]). Store the HumatroPen without the needle attached. Avoid freezing the reconstituted cartridge of Humatrope.
Vials: 5 mg (No. 7335)–(6s) NDC 0002-7335-16, and 5-mL vials of Diluent for Humatrope (No. 7336)
Cartridges: Cartridge Kit (MS8089) NDC 0002-8089-01
6 mg cartridge (VL7554), and prefilled syringe of Diluent for Humatrope (VL7557)
Cartridge Kit (MS8090) NDC 0002-8090-01
12 mg cartridge (VL7555), and prefilled syringe of Diluent for Humatrope (VL7558)
Cartridge Kit (MS8091) NDC 0002-8091-01
24 mg cartridge (VL 7556), and prefilled syringe of Diluent for Humatrope (VL7558)
(Above information has been provided by PDR.)
- Saizen ®