Humatrope (Somatropin)

HUMATROPE®

Lilly

Somatropin

Growth Stimulant

Action And Clinical Pharmacology: Somatropin is a polypeptide hormone of recombinant DNA origin. The amino acid sequence is identical to that of human growth hormone of pituitary origin. Somatropin is synthesized in a strain of E. coli which has been modified by the addition of the gene for human growth hormone.

Somatropin stimulates linear growth in pediatric patients lacking adequate normal endogenous growth hormone. Treatment of growth hormone-deficient pediatric patients and patients with Turner Syndrome with somatropin produces increased growth rate and IGF-I (Insulin-like Growth Factor-I/Somatomedin C) concentrations similar to those seen in therapy with human growth hormone of pituitary origin. As a result of replacement therapy in growth hormone deficient adults, body composition improved, HDL cholesterol values normalized, and health related quality of life measures concerning physical mobility and social isolation improved in placebo-controlled clinical trials. Exercise capacity improved as compared to placebo.

In addition, the following actions have been demonstrated for somatropin and/or human growth hormone of pituitary origin.

Tissue Growth: 1. Skeletal Growth: Somatropin stimulates skeletal growth in pediatric patients with growth hormone deficiency. The measurable increase in body length after administration of either Humatrope or human growth hormone of pituitary origin results from an effect on the growth plates of long bones. Concentrations of IGF-1, which may play a role in skeletal growth, are low in the serum of growth hormone-deficient pediatric patients but increase during treatment with somatropin. 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 to normal pediatric populations. Treatment with human growth hormone of pituitary origin results in an increase in both the number and the 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 somatropin results in a similar decrease in serum urea nitrogen.

Carbohydrate Metabolism: Pediatric patients with hypopituitarism sometimes experience fasting hypoglycemia, which is improved by treatment with somatropin. 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 A1c levels remained in the normal range.

Lipid Metabolism: In growth hormone-deficient patients, long-term administration of human growth hormone of pituitary origin has resulted in lipid mobilization, reduction in body fat stores, and an increase in 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 somatropin 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 somatropin.

Pharmacokinetics: In vitro, preclinical, and clinical testing have demonstrated that Humatrope is therapeutically equivalent to human growth hormone of pituitary origin with equivalent pharmacokinetics in normal adults.

Absorption: Humatrope has been studied following i.m., s.c. and i.v. administration in adult volunteers. The absolute bioavailability of somatropin is 75% and 63% after s.c. and i.m. administration respectively.

Distribution: The volume of distribution of somatropin after i.v. 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/h/kg. The mean half-life of i.v. somatropin is 0.36 hours, whereas s.c. and i.m. administered somatropin have mean half-lives of 3.8 and 4.9 hours, respectively. The longer half-life observed after s.c. or i.m. administration is due to slow absorption from the injection site.

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.

Indications And Clinical Uses: Children: For the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of normal endogenous growth hormone and whose epiphyses are not closed.

Adults: For replacement of endogenous growth hormone in adults with growth hormone deficiency who meet both of the following 2 criteria: 1. Biochemical diagnosis of somatotropin deficiency syndrome, by means of a negative response to a standard growth hormone stimulation test.

Turner Syndrome: For the treatment of short stature associated with Turner Syndrome in patients whose epiphyses are not closed.

Contra-Indications: Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses.

Somatropin should not be used or should be discontinued when there is any evidence of active malignancy. Antimalignancy treatment must be complete with evidence of remission prior to the institution of therapy.

For patients with a known sensitivity to either m-cresol or glycerin, somatropin should not be reconstituted with the supplied diluent for somatropin.

Manufacturers’ Warnings In Clinical States: If patients are sensitive to m-cresol or glycerin or if sensitivity to the diluent develops, the vials should be reconstituted with Sterile Water for Injection, USP. Use only 1 somatropin dose per vial and discard unused portion (see Dosage).

Precautions: General: Somatropin therapy should be directed by physicians experienced in the diagnosis and management of patients with growth hormone deficiency, Turner syndrome or adult patients with either childhood-onset or adult-onset growth hormone deficiency.

Patients with pre-existing tumors or with growth hormone deficiency secondary to an intracranial lesion should be examined routinely for progression or recurrence of the underlying disease process. In pediatric patients, clinical literature has demonstrated no relationship between human growth hormone replacement therapy and CNS tumor recurrence. In adults, it is unknown whether there is any relationship between growth hormone replacement therapy and CNS tumor recurrence.

For patients with diabetes mellitus, the dose of insulin might require adjustment when somatropin 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 therapy with human growth hormone.

In patients with hypopituitarism (multiple hormonal deficiencies) standard hormonal replacement therapy should be monitored closely when human growth hormone therapy is administered. Hypothyroidism may develop during treatment with human growth hormone. Inadequate treatment of hypothyroidism may prevent optimal response to human growth hormone.

If injected s.c., the injection site should be rotated to minimize the risk of lipoatrophy occurring.

Children (see General): Patients with endocrine disorders, including growth hormone deficiency, may develop slipped capital epiphyses more frequently. Any pediatric patient with 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 pediatric patients 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.

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting has been reported in a small number of patients treated with growth hormone products. Symptoms usually occurred within the first 8 weeks of the initiation of growth hormone therapy. In all reported cases, IH-associated signs and symptoms resolved after termination of therapy or a reduction of the growth hormone dose. Funduscopic examination of patients is recommended at the initiation and periodically during the course of growth hormone therapy.

Adults (see Precautions, General): Patients with epiphyseal closure who were treated with growth hormone replacement therapy in childhood should be re-evaluated according to the criteria in Indications before continuation of growth hormone replacement therapy at the reduced dose level required for growth hormone-deficient adults.

Experience in patients above 60 years is lacking.

Experience with prolonged treatment in adults is limited.

Turner Syndrome (see Precautions, General): Skeletal abnormalities including scoliosis are commonly seen in untreated Turner syndrome patients.

Patients with Turner syndrome may be at increased risk for development of intracranial hypertension.

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 Effects).

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 Precautions, General).

Drug Interactions: Excessive glucocorticoid therapy will inhibit the growth promoting effect of human growth hormone. Patients with coexisting ACTH deficiency should have their glucocorticoid replacement dose carefully adjusted to avoid an inhibitory effect on growth.

Pregnancy: Animal reproduction studies and animal studies for impairment of fertility with somatropin have not been performed. It is not known whether somatropin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Somatropin should be given to a pregnant woman only if clearly needed.

Lactation: There have been no studies conducted with somatropin 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 somatropin is administered to a nursing woman.

Carcinogenesis/Mutagenesis: Long-term animal studies for carcinogenicity with this human growth hormone (somatropin) have not been performed. There has been no evidence to date of somatropin-induced mutagenicity. Patients developing neoplasia should be reported to the HPB by the treating physician.

Information to be Provided to the Patient: Patients being treated with growth hormone and/or their parents should be informed of the potential benefits and risks associated with treatment. If home use is determined to be desirable by the physician, 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.

If home use is prescribed, a puncture resistant container for the disposal of used syringes and needles should be recommended to the patient. Patients and/or their parents should be thoroughly instructed in the importance of proper needle disposal and cautioned against any reuse of needles and syringes.

Adverse Reactions: Growth-hormone Deficient Pediatric Patients: As with all protein pharmaceuticals, a small percentage of patients may develop antibodies to the protein. During the first 6 months of somatropin therapy in 314 naive patients, only 1.6% developed specific antibodies to somatropin (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. Mild and transient edema (either localized or generalized) was observed in 2.5% of patients 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 and recombinant somatrem and somatropin. The relationship, if any, between leukemia and growth hormone therapy is uncertain.

Adult Patients: In clinical studies in which high doses of somatropin 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 trials, adult-onset growth hormone deficient patients experienced a statistically significant increase in edema (somatropin 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 somatotropin deficiency syndrome, edema, muscle pain and joint pain and 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.

In growth hormone deficient adults, treatment-emergent adverse events reported after 18 months of therapy which are possibly related to replacement therapy but were not statistically significant during the first 6 months, include carpal tunnel syndrome, edema, arthralgia, paresthesia, hypesthesia, myalgia, peripheral edema, back pain, headache and joint disorder.

Adult patients treated with growth hormone, following diagnosis of growth hormone deficiency in childhood, reported side effects less frequently than those with adult onset growth hormone deficiency.

Turner Syndrome: 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, concurrent controlled trial, there was a statistically significant increase, as compared to untreated controls, in otitis media (43% vs 26%), ear disorders (18% vs 5%) and surgical procedures (45% vs 27%) in patients receiving somatropin.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: 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 under Dosage).

Dosage And Administration: When injected s.c., the injection sites should be varied in order to avoid lipoatrophy.

Growth Hormone-deficient Pediatric Patients: The recommended weekly dosage is 0.18 mg/kg of body weight (0.54 IU/kg based on a specific activity of 3 IU/mg protein). 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/week or daily. The s.c. route of administration is preferable; i.m. injection is also acceptable. The dosage and administration schedule for somatropin should be individualized for each patient.

Growth Hormone-deficient Adult Patients: The recommended dosage at the start of therapy is not more than 0.006 mg/kg/day (0.018 IU/kg/day) given as a daily s.c. injection. The dose may be increased according to individual patient requirements to a maximum of 0.0125 mg/kg/day (0.0375 IU/kg/day).

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.

Turner Syndrome: A weekly dosage of up to 0.375 mg/kg (1.125 IU/kg) of body weight administered by s.c. injection is recommended. It should be divided into equal doses given either daily or on 3 alternate days.

Humatrope Vials: Reconstitute each vial of Humatrope with 1.5 to 5 mL of diluent for Humatrope. Inject the diluent for Humatrope (m-cresol and glycerin solution) into the vial of Humatrope aiming the stream of liquid against the glass wall. Following reconstitution, swirl the vial with a gentle rotary motion until the contents are completely dissolved. Do not shake. The resulting solution should be clear, without particulate matter. If the solution is cloudy or contains particulate matter, the contents must not be injected.

Before and after injections, the septum of the vial should be wiped with rubbing alcohol or another alcoholic antiseptic solution to prevent contamination of the contents by repeated needle insertions. Somatropin should be administered using sterile, disposable syringes and needles. The syringes should be of small enough volume that the prescribed dose can be drawn from the vial with reasonable accuracy. The needle should be of sufficient length (usually 2.5 cm or more) to ensure that the injection reaches the muscular layer for i.m. injections.

If sensitivity to the diluent should occur, the vials may be reconstituted with Sterile Water for Injection, USP. When reconstituting with water, use only once and discard the unused portion. The vial should be used immediately after reconstitution. Although not recommended, the solution can be stored refrigerated (2 to 8°C) but must be used within 24 hours.

Humatrope Cartridges: Each Humatrope cartridge (for use with the Humatro-Pen II) should be reconstituted using the accompanying diluent syringe and the diluent connector. Following cartridge attachment to the Humatro-Pen II, attach the diluent connector to the cartridge and then inject the entire contents of the pre-filled diluent syringe into the cartridge. The diluent connector automatically aims the stream of liquid against the glass wall of the cartridge. Following reconstitution, the cartridge should be gently rocked back and forth until the contents are completely dissolved. Do not shake . The resulting solution should be clear, without particulate matter. If the solution is cloudy or contains particulate matter, the contents must not be injected.

If sensitivity to the accompanying diluent occurs, Sterile Water for Injection, USP, may be used for reconstitution. Attach the cartridge to the Humatro-Pen II and inject 3.15 mL of Sterile Water for Injection, USP, into the cartridge through the rubber septum, aiming the stream of liquid against the glass wall of the cartridge. Following reconstitution, the cartridge should be gently rocked back and forth until the contents are completely dissolved. Do not shake . The resulting solution should be clear, without particulate matter. If the solution is cloudy or contains particulate matter, the contents must not be injected.

Before and after injections, the septum of the cartridge should be wiped with rubbing alcohol or another alcoholic antiseptic solution. The Sterile Water for Injection, USP, should be administered using a sterile, disposable syringe and needle. The syringe should be of small enough volume that 3.15 mL can be measured with reasonable accuracy.

Humatrope reconstituted in this manner should be used immediately. Although not recommended, the solution can be stored refrigerated (2 to 8°C) but must be used within 24 hours. Discard any unused portion. However, to minimize waste, the smallest vials of Humatrope rather than cartridges are recommended.

Humatrope cartridges are designed for use only with the Humatro-Pen II. The diluent connector is for single use only. Discard it after use. A sterile needle should be used for each administration of somatropin.

For complete instructions on the use of the Humatro-Pen II, see the Humatro-Pen II Instruction Manual.

Stability and Storage: Before Reconstitution: Vials of Humatrope, Humatrope cartridges for use with the Humatro-Pen II and the supplied diluent for Humatrope are stable when stored at 2 to 8°C. Protect from light. Avoid freezing diluent for Humatrope. Expiration dates are stated on the labels.

After Reconstitution: Vials of Humatrope and Humatrope cartridges for use with the Humatro-Pen II are stable for up to 21 days when reconstituted with the supplied diluent for Humatrope and stored at 2 to 8°C. Avoid freezing the reconstituted vials and cartridges of Humatrope and the diluent for Humatrope.

If Humatrope vials or cartridges are reconstituted with Sterile Water for Injection, USP, they should be used immediately after reconstitution. Although not recommended, the solution can be stored refrigerated (2 to 8°C) but must be used within 24 hours.

Availability And Storage: Vial Combination Package: Each package contains: 1 vial of somatropin 5 mg (15 IU) and 1 vial of diluent. Nonmedicinal ingredients: Vial: dibasic sodium phosphate, glycine and mannitol. Diluent: glycerin and m-cresol.

Cartridge Combination Packages for Use with Humatro-Pen II: Each package contains: 1 cartridge of somatropin 6.7 mg (20 IU) or 13.3 mg (40 IU) with 3.15 mL syringe diluent and diluent connector. Nonmedicinal ingredients: Cartridges: dibasic sodium phosphate, glycine and mannitol. Diluent: glycerin and m-cresol.

All vials and cartridges of Humatrope and accompanying diluent may contain dimethicone, hydrochloric acid, phosphoric acid and sodium hydroxide.

Humatro-Pen II is available separately with a Humatro-Pen II Instruction Manual.

HUMATROPE® Lilly Somatropin Growth Stimulant

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