TEV-TROPIN

TEV-TROPIN- somatropin
Gate Pharmaceuticals

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DESCRIPTION

TEV-TROPIN® (somatropin, rDNA origin, for injection), a polypeptide of recombinant DNA origin, has 191 amino acid residues and a molecular weight of about 22,124 daltons. It has an amino acid sequence identical to that of human growth hormone of pituitary origin. TEV-TROPIN® is a strain of Escherichia coli modified by insertion of the human growth hormone gene.
TEV-TROPIN® is a sterile, white, lyophilized powder, intended for subcutaneous administration, after reconstitution with the accompanying diluent.
TEV-TROPIN® 5 mg vial contains recombinant somatropin 5 mg and mannitol 30 mg. The 5 mg vial is supplied in a combination package with an accompanying 5 mL vial of diluting solution. The diluent contains bacteriostatic 0.9% sodium chloride injection, USP, (normal saline), 0.9% benzyl alcohol as a preservative, and water for injection.
TEV-TROPIN® 10 mg vial contains recombinant somatropin 10 mg, mannitol 10 mg, disodium phosphate dodecahydrate 3.57 mg, and sodium dihydrogen phosphate dehydrate 0.79 mg. The 10 mg vial is supplied in a combination package with an accompanying 1 mL syringe of diluting solution. The diluent contains bacteriostatic water for injection with 0.33% metacresol as a preservative.
TEV-TROPIN® is a highly-purified preparation. Reconstituted solutions have a pH in the range of 7.0 to 9.0.

CLINICAL PHARMACOLOGY

Clinical trials have demonstrated that TEV-TROPIN® is equivalent in its therapeutic effectiveness and in its pharmacokinetic profile to those of human growth hormone of pituitary origin (somatropin). TEV-TROPIN® stimulates linear growth in children who lack adequate levels of endogenous growth hormone. Treatment of growth hormone-deficient children with TEV-TROPIN® produces increased growth rates and IGF-1 (Insulin-Like Growth Factor-1) concentrations that are similar to those seen after therapy with human growth hormone of pituitary origin.

Both TEV-TROPIN® and somatropin have also been shown to have other actions including:

  1. Tissue Growth
    1. Skeletal Growth. TEV-TROPIN® stimulates skeletal growth in patients with growth hormone deficiency. The measurable increase in body length after administration of TEV-TROPIN® results from its effect on the epiphyseal growth plates of long bones. Concentration of IGF-1, which may play a role in skeletal growth, are low in the serum of growth hormone-deficient children but increase during treatment with TEV-TROPIN®. Mean serum alkaline phosphatase concentrations are increased.
    2. Cell Growth. It has been shown that there are fewer skeletal muscle cells in short statured children who lack endogenous growth hormone as compared with normal children. 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.
  2. 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, results from treatment with somatropin.
  3. Carbohydrate Metabolism
    Children with hypopituitarism sometimes experience fasting hypoglycemia that is improved by treatment with somatropin. Large doses of somatropin may impair glucose tolerance.
  4. Lipid Metabolism
    Administration of somatropin to growth hormone-deficient patients mobilizes lipid, reduces body fat stores, and increases plasma fatty acids.
  5. Mineral Metabolism
    Sodium, potassium, and phosphorous are conserved by somatropin. Serum concentrations of inorganic phosphates increased in patients with growth hormone deficiency after therapy with TEV-TROPIN® or somatropin. Serum calcium concentrations are not significantly altered in patients treated with either somatropin or TEV-TROPIN®.
  6. Connective Tissue Metabolism
    Somatropin stimulates the synthesis of chondroitin sulfate and collagen as well as the urinary excretion of hydroxyproline.

PHARMACOKINETICS

Following intravenous administration of 0.1 mg/kg of TEV-TROPIN® , the elimination half-life was about 0.42 hours (approximately 25 minutes) and the mean plasma clearance (±SD) was 133 (±16) mL/min in healthy male volunteers.

In the same volunteers, after a subcutaneous injection of 0.1 mg/kg TEV-TROPIN® to the forearm, the mean peak serum concentration (±SD) was 80 (±50) ng/mL which occurred approximately 7 hours post-injection and the apparent elimination half-life was approximately 2.7 hours. Compared to intravenous administration, the extent of systemic availability from subcutaneous administration was approximately 70%.

INDICATION AND USAGE

TEV-TROPIN® is indicated for the treatment of children who have growth failure due to an inadequate secretion of normal endogenous growth hormone.

CONTRAINDICATIONS

TEV-TROPIN® 5 mg reconstituted with bacteriostatic 0.9% sodium chloride injection, USP (normal saline) (benzyl alcohol preserved) should not be administered to patients with a known sensitivity to benzyl alcohol (see WARNINGS).
TEV-TROPIN® 10 mg reconstituted with bacteriostatic water for injection containing 0.33% metacresol should not be used if the patient is allergic to metacresol.
Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses.
Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.
In general, somatropin is contraindicated in the presence of active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of recurrent activity. Since growth hormone deficiency may be an early sign of the presence of a pituitary tumor (or, rarely, other brain tumors), the presence of such tumors should be ruled out prior to initiation of treatment. Somatropin should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor.
Treatment with pharmacologic amounts of somatropin is contraindicated in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n = 522) with these conditions in intensive care units revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin-treated patients (doses 5.3 to 8 mg/day) compared to those receiving placebo (see WARNINGS).
Somatropin is contraindicated in patients with Prader-Willi syndrome who are severely obese or have severe respiratory impairment (see WARNINGS). TEV-TROPIN® is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.

WARNINGS

Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic doses of somatropin (see CONTRAINDICATIONS ). The safety of continuing somatropin 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 somatropin in patients experiencing acute critical illnesses should be weighed against the potential risk.

There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstructions or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin. If during treatment with somatropin, patients show signs of upper airway obstruction (including onset of or increased snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with Prader-Willi syndrome treated with somatropin should also have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively (see CONTRAINDICATIONS ). TEV-TROPIN® is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.

Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment, with some evidence supporting a greater risk in children compared with adults. Published literature indicates that girls who have Turner syndrome may be at greater risk than other somatropin-treated children. Pancreatitis should be considered in any somatropin-treated patient, especially a child, who develops persistent, severe abdominal pain.

Benzyl alcohol, a component used to reconstitute the TEV-TROPIN® 5 mg vial, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome,” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.
When administering TEV-TROPIN® 5 mg to newborns, reconstitute with sterile normal saline for injection, USP. WHEN RECONSTITUTING WITH STERILE NORMAL SALINE, USE ONLY ONE DOSE PER VIAL AND DISCARD THE UNUSED PORTION.

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