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UNITROPIN (rHGH)

UNITROPIN (somatropin rDNA origin for injection)  rHGH  Human Growth Hormone  15 IU vial

Somatropin1-249x300

CLINICAL PHARMACOLOGY

UNITROPIN (somatropin [rDNA origin] for injection) is indicated for replacement of endogenous human growth hormone (hgh) in select patient populations with growth hormone deficiency, generally due to inadequate secretion of endogenoushuman growth hormone (hgh). In vitro, preclinical, and clinical tests have demonstrated that UNITROPIN lyophilized powder is therapeutically equivalent tohuman growth hormone of pituitary origin and achieves similar pharmacokinetic profiles in normal adults

DESCRIPTION

UNITROPIN lyophilized powder contains somatropin [rDNA origin], which is a polypeptide hormone of recombinant DNA origin. It has 191 amino acid residues and a molecular weight of 22,124 daltons. The amino acid sequence of the product is identical to that of human growth hormone (HGH) of pituitary origin (somatropin). UNITROPIN is synthesized in a strain of Escherichia coli that has been modified by the addition of the gene for human growth hormone (rHGH).UNITROPIN is a sterile white lyophilized powder intended for subcutaneous injection.

INDICATIONS AND USAGE

UNITROPIN is a recombinant human growth hormone indicated for:

Pediatric: Treatment of children with growth failure due to growth hormone deficiency (GHD), Prader-Willi syndrome, Small for Gestational Age, Turner syndrome, and Idiopathic Short Stature.

Adult: Treatment of adults with either adult onset or childhood onset GHD

DOSAGE AND ADMINISTRATION (SUMMARY)

UNITROPIN should be administered subcutaneously:

Pediatric GHD0.16 to 0.24 mg/kg/week

Prader-Willi Syndrome: 0.24 mg/kg/week

Small for Gestational AgeUp to 0.48 mg/kg/week

Turner Syndrome0.33 mg/kg/week

Idiopathic Short Statureup to 0.47 mg/kg/week

Adult GHDEither a non-weight based or a weight based dosing regimen may be followed, with dose adjustment based on treatment response and serum IGF-I assay. (See Dosing of Adult Patients)

DOSAGE FORM AND STRENGTHS

UNITROPIN lyophilized powder in a multi-dose vial. One vial of lyophilized powder product contains 5mg of Somatropin USP (15 IU approx.), Mannitol BP 45mg (buffer). Sodium Phosphate monobasic and dibasic 1.7mg (preservative), and Glycine 1.7mg.

After reconstitution, each UNITROPIN vial delivers 5mg (approx. 15 IU). Each package includes an ampule of bacteriostatic water as a solvent (2ml).

WARNINGS AND PRECAUTIONS

Acute Critical Illness: Potential benefit of treatment continuation should be weighed against the potential risk.

Prader-Willi syndrome in Children: Evaluate for signs of upper airway obstruction and sleep apnea before initiation of treatment. Discontinue treatment if these signs occur.

Neoplasm: Monitor patients with preexisting tumors for progression or recurrence. Increased risk of a second neoplasm in childhood cancer survivors treated with somatropinin particular meningiomas in patients treated with radiation to the head for their first neoplasm

Impaired Glucose Tolerance and Diabetes Mellitus: May be unmasked. Periodically monitor glucose levels in all patients. Doses of concurrent antihyperglycemic drugs in diabetics may require adjustment.

Intracranial Hypertension: Exclude preexisting papilledema. May develop and is usually reversible after discontinuation or dose reduction.

Fluid Retention (i.e., edema, arthralgia, carpal tunnel syndrome especially in adults): May occur frequently. Reduce dose as necessary.

Hypopituitarism: Closely monitor other hormone replacement therapies.

Hypothyroidism: May first become evident or worsen.

Slipped Capital Femoral Epiphysis: May develop. Evaluate children with the onset of a limp or hip/knee pain.

Progression of Preexisting Scoliosis: May develop.

ADULT PATIENTS

UNITROPIN is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who meet either of the following two criteria:

Adult Onset (AO): Patients who have growth hormone deficiency, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or

Childhood Onset (CO): Patients who were growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes.

Patients who were treated with somatropin for growth hormone deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin therapy at the reduced dose level recommended for growth hormone deficient adults.

DOSAGE AND ADMINISTRATION

The weekly dose should be divided into 6 or 7 subcutaneous injections. UNITROPIN must not be injected intravenously.

Dosing of Pediatric Patients

General Pediatric Dosing Information

UNITROPIN dosage and administration schedules should be individualized based on the growth response of each patient.

Response to somatropin therapy in pediatric patients tends to decrease with time.

Treatment with UNITROPIN for short stature should be discontinued when the epiphyses are fused.

Pediatric Growth Hormone Deficiency (GHD)

Generally, a dose of 0.16 to 0.24 mg/kg body weight/week is recommended.

Prader-Willi Syndrome

Generally, a dose of 0.24 mg/kg body weight/week is recommended.

Turner Syndrome Generally, a dose of 0.33 mg/kg body weight/week is recommended.

Idiopathic Short Stature

Generally, a dose up to 0.47 mg/kg body weight/week is recommended.

Small for Gestational Age:  Generally, a dose of up to 0.48 mg/kg body weight/week is recommended.

Dosing of Adult Patients

Adult Growth Hormone Deficiency (GHD)

Either of two approaches to UNITROPIN dosing may be followed: a non-weight based regimen or a weight based regimen.

Non-weight based based on published consensus guidelines, a starting dose of approximately 0.2 mg/day (range, 0.15-0.30 mg/day) may be used without consideration of body weight. This dose can be increased gradually every 1-2 months by increments of approximately 0.1-0.2 mg/day, according to individual patient requirements based on the clinical response and serum insulin-like growth factor I (IGF-I) concentrations. The dose should be decreased as necessary on the basis of adverse events and/or serum IGF-I concentrations above the age- and gender-specific normal range.

Weight basedthe recommended dosage at the start of treatment is not more than 0.04 mg/kg/week. The dose may be increased according to individual patient requirements to not more than 0.08 mg/kg/week at 48 week intervals. Clinical response, side effects, and determination of age- and gender-adjusted serum IGF-I concentrations should be used as guidance in dose titration.

A lower starting dose and smaller dose increments should be considered for older patients, who are more prone to the adverse effects of somatropin than younger individuals. In addition, obese individuals are more likely to manifest adverse effects when treated with a weight-based regimen. In order to reach the defined treatment goal, estrogen-replete women may need higher doses than men. Oral estrogen administration may increase the dose requirements in women.

Preparation and Administration

UNITROPIN is provided in 5 mg vials (approx. 15 IU).

Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. UNITROPIN MUST NOT BE INJECTED if the solution is cloudy or contains particulate matter. Use it only if it is clear and colorless.

UNITROPIN may be given in the thigh, buttocks, or abdomen; the site of SC injections should be rotated daily to help prevent lipoatrophy.

CONTRAINDICATIONS

Acute Critical Illness

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.

Prader-Willi Syndrome in Children

Somatropin is contraindicated in patients with Prader-Willi syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe respiratory impairment. There have been reports of sudden death when somatropin was used in such patients.

Active Malignancy

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. Somatropin should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor.

Diabetic Retinopathy

Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.

Closed Epiphyses

Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses.

Hypersensitivity

UNITROPIN is contraindicated in patients with a known hypersensitivity to somatropin or any of its preservatives or other excipients. Localized reactions are the most common hypersensitivity reactions.

WARNINGS AND PRECAUTIONS

Acute Critical Illness

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 amounts of somatropin

Neoplasms

Patients with preexisting tumors or growth hormone deficiency secondary to an intracranial lesion should be examined routinely for progression or recurrence of the underlying disease process. Patients should be monitored carefully for any malignant transformation of skin lesions.

Glucose Intolerance

Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a result, previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked during somatropin treatment. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus, such as obesity, Turner syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during somatropin therapy. The doses of anti-hyperglycemic drugs (i.e., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients.

Intracranial Hypertension

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting has been reported in a small number of patients treated with somatropin products. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose.

Fluid Retention

Fluid retention during somatropin replacement therapy in adults may occur. Clinical manifestations of fluid retention are usually transient and dose dependent.

Hypopituitarism

Patients with hypopituitarism (multiple pituitary hormone deficiencies) should have their other hormonal replacement treatments closely monitored during somatropin treatment.

Hypothyroidism

Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response in children. Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism. In patients with growth hormone deficiency, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Therefore, patients treated with somatropin should have periodic thyroid function tests and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated.

Local and Systemic Reactions

As with any protein, local or systemic allergic reactions may occur. Patients should be informed that such reactions are possible and that prompt medical attention should be sought if allergic reactions occur.

Laboratory Tests

Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and IGF-I may increase during somatropin therapy.

ADVERSE REACTIONS

Most Serious and/or Most Frequently Observed Adverse Reactions

This list presents the most serious and/or most frequently observed adverse reactions during somatropin treatment:

  • Sudden death in pediatric patients with Prader-Willi syndrome with risk factors including severe obesity, history of upper airway obstruction or sleep apnea and unidentified respiratory infection.
  • Intracranial tumors, in particular meningiomas, in young adults treated with radiation to the head as children for a first neoplasm and somatropin.
  • Glucose intolerance including impaired glucose tolerance/impaired fasting glucose as well as overt diabetes mellitus.
  • Intracranial hypertension.
  • Significant diabetic retinopathy.
  • Slipped capital femoral epiphysis in pediatric patients.
  • Progression of preexisting scoliosis in pediatric patients.
  • Fluid retention manifested by edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias.
  • Unmasking of latent central hypothyroidism.
  • Injection site reactions/rashes and lipoatrophy (as well as rare generalized hypersensitivity reactions)

Clinical Trials Experience

Clinical Trials in children with GHD

In clinical studies with UNITROPIN in pediatric GHD patients, the following events were reported infrequently: injection site reactions, including pain or burning associated with the injection, fibrosis, nodules, rash, inflammation, pigmentation, or bleeding; lipoatrophy; headache; hematuria; hypothyroidism; and mild hyperglycemia.

Clinical Trials in PWS

In two clinical studies with UNITROPIN in pediatric patients with Prader-Willi syndrome, the following drug-related events were reported: edema, aggressiveness, arthralgia, benign intracranial hypertension, hair loss, headache, and myalgia.

Clinical Trials in adults with GHD

In clinical trials with UNITROPIN in 1,145 GHD adults, the majority of the adverse events consisted of mild to moderate symptoms of fluid retention, including peripheral swelling, arthralgia, pain and stiffness of the extremities, peripheral edema, myalgia, paresthesia, and hypoesthesia. These events were reported early during therapy, and tended to be transient and/or responsive to dosage reduction.

Adverse events may include swelling, peripheral arthralgia, upper respiratory infection, pain in the extremities, peripheral edema, paresthesia, headache, stiffness of extremities, fatigue, myalgia, and back pain.

Anti-hGH Antibodies

As with all protein drugs, a small percentage of patients may develop antibodies to the protein. In a very small number of patients, when binding capacity was greater than 2 mg/L, interference with the growth response was observed.

Periplasmic Escherichia coli Peptides Preparations of UNITROPIN contain a small amount of periplasmic Escherichia coli peptides (PECP). Anti-PECP antibodies are found in a small number of patients treated with UNITROPIN, but these appear to be of no clinical significance.

Post-Marketing Experience

Because these adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following additional adverse reactions have been observed during the appropriate use of somatropin: headaches (children and adults), gynecomastia (children), and pancreatitis (children).

DRUG INTERACTIONS

11 β-Hydroxysteroid Dehydrogenase Type 1 The microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. GH and somatropin inhibit 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. As a consequence, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with somatropin. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1.

Pharmacologic Glucocorticoid Therapy and Supraphysiological Glucocortioid Treatment

Such treatments may attenuate the growth promoting effects of somatropin in children. Therefore, glucocorticoid replacement dosing should be carefully adjusted in children receiving concomitant somatropin and glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth.

Cytochrome P450-Metabolized Drugs

Limited published data indicate that somatropin treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CYP450 liver enzymes. However, formal drug interaction studies have not been conducted.

Oral Estrogen

In patients on oral estrogen replacement, a larger dose of somatropin may be required to achieve the defined treatment goal.

Insulin and/or Oral Hypoglycemic Agents

In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral agent may require adjustment when somatropin therapy is initiated.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B. Reproduction studies carried out with UNITROPIN at doses of 0.3, 1, and 3.3 mg/kg/day administered SC in the rat and 0.08, 0.3, and 1.3 mg/kg/day administered intramuscularly in the rabbit (highest doses approximately 24 times and 19 times the recommended human therapeutic levels, respectively, based on body surface area) resulted in decreased maternal body weight gains but were not teratogenic

There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed.

Nursing Mothers

There have been no studies conducted with UNITROPIN 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 administering UNITROPIN to a nursing woman.

Geriatric Use

The safety and effectiveness of UNITROPIN in patients aged 65 and over have not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of UNITROPIN, and therefore may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered.

OVERDOSAGE

Short-Term

Short-term overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Furthermore, overdose with somatropin is likely to cause fluid retention.

Long-Term

Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess growth hormone.

CLINICAL PHARMACOLOGY

Mechanism of Action

In vitro, preclinical, and clinical tests have demonstrated that UNITROPIN lyophilized powder is therapeutically equivalent to human growth hormone of pituitary origin and achieves similar pharmacokinetic profiles in normal adults. In pediatric patients who have growth hormone deficiency (GHD), have Prader-Willi syndrome (PWS), were born small for gestational age (SGA), have Turner syndrome (TS), or have Idiopathic short stature (ISS), treatment with UNITROPIN stimulates linear growth. In patients with GHD or PWS, treatment with UNITROPIN also normalizes concentrations of IGF-I (Insulin-like Growth Factor-I/Somatomedin C). In adults with GHD, treatment with UNITROPIN results in reduced fat mass, increased lean body mass, metabolic alterations that include beneficial changes in lipid metabolism, and normalization of IGF-I concentrations.

Additionally, the following actions have been demonstrated for somatropin:

PHARMACODYNAMICS

Tissue Growth

A. Skeletal Growth: UNITROPIN stimulates skeletal growth in pediatric patients with GHD, PWS, SGA, TS, or ISS. The measurable increase in body length after administration of UNITROPIN results from an effect on the epiphyseal plates of long bones. Concentrations of IGF-I, which may play a role in skeletal growth, are generally low in the serum of pediatric patients with GHD, PWS, or SGA, but tend to increase during treatment with UNITROPIN.

B. 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 the normal pediatric population. Treatment with somatropin 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 somatropin therapy.

Carbohydrate Metabolism

Pediatric patients with hypopituitarism sometimes experience fasting hypoglycemia that is improved by treatment with UNITROPIN. Large doses of growth

hormone may impair glucose tolerance.

Lipid Metabolism

In GHD patients, administration of somatropin has resulted in lipid mobilization, reduction in body fat stores, and increased plasma fatty acids.

Mineral Metabolism

Somatropin induces retention of sodium, potassium, and phosphorus. Serum concentrations of inorganic phosphate are increased in patients with GHD after therapy with UNITROPIN. Serum calcium is not significantly altered. Growth hormone could increase calciuria.

Body Composition

Adult GHD patients treated with UNITROPIN at the recommended adult dose demonstrate a decrease in fat mass and an increase in lean body mass. When these alterations are coupled with the increase in total body water, the overall effect of UNITROPIN is to modify body composition, an effect that is maintained with continued treatment.

Pharmacokinetics

Absorption

Following a 0.03 mg/kg subcutaneous (SC) injection in the thigh of 1.3 mg/mL UNITROPIN to adult GHD patients, approximately 80% of the dose was systemically available as compared with that available following intravenous dosing. Results were comparable in both male and female patients. Similar bioavailability has been observed in healthy adult male subjects.

In healthy adult males, following an SC injection in the thigh of 0.03 mg/kg, the extent of absorption (AUC) of a concentration of 5.3 mg/mL UNITROPIN was 35% greater than that for 1.3 mg/mL UNITROPIN.

In a similar study involving pediatric GHD patients, 5.3 mg/mL UNITROPIN yielded a mean AUC that was 17% greater than that for 1.3 mg/mL UNITROPIN.

Distribution

The mean volume of distribution of UNITROPIN following administration to GHD adults was estimated to be 1.3 (+/- 0.8) L/kg.

Metabolism

The metabolic rate of UNITROPIN involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products are returned to the systemic circulation. The mean terminal half-life of intravenous UNITROPIN in normal adults is 0.4 hours, whereas subcutaneously administered UNITROPIN has a half-life of 3.0 hours in GHD adults. The observed difference is due to slow absorption from the subcutaneous injection site.

Excretion

The mean clearance of subcutaneously administered UNITROPIN in 16 GHD adult patients was 0.3 (+/- 0.11) L/hrs/kg.

Special Populations

Pediatric: The pharmacokinetics of UNITROPIN are similar in GHD pediatric and adult patients.

Gender: No gender studies have been performed in pediatric patients; however, in GHD adults, the absolute bioavailability of UNITROPIN was similar in males and females.

Renal or hepatic insufficiency: No studies have been conducted with UNITROPIN in these patient populations.

NONCLINICAL TOXICOLOGY

Carcinogenesis and Mutagenesis

Carcinogenicity studies have not been conducted with UNITROPIN. No potential mutagenicity of UNITROPIN was revealed in a battery of tests including induction of gene mutations in bacteria (the Ames test), gene mutations in mammalian cells grown in vitro (mouse L5178Y cells), and chromosomal damage in intact animals (bone marrow cells in rats).

CLINICAL STUDIES

Adult Growth Hormone Deficiency (GHD)

UNITROPIN lyophilized powder was compared with placebo in six randomized clinical trials involving a total of 172 adult GHD patients. These trials included a 6­month double-blind treatment period, during which 85 patients received UNITROPIN and 87 patients received placebo, followed by an open-label treatment period in which participating patients received UNITROPIN for up to a total of 24 months. UNITROPIN was administered as a daily SC injection at a dose of 0.04 mg/kg/week for the first month of treatment and 0.08 mg/kg/week for subsequent months.

Beneficial changes in body composition were observed at the end of the 6-month treatment period for the patients receiving UNITROPIN as compared with the placebo patients. Lean body mass, total body water, and lean/fat ratio increased while total body fat mass and waist circumference decreased. These effects on body composition were maintained when treatment was continued beyond 6 months. Bone mineral density declined after 6 months of treatment but returned to baseline values after 12 months of treatment.

HOW SUPPLIED AND HANDLING

UNITROPIN lyophilized powder is available in the following packages:

5 mg multi-dose vial – 1 vial per box. After reconstitution, each UNITROPIN vial delivers 5mg (approx. 15 IU). Supplied with bacteriostatic water ampule as a solvent.

Storage and Handling

Except as noted below, store UNITROPIN lyophilized powder under refrigeration at 2 C to 8 C. Do not freeze. Protect from light.

Shelf Life: 2 years

Unigen Life Sciences Ltd.

ING Tower 6/F, 308 Des Voeux Road

Central, Hong Kong

Unigen Life Sciences Ltd. – WHO-GMP FDA Approved Steroid Hormone Manufacturer – Testosterone, Nandrolone, Stanozolol, Oxandrolone, Mesterolone, T3,T4