SOMAPURE

1.Description

Somapure (recombinant Human Growth Hormone- Rdna origine) is a human growth hormone
produced by recombinant DNA technolnogy. It has 191 amino acid sequence and i are identical to the
dominant form of this human pituitary growth hormone. It has a molecular weight of 22,125 daltons.

Somapure( rHGH) is a sterile, non-pyrogenic, white lyophilized powder intended for subcu- taneous
or intramuscular injection, after reconstitution with sterile Water for Injection (0,3% m-Cresol)

2. Clinical pharmacology

2.1 Mechanism of Action

Somatropin (as well as endogenous HGH) binds to a dimeric GH receptor in the cell membrane of
target cells resulting in intracellular signal transduction and a host of pharma- codynamic effects.
Some of these pharmacodynamic effects are primarily mediated by IGF- produced in the liver and
also locally (e.g., skeletal growth, protein synthesis), while others are primarily a consequence of the
direct effects of somatropin (e.g., lipolysis) [see Clinical Phama- cology.

2.2 Pharmacodynamics

Tissue Growth

The primary and most intensively studied action of somatropin is the stimulation of linear growth.
This effect is demonstrated in children with GHD.

Skeletal Growth

The measurable increase in bone length after administration of somatropin results from its effect on
the cartilaginous growth areas of long bones. Studies in vitro have shown that the incorporation of
sulfate into proteoglycans is not due to a direct effect of somatropin, but rather is mediated by the
somatomedins or insulin-like growth factors (IGFs). The somatomed ins, among them IGF-I, are
polypeptide hormones which are synthesized in the liver, kidney, and various other tissues. IGF-I
levels are low in the serum of hypopituitary dwarfs and hypophysectomized humans or animals, and
increase after treatment with somatropin.

Cell Growth

It has been shown that the total number of skeletal muscle cells is markedly decreased in children
with short stature lackin endogenous GH compared with nomal children, and that treatment with
somatropin results in an increase in both the number and size f muscle cells.

Organ Growth

Somatropin influences the size of internal organs, and it also increases red cell mass.

Protein Metabolism

Linear growth is facilitated in part by increased cellular protein synthesis. This synthesis growth are
reflected by nitrogen retention which can be quantitated by observing the decline in urinary nitrogen
excretion and blood urea nitrogen following the initiation of somatropin therapy.
Carbohydrate Metabolism

Hypopituitary child ren sometimes experience fasting hypoglycemia that may be improved by
treatment with somatropin. In healthy subjects, large doses of somatropin may impair glucose
tolerance.

Although the precise mechanism of the diabetogenic effect of somatropin is not known, it is
attributed to blocking the action of insulin rather than blocking insulin secretion. Insulin levels in
serum actually increase as somatropin levels increase. Administration of human growth hormone to
nomal adults and patients with growth hormone deficiency results in increases in mean serum fasting
and postprandial insulin levels, although mean values remain in the normal range. In addition, mean
fasting and postprandial glucose and hemoglobin A1 c levels remain in the normal range.

Lipid Metabolism

Somatropin stimulates intracellular lipolysis, and administration of somatropin leads to an in- crease
in plasma free fatty acids and triglycerides. Untreated GHD is associated with increased body fat
stores, including increased abdominal visceral and subcutaneous adipose tissue. Treatment of
growth hormone deficient patients with somatropin results in a general re- duction of fat stores, and
decreased serum levels of low density lipoprotein (LDL) cholesterol.

Mineral Metabolism

Administration of somatropin results in an increase in total body potassium and phosphorus and to a
lesser extent sodium. This retention is thought to be the result of cell growth. Serum levels of
phosphate increase in children with GHD after somatropin therapy due to metabolic activity
associated with bone growth.Serum calcium levels are not altered. Although calcium excretion in the
urine is increased, there is a simultaneous increase in caIcium absorption from the intestine.
Negative calcium balance, however, may occasionally occur during somatropin treatment.

Connective Tissue Metabolism

Somatropin stimulates the synthesis of chondroitin sulfate and collagen, and increases the urinary
excretion of hydroxyproline.

3. Indications

Samopure is a prescription product for the treatment of growth failure in children:

Who do not make enough growth hormone on their own. This condition is called growth hor- mone
deficiency (GHD).

With a genetic condition called Prader-Willi syndrome (PWS). Growth hormone is not right for all
children with PWS. Check with your doctor.

Who were born smaller than most other babies born after the same number weeks of preg- nancy.
Some of these babies may not show catch-up growth by age 2 years. This condition is called small for
gestational age (SGA)

With a genetic condition called Turner syndrome (TS).

With idiopathic short stature (ISS), which means that they are shorter than 98.8% of other children of
the same age and sex; they are growing at a rate that is not likely to allow them to reach normal
adult height, and their growth plates have not closed. Other causes of short height should be ruled
out. ISS has no known cause.
Somapure is a prescription product for the replacement of growth hormone in adults with growth
hormone deficiency (GHD) that started either in childhood or as an adult. Your doctor should do tests
to be sure you have GHD, as appropriate.

4. Contraindications

Do not use Somapure, if:

-you are allergic to any ingredient in Somapure or in the diluent, including metacresol

-you have active or recurring cancer or brain tumor, or you currently receive treatment for cancer

-you have severe breathing problems (e.g., respiratory failure) or a serious illness caused by
complications from a surgery or injury

-you have a certain type of eye problem caused by diabetes (diabetic retinopathy)

-the patient is a child who has Prader-Willi syndrome and is severely overweight or has severe
breathing problems (e.g., respiratory infection, history of airway blockage or sleep apnea)

- the patient is a child who has epiphyseal closure (bone growth is complete)

- Contact your doctor or health care provider right away if any of these apply to you

5. Instructions for reconstitution

Powder must be dissolved only with the solvent provided.

1-Apply the needle to the syringe.Remove the plastic cover from the vial

2-Break the top of the ampoule containing the solvent. Remove the plastic cover of the needle. Make
sure the needle is well applied to the syringe. Slowly absorb all the solvent.

3-Inject all the solvent to the vial. This will create a 3,33mg/ml solution. To prevent foaming, the
solvent should be injected into the vial by aiming the stream of liquid against the glass wall.

4-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 clear and colorless,
without particulate matter.

6. Adverse reactions

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

 Sudden death in pediatric patients with Prader-Willi synd rome with risk factors including
severe obesity, history of upper airway obstruction or sleep apnea and unidentified respira-
tory infection
 Intracranial tumors, radiation to the head as children for a first neoplasm and somatropin
 Glucose intolerance including impaired glucose tolerance/impaired fasting glucose well s
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)
 Pancreatitis

7. Warnings and precautions

Acute Critical Ilness: 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 for GHD. Discontinue treatment if these signs ocur

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

Impaired Glucose Tolerance and Diabetes Mellitus: May be unmasked. Periodically moni- tor
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 (edema, arthralgia, carpal tunnel syndrome - especially in adults): May occur
frequently. Reduce dose as necessary

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

Pancreatitis: Consider pancreatitis in patients with persistent severe abdominal pain.

8. Interaction with other drugs

8.1 Inhibition of 11i-Hydroxysteroid Dehydrogenase Type 1

The microsomal enzyme 11i-hydroxysteroid dehydrogenase type 1 (11iHSD-1) is required for

conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. GH and
somatropin inhibit 11iHSD-1. Consequently, individuals with untreated GHD have relative increases in
11iHSD-1 and serum cortisol. Introduction of somatropin treatment may result in inhibition of
11iHSD-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 treat- ed with cortisone acetate and prednisone since
conversion of these drugs to their biologically active metabolites is dependent on the activity of
11iHSD-1

8.2 Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment

Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate

the growth promoting effects of somatropin in children. Therefore, glucocorticoid replacement
dosing should be carefully adjusted in children receiving concomitant soma tropin and glucocorticoid
treatments to avoid both hypo-adrenalism and growth.

8.3 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 ad- ministration may alter
the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroid
s, sex steroids, anticonvulsants, cyclosporine). Careful monitoring is advisable when somatropin is
administered in combination with other drugs known be metabolized by CYP450 liver enzymes.
However, formal drug interaction studies have not been conducted.

8.4 Oral Estrogen

Because oral estrogens may reduce the serum IGF-1 response to somatropin treatment, girls and
women receiving oral estrogen replacement may require greater somatropin dosages.

8.5 Insulin and/or Oral/Injectable Hypoglycemic Agents

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

9. Over dosage

Short-Term

Short-term over dosage could lead initially to hypoglycemia and subsequently to hyperglyce- mia.
Furthermore, overdose with somatropin is likely to cause fluid retention.

Long-Term

Long-term over dosage could result in signs and symptoms consistent of gigatism and/or consistent
with the known effects of excess growth hormone.

10. Storage

Shelf life

 This product can be used not more than 3 years from the production date (see box)
 After reconstitution, may be stored for a maximum of 14 days in refrigerator at 2°C-8°C.
 Store vials in an upright position.
 Store in a refrigerator (2°C-8°C). Keep in the outer carton in order to protect from light
 For one month can be stored at room temperature.