Prescription Drug Information: Saizen (Page 3 of 5)

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SAIZEN with the incidence of antibodies to other products may be misleading. In the case of growth hormone, antibodies with binding capacities lower than 2 mg/mL have not been associated with growth attenuation. In a very small number of patients treated with somatropin, when binding capacity was greater than 2 mg/mL, interference with the growth response was observed.

6.3 Post-Marketing Experience

The following adverse reactions have been identified during post approval use of SAIZEN. Because these reactions 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.

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products [See Warnings and Precautions (5.6)].

Leukemia has been reported in a small number of growth hormone deficient patients treated with growth hormone. It is uncertain whether this increased risk is related to the pathology of growth hormone deficiency itself, growth hormone therapy, or other associated treatments such as radiation therapy for intracranial tumors. So far, epidemiological data fail to confirm the hypothesis of a relationship between growth hormone therapy and leukemia.

The following additional adverse reactions have been observed during the appropriate use of somatropin: headaches (children and adults), gynecomastia (children), and pancreatitis (children and adults) (see Warnings and Precautions [5.14]).

7 DRUG INTERACTIONS

7.1 Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-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 [see Warnings and Precautions (5.8)].

7.2 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 somatropin and glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth.

7.3 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 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.

7.4 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 [see Dosage and Administration (2.2)].

7.5 Insulin and/or Oral/Injectable Hypoglycemic Agents

In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral/injectable agent may require adjustment when somatropin therapy is initiated [see Warnings and Precautions (5.4)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Reproduction studies have been performed in rats and rabbits at doses up to 31 and 62 times, respectively, the human (child) weekly dose based on body surface area. The results have revealed no evidence of impaired fertility or harm to the fetus due to SAIZEN. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether SAIZEN is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SAIZEN is administered to a nursing woman.

8.5 Geriatric Use

The safety and effectiveness of SAIZEN in patients aged 65 and over has not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of SAIZEN, and therefore may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for older patients [see Dosage and Administration (2.2)].

8.6 Hepatic Impairment

A reduction in somatropin clearance has been noted in patients with hepatic dysfunction as compared with normal controls. However, no studies have been conducted for SAIZEN in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Subjects with chronic renal failure tend to have decreased clearance of somatropin compared to those with normal renal function. However, no studies have been conducted for SAIZEN in patients with renal impairment [see Clinical Pharmacology (12.3)].

8.8 Gender Effect

In adults, the clearance of somatropin in both men and women tends to be similar. No gender studies have been performed in children.

10 OVERDOSAGE

Short-term

Short-term overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Moreover, 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 human growth hormone.

11 DESCRIPTION

SAIZEN is a human growth hormone produced by recombinant DNA technology. SAIZEN has 191 amino acid residues and a molecular weight of 22,125 daltons. Its amino acid sequence and structure are identical to the dominant form of human pituitary growth hormone. SAIZEN is produced by a mammalian cell line (mouse C127) that has been modified by the addition of the human growth hormone gene.

SAIZEN is a sterile, non pyrogenic, white, lyophilized powder intended for subcutaneous injection after reconstitution with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol). The reconstituted solution has a pH of 6.5 to 8.5.

Vials

SAIZEN is available in 5 mg and 8.8 mg vials. The quantitative composition per vial is:

5 mg vial:

Each vial contains 5.0 mg somatropin, 34.2 mg sucrose and 1.16 mg O-phosphoric acid. The pH is adjusted with sodium hydroxide or O-phosphoric acid.

8.8 mg vial:

Each vial contains 8.8 mg somatropin, 60.2 mg sucrose and 2.05 mg O-phosphoric acid. The pH is adjusted with sodium hydroxide or O-phosphoric acid.

Diluent

The diluent is Bacteriostatic Water for Injection, USP containing 0.9% Benzyl Alcohol added as an antimicrobial preservative.

Reconstitution devices:

saizenprep® reconstitution device

SAIZEN 8.8 mg vial supplied with the saizenprep® reconstitution device. Each vial contains 8.8 mg somatropin, 60.2 mg sucrose and 2.05 mg O-phosphoric acid. The pH is adjusted with sodium hydroxide or O-phosphoric acid.

Diluent

The diluent supplied with saizenprep® reconstitution device is 0.3% (w/v) metacresol in Sterile Water for Injection added as an antimicrobial preservative. The reconstituted solution has a pH of 6.5 to 8.5.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Somatropin (as well as endogenous growth hormone) binds to dimeric growth hormone receptors located within the cell membranes of target tissue cells resulting in intracellular signal transduction and a host of pharmacodynamic effects. Some of these pharmacodynamic effects are primarily mediated by IGF-1 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 Pharmacodynamics (12.2)].

12.2 Pharmacodynamics

Tissue Growth

Skeletal Growth: SAIZEN stimulates skeletal growth in prepubertal children with pituitary growth hormone deficiency. Skeletal growth is accomplished at the epiphyseal plates at the ends of long bone. Growth and metabolism of epiphyseal plate cells are directly stimulated by growth hormone and one of its mediators, insulin-like growth factor-1. Serum levels of insulin-like growth factor-1 (IGF-1) are low in children and adolescents who are growth hormone deficient, but increase during treatment with SAIZEN. Linear growth continues until the growth plates fuse at the end of puberty.

Cell Growth: Treatment with pituitary-derived human growth hormone results in an increase in both the number and the size of skeletal muscle cells.

Organ Growth: Somatropin influences the size and function of internal organs and increases red cell mass.

Protein Metabolism

Linear growth is facilitated in part by increased cellular protein synthesis. This is reflected by increased cellular uptake of amino acids and nitrogen retention as demonstrated by a decline in urinary nitrogen excretion and blood urea nitrogen during somatropin therapy.

Carbohydrate Metabolism

Somatropin is a modulator of carbohydrate metabolism. Children with inadequate secretion of growth hormone sometimes experience fasting hypoglycemia that is improved by treatment with somatropin. SAIZEN therapy may decrease glucose tolerance. Administration of SAIZEN to normal adults and patients with growth hormone deficiency resulted in transient increases in mean serum fasting and postprandial insulin levels. However, glucose levels remained in the normal range.

Lipid Metabolism

Acute administration of somatropin to humans results in lipid mobilization. Nonesterified fatty acids increase in plasma within one hour of SAIZEN administration. In growth hormone deficient patients, long-term somatropin administration often decreases body fat. Mean cholesterol levels decreased in patients treated with SAIZEN. The clinical significance of this decrease in cholesterol level is unknown.

Mineral Metabolism

Somatropin administration results in the retention of total body potassium, phosphorus, and sodium. Serum calcium levels appear to be unaffected.

Connective Tissue/Bone Metabolism

Somatropin stimulates the synthesis of chondroitin sulfate and collagen as well as the urinary excretion of hydroxyproline.

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