Carcinogenesis, Mutagenesis, Impairment of Fertility:
Long-term animal studies for carcinogenicity have not been performed with Saizen®.  There is no evidence from animal studies to date of Saizen®-induced mutagenicity or impairment of fertility.

Pregnancy:
Teratogenic Effects:  Pregnancy Category B.  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.

Nursing Women:
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.

Geriatric Use:
The safety and effectiveness of Saizen® in patients aged 65 and over has not been eva luated 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 DOSING AND ADMINISTRATION).

ADVERSE REACTIONS
Growth Hormone Deficient Pediatric Patients

As with all protein pharmaceuticals, a small percentage of patients may develop antibodies to the protein.  Anti-growth hormone (GH) antibody capacities below 2 mg/L have not been associated with growth attenuation.  In some cases when binding capacity exceeds 2 mg/L, growth attenuation has been described.  In clinical studies with Saizen® involving 280 patients (204 naive and 76 transfer patients), one patient at 6 months of therapy developed anti-GH antibodies with binding capacities exceeding 2 mg/L.  Despite the high binding capacity, these antibodies were not growth attenuating.  The patient was subsequently shown to have a hGH-N gene defect.  Thus, genetic analysis should be undertaken in any patient in whom anti-GH antibodies with high binding capacities occur.  No antibodies against proteins of the host cells were detected in the sera of patients treated up to five years.

Any patient with well–documented growth hormone deficiency who fails to respond to therapy should be tested for antibodies to human growth hormone and for thyroid status.

In clinical studies in which Saizen® was administered to growth hormone deficient children, the following events were infrequently seen:  local reactions at the injection site (such as pain, numbness, redness and swelling), hypothyroidism, hypoglycemia, seizures, exacerbation of preexisting psoriasis and disturbances in fluid balance.

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 betwee