Pharmacotherapeutic group: Anterior pituitary lobe hormones and analogues. ATC code: H01AC01.
Pharmacology: Pharmacodynamics: Saizen contains recombinant human growth hormone (r-hGH) produced by genetically engineered mammalian cells.
It is a peptide of 191 amino acids identical to human pituitary growth hormone with respect to amino acid sequence and composition as well as peptide map, isoelectric point, molecular weight, isomeric structure and bioactivity.
Growth hormone is synthesised in a transformed murine cell line that has been modified by the addition of the gene for pituitary growth hormone.
Saizen is an anabolic and anticatabolic agent, which exerts effects not only on growth but also on body composition and metabolism. It interacts with specific receptors on a variety of cell types including myocytes, hepatocytes, adipocytes, lymphocytes and hematopoietic cells. Some, but not all of its effects are mediated through another class of hormones known as somatomedins (IGF-1 and IGF-2).
Depending on the dose, the administration of Saizen elicits a rise in IGF-1, IGFBP-3, non-esterified fatty acids and glycerol, a decrease in blood urea, and decreases in urinary nitrogen, sodium and potassium excretion. The duration of the increase in growth hormone levels may play a role in determining the magnitude of the effects. A relative saturation of the effects of Saizen at high doses is probable. This is not the case for glycaemia and urinary C-peptide excretion, which are significantly elevated after high doses (20 mg).
In a randomised clinical trial, three years treatment of pre-pubertal short children born SGA with a dose of 0.067 mg/kg/day resulted in a mean gain of +1.8 height-SDS. In those children who did not receive treatment beyond 3 years, part of the treatment benefit was lost, but the patients retained a significant gain of +0.7 height-SDS at final height (p<0.01 compared to baseline). Patients who received a second treatment course after a variable period of observation experienced a total gain of +1.3 height-SDS (p<0.001 [for Solution for injection/Powder for injection 8 mg clickeasy vial only] & p=0.001 [for Powder for injection 3.33 mg vial only] compared to baseline) at final height. (The mean cumulative treatment duration in the latter group was 6.1 years.) The gain in height-SDS (+1.3±1.1) at final height in this group was significantly (p<0.05) different from the gain in height-SDS obtained in the first group (+0.7±0.8) that received only 3.0 years of treatment on average.
A second clinical trial investigated two different dose regimens over four years. One group was treated with 0.067 mg/kg/day for 2 years and then observed without treatment for 2 years. The second group received 0.067 mg/kg/day in the first and third year and no treatment in the second and fourth year. Either treatment regimen resulted in a cumulative administered dose of 0.033 mg/kg/day over the four-year study period. Both groups showed a comparable acceleration of growth and a significant improvement of +1.55 (p<0.0001) and + 1.43 (p<0.0001) height-SDS respectively at the end of the four year study period. Long-term safety data are still limited.
Pharmacokinetics: The pharmacokinetics of Saizen are linear at least up to doses of 8 IU (2.67 mg). At higher doses (60 IU/20 mg) some degree of non-linearity cannot be ruled out, however with no clinical relevance.
Following intravenous administration in healthy volunteers the volume of distribution at steady-state is around 7 L, total metabolic clearance is around 15 L/h, while the renal clearance is negligible, and the drug exhibits an elimination half-life of 20 to 35 min.
Following single-dose subcutaneous and intramuscular administration of Saizen, the apparent terminal half-life is much longer, around 2 to 4 hours. This is due to a rate limiting absorption process.
Maximum serum growth hormone concentrations are reached after approximately 4 hours and serum growth hormone levels return to baseline within 24 hours, indicating that no accumulation of growth hormone will occur during repeated administrations.
The absolute bioavailability of both routes is 70-90%.
Solution for injection: Saizen solutions for injection (5.83 and 8.00 mg/ml) administered subcutaneously have been shown to be bioequivalent versus the 8 mg freeze-dried formulation.
Renal impairment: Somatropin clearance is known to be reduced in patients with renal impairment. However, the clinical significance of this finding is unknown.
For prepubertal children with growth failure due to chronic renal failure a specific posology is recommended (see Dosage & Administration).
Hepatic impairment: Somatropin clearance is known to be reduced in patients with hepatic impairment. However, as Saizen has not been studied in patients with hepatic impairment, the clinical significance of this finding is unknown.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for human based on conventional studies of safety pharmacology, single and repeated dose toxicity and genotoxicity. Formal carcinogenicity bioassays were not performed. This is justified, given the proteinous nature of the drug substance and the negative outcome of the genotoxicity testing. The potential effects of recombinant human growth hormone on the growth of pre-existing tumours have been evaluated through in vitro and in vivo experiments which have shown that recombinant human growth hormone is not expected to cause or stimulate tumours in patients.
Reproductive toxicology studies do not indicate any adverse effect on fertility and reproduction, despite administration of doses sufficiently high to produce some pharmacological effects on growth.
Solution for injection: The local tolerability of Saizen solution for injection was shown to be good and suitable for subcutaneous administration, when injected in animals at a concentration of 8.00 mg/m1 and volumes of 1 ml/site.
Powder for injection 8 mg click.easy vial: The local tolerability of Saizen solutions containing 0.3% metacresol when injected in animals was considered good and found suitable for subcutaneous or intramuscular administration.