Pharmacotherapeutic group: Somatropin and somatropin agonists. ATC: H01AC01.
Pharmacology: Pharmacodynamics: Mechanism of action: Norditropin NordiFlex contains somatropin, which is human growth hormone produced by recombinant DNA-technology. It is an anabolic peptide of 191 amino acids stabilized by two disulphide bridges with a molecular weight of approximately 22,000 Daltons.
The major effects of somatropin are stimulation of skeletal and somatic growth and pronounced influence on the body's metabolic processes.
Pharmacodynamic effect: When growth hormone deficiency is treated a normalisation of body composition takes place resulting in an increase in lean body mass and a decrease in fat mass.
Somatropin exerts most of its actions through insulin-like growth factor I (IGF-I), which are produced in tissues throughout the body, but predominantly by the liver.
More than 90% of IGF-I is bound to binding proteins (IGFBPs) of which IGFBP-3 is the most important.
A lipolytic and protein sparing effect of the hormone becomes of particular importance during stress.
Somatropin also increases bone turnover indicated by an increase in plasma levels of biochemical bone markers. In adults bone mass is slightly decreased during the initial months of treatment due to more pronounced bone resorption, however, bone mass increases with prolonged treatment.
Clinical efficacy and safety: In clinical trials in short children born SGA doses of 0.033 and 0.067 mg/kg/day have been used for treatment until final height. In 56 patients who were continuously treated and have reached (near) final height, the mean change from height at start of treatment was +1.90 SDS (0.033 mg/kg/day) and +2.19 SDS (0.067 mg/kg/day). Literature data from untreated SGA children without early spontaneous catch-up suggest a late growth of 0.5 SDS. Long-term safety data are still limited.
Pharmacokinetics: I.v. infusion of Norditropin (33 ng/kg/min for 3 hours) to nine growth hormone deficient patients, gave the following results: Serum half-time of 21.1 ± 1.7 min., metabolic clearance rate of 2.33 ± 0.58 ml/kg/min. and a distribution space of 67.6 ± 14.6 ml/kg.
S.c. injection of Norditropin SimpleXx (Norditropin SimpleXx is the cartridge containing the solution for injection in Norditropin NordiFlex) 2.5 mg/m2 in 31 healthy subjects (with endogenous somatropin suppressed by continuous infusion of somatostatin) gave the following results: Maximal concentration of human growth hormone (42 - 46 ng/ml) after approximately 4 hours. Thereafter human growth hormone declined with a half-life of approximately 2.6 hours. In addition the different strengths of Norditropin SimpleXx were demonstrated to be bioequivalent to each other and to conventional Norditropin after subcutaneous injection to healthy subjects.
Toxicology: Preclinical safety data: The general pharmacological effects on the CNS, cardiovascular, and respiratory systems following administration of Norditropin SimpleXx with and without forced degradation were investigated in mice and rats; renal function was also evaluated. The degraded product showed no difference in effect when compared with Norditropin SimpleXx and Norditropin. All three preparations showed the expected dose dependent decrease in urine volume and retention of sodium and chloride ions.
In rats, similar pharmacokinetics has been demonstrated between Norditropin SimpleXx and Norditropin. Degraded Norditropin SimpleXx has also been demonstrated to be bioequivalent with Norditropin SimpleXx.
Single and repeated dose toxicity and local tolerance studies of Norditropin SimpleXx or the degraded product did not reveal any toxic effect or damage to the muscle tissue.
The toxicity of poloxamer 188 has been tested in mice, rats, rabbits, and dogs and no findings of toxicological relevance were revealed.
Poloxamer 188 was rapidly absorbed from the injection site with no significant retention of the dose at the site of injection. Poloxamer 188 was excreted primarily via the urine.
Norditropin SimpleXx is the cartridge containing the solution for injection in Norditropin NordiFlex.